July 12, 2021 - Free Activators

Our set conversion date is July 12th, 2021. Your old card will be inactive on July 12, 2021 at 12:00am. instructions on the activation label. Figure: EFAS flood forecast from 12.07.2021 00:00 UTC in parts of Western Germany (EMSR517 Mapping Website, EMSR517 Activation Viewer). I didn't receive a letter in late June / early July from the University. I didn't receive an activation code in the Individual Notice letter or email. July 12, 2021 - Free Activators

July 12, 2021 - Free Activators -

Microsoft Office 2019 Product Key Free

You need a free license key for Office 2019, Professional, Home and Business 2019. Depending on your model, you can activate the tool for 32-bit and 64-bit. In short, they are focusing on demand. You will have an excellent documentation experience and will be able to access some of the functions and tools that are restricted in the previous version.

Where to get the Microsoft Office 2019 key?

There is no need to look anywhere; Here is the answer to your question. Some of the keys may not work on your PC. Test everyone one by one in section below.

This method is legal. You can read these articles to know:
https://docs.microsoft.com/en-us/deployoffice/vlactivation/gvlks
https://docs.microsoft.com/en-us/deployoffice/vlactivation/activate-office-by-using-kms

Microsoft Office 2019  Product Key Full:

BGY78-HUNGY-7TFVD-5RSE4-KWA3Z
D5RE4S-ZW3E4-XTFV6B8-HYNU-J9IMN
D5RS4-WA3ZE-4SXTF-6V7BG-Y8MHU
X4SDC-RTFVBG-8NHUI-JM0KO-M9NUB
N9UGY-7TFVE-S4WA3-ZE4SX-THFV6
HB8UTF-V6E4SX-ZW3AS-E4XTFV-6B8HY
J8BY7T-V6CR5-E4ZWS-EXD5CT-FVBG8H
NUJ8HB-YV7T5R-XE4SZA-W3ZSE-4XTFV
V6BY8-NHU9IN-8YT76R-E54W-O3WAZ
8Y7TV6-DC5RE4-SXDCR-TFVBG-Y8NHU
6B8YNH-U9B8Y-V7T6D5R-ESZWA-3SE4
XTFV68-NHUJ9-IH8BGF-DCXE4-SZ4XT
QZA3W-SE4XD-5CR6T-FV7BGY-8HUN9
4SXDCE-TFV68N-HYU9IJ-MN8H-UTFV6
IJM9NH-8UBY7T-6DC5R-E4SEXD-C5RTF
BG8NH-UIJMK-OJIN9U-B8Y7TV-6C5RE
UN9JIH-8UBYV7-CR65X-E4SZX-DCRTFV
VBY8NH-UIJ98N-HBGTFV6-E4SX-Z3WA
FV68NH-UBGFV6-DC5SX4-ZKWS-4XETF

Microsoft Office 2019 Serial Number:

  1. 7Y8UH-Y6T5S-W3E4X-DCR6T-KFV7B
  2. XDCRT-FV7BG-8YHUN-YTFVD-BVCSA
  3. Y8NHU-9HY7G-T6FD5-RS4WS-GJZE4

Microsoft Office 2019 Key:

  1. ZAQ3W-SE4XT-FV6BY-8HUNI-J9DSM
  2. 6TFV7-BGY8H-UN9IJ-98NHU-BGKY7
  3. 8NHUB-GTFV6-DE4SW-4SEX5-DG1CR

Product Key For Microsoft Office 2019:

  • AE4SX-5CR6T-FV7BG-8YHUN-KY7GT
  • 7B8HU-YGTFV-54WA4-ESXD5-FR6TF
  • 6F5RD-E4S4A-ZWSXE-D5CRT-KFVGY

The list of Key Ms Office 2019 is constantly updated 12/2020

  • W8W6K-3N7KK-PXB9H-8TD8W-BWTH9
  • VQ9DP-NVHPH-T9HJC-J9PDT-KTQRG
  • XM2V9-DN9HH-QB449-XDGKC-W2RMW
  • KDNJ9-G2MPB-HWJB4-DC6C2-DDCWD
  • Office Professional Plus 2019: NMMKJ-6RK4F-KMJVX-8D9MJ-6MWKP
  • Office Standard 2019: 6NWWJ-YQWMR-QKGCB-6TMB3-9D9HK
  • Project Professional 2019: B4NPR-3FKK7-T2MBV-FRQ4W-PKD2B
  • Project Standard 2019: C4F7P-NCP8C-6CQPT-MQHV9-JXD2M
  • Visio Professional 2019: 9BGNQ-K37YR-RQHF2-38RQ3-7VCBB
  • Visio Standard 2019: 7TQNQ-K3YQQ-3PFH7-CCPPM-X4VQ2
  • Access 2019: 9N9PT-27V4Y-VJ2PD-YXFMF-YTFQT
  • Excel 2019: TMJWT-YYNMB-3BKTF-644FC-RVXBD
  • Outlook 2019: 7HD7K-N4PVK-BHBCQ-YWQRW-XW4VK
  • PowerPoint 2019: RRNCX-C64HY-W2MM7-MCH9G-TJHMQ
  • Publisher 2019: G2KWX-3NW6P-PY93R-JXK2T-C9Y9V
  • Skype for Business 2019: NCJ33-JHBBY-HTK98-MYCV8-HMKHJ
  • Word 2019: PBX3G-NWMT6-Q7XBW-PYJGG-WXD33

How to activate the latest version of Microsoft Office version?

With the MS Office 2019 product key free, you can install it on your PC. If you are not sure which version of Office is activated on your PC,follow 7 steps bellow to active it :

Step 1:

Open any of the office applications like PowerPoint, editor, word, excel and go to file.

Step 2:

From the file, look for the account option.

Step 3:

Look under the product information title and find the activation status of the office. If it shows active status, then you have a licensed copy from the Microsoft office. But if it shows a box highlighted in yellow then you need activation.

Stage 4:

Now you know that your system needs the key to activate the office.

Step 5:

Now open again open any of the apps, and you will find the box that shows your office pack needs activation.

Step 6:

Find and click on a tab titled “change product key”.

Step 7:

A box appears on the screen. Enter the above keys and wait until validated.

Источник: https://www.wmlcloud.com/windows/product-key-free-microsoft-office-2019-serial-number-04-2021/

Summary

Learn more about this security update, including improvements and fixes, any known issues, and how to get the update.

Important: Windows Server 2008 Service Pack 2 (SP2) has reached the end of mainstream support and is now in extended support. Starting in July 2020, there will no longer be optional, non-security releases (known as "C" releases) for this operating system. Operating systems in extended support have only cumulative monthly security updates (known as the "B" or Update Tuesday release).

Verify thatyou have installed the required updates listed in the How to get this update section before installing this update. 

For information about the various types of Windows updates, such as critical, security, driver, service packs, and so on, please see the following article. To view other notes and messages, see the Windows Server 2008 Service Pack 2 update history home page.

Improvements and fixes

This security update includes improvements and fixes that were a part of update KB5005606 (released September 14, 2021) and addresses the following issues:

  • Addresses an issue in which an Internet print server cannot package the driver to send to the client.

  • Implements a Group Policy setting for the following registry value:

    • Registry location: HKEY_LOCAL_MACHINE\Software\Policies\Microsoft\Windows NT\Printers\PointAndPrint

    • Value name: RestrictDriverInstallationToAdministrators

    • Value data: 1

    For more information, see KB5005652.

  • Adds the ability to configure period or dot (.) delimited IP addresses interchangeably with fully qualified host names in the following Group Policy settings:

  • Addresses an issue in which Security Account Manager (SAM) events are not displayed properly in the Event Viewer.

  • Addresses a known issue that might prevent devices from downloading and installing printer drivers when the devices attempt to connect to a network printer for the first time. We have observed this issue on devices that access printers using a print server that uses HTTP connections.

  • Addresses a known issue that might ask for administrative credentials every time you attempt to print. This occurs in environments in which the print server and print client are in different times zones.

For more information about the resolved security vulnerabilities, please refer to the new Security Update Guide website and the October 2021 Security Updates.

Known issues in this update

Symptom

Workaround

After installing this update and restarting your device, you might receive the error, “Failure to configure Windows updates. Reverting Changes. Do not turn off your computer”, and the update might show as Failed in Update History.

This is expected in the following circumstances:

  • If you are installing this update on a device that is running an edition that is not supported for ESU. For a complete list of which editions are supported, see KB4497181.

  • If you do not have an ESU MAK add-on key installed and activated.

If you have purchased an ESU key and have encountered this issue, please verify you have applied all prerequisites and that your key is activated. For information on activation, please see this blog post. For information on the prerequisites, see the "How to get this update" section of this article.

Certain operations, such as rename, that you perform on files or folders that are on a Cluster Shared Volume (CSV) may fail with the error, “STATUS_BAD_IMPERSONATION_LEVEL (0xC00000A5)”. This occurs when you perform the operation on a CSV owner node from a process that doesn’t have administrator privilege.

Do one of the following:

  • Perform the operation from a process that has administrator privilege.

  • Perform the operation from a node that doesn’t have CSV ownership.

Microsoft is working on a resolution and will provide an update in an upcoming release.

After installing this update, Windows print clients might encounter the following errors when connecting to a remote printer shared on a Windows print server:

  • 0x000006e4 (RPC_S_CANNOT_SUPPORT)

  • 0x0000007c (ERROR_INVALID_LEVEL)

  • 0x00000709 (ERROR_INVALID_PRINTER_NAME)

Note The printer connection issues described in this issue are specific to print servers and are not commonly observed in devices designed for home use. Printing environments affected by this issue are more commonly found in enterprises and organizations.

For workarounds and the latest status for this issue, please see Windows release health.

We are presently investigating and will provide an update in an upcoming release.

How to get this update

Before installing this update

IMPORTANT Customers who have purchased the Extended Security Update (ESU) for on-premises versions of these operating systems must follow the procedures in KB4522133 to continue receiving security updates after extended support ends on January 14, 2020.

For more information about ESU and which editions are supported, see KB4497181.

Prerequisite:

You must install the updates listed below and restart your device before installing the latest Rollup. Installing these updates improves the reliability of the update process and mitigates potential issues while installing the Rollup and applying Microsoft security fixes.

  1. The April 9, 2019 servicing stack update (SSU) (KB4493730). To get the standalone package for this SSU, search for it in the Microsoft Update Catalog. This update is required to install updates that are only SHA-2 signed.

  2. The latest SHA-2 update (KB4474419) released October 8, 2019. If you are using Windows Update, the latest SHA-2 update will be offered to you automatically. This update is required to install updates that are only SHA-2 signed. For more information on SHA-2 updates, see 2019 SHA-2 Code Signing Support requirement for Windows and WSUS.

  3. The Extended Security Updates (ESU) Licensing Preparation Package (KB4538484) or the Update for the Extended Security Updates (ESU) Licensing Preparation Package (KB4575904). The ESU licensing preparation package will be offered to you from WSUS. To get the standalone package for ESU licensing preparation package, search for it in the Microsoft Update Catalog.

After installing the items above, Microsoft strongly recommends that you install the latest SSU (KB5006750). If you are using Windows Update, the latest SSU will be offered to you automatically if you are an ESU customer. To get the standalone package for the latest SSU, search for it in the Microsoft Update Catalog. For general information about SSUs, see Servicing stack updates and Servicing Stack Updates (SSU): Frequently Asked Questions.

Install this update

Release Channel

Available

Next Step

Windows Update and Microsoft Update

Yes

None. This update will be downloaded and installed automatically from Windows Update if you are an ESU customer.

Microsoft Update Catalog

Yes

To get the standalone package for this update, go to the Microsoft Update Catalog website.

Windows Server Update Services (WSUS)

Yes

This update will automatically sync with WSUS if you configure Products and Classifications as follows:

Product:  Windows Server 2008 Service Pack 2

Classification: Security Updates

File information

For a list of the files that are provided in this update, download the file information for update 5006736.

Источник: https://support.microsoft.com/en-us/topic/october-12-2021-kb5006736-monthly-rollup-c5fc0c8f-92dd-40ad-9e4a-b13528b78ca5

How to upgrade to Windows 10 for free in 2021

Editors Note: Windows 11 arrives this fall. Before getting too excited, see our Windows 11 system requirements guide to see if your laptop or desktop is compatible. Windows 11 will be a free upgrade, much like Windows 10. If you can't wait to see the new OS, you can download a Windows 11 preview build. Be cautious though, we recommend doing this only on a system that doesn't contain valuable data. 

Microsoft shut down its free Windows 10 upgrade program in November 2017. If you didn’t get your free version of its best operating system to date, you were pretty much out of luck. Or, so we thought. It turns out, you can still upgrade to Windows 10 without spending a dime. 

It turns out there are several methods of upgrading from older versions of Windows (Windows 7, Windows 8, Windows 8.1) to Windows 10 Home without paying the $139 fee for the latest operating system. 

Keep in mind that this workaround won't necessarily work all the time. If it doesn't, you'll need to pay the Windows 10 Home license fee or, if your system is older than 4 years, you might want to buy a new one (all new PCs run on some version of Windows 10). You will certainly need to upgrade from Windows 7 or Windows 8 if you are still running those legacy operating systems as Microsoft no longer supports them. 

How to Upgrade to Windows 10 for free

1. Ensure you're using a genuine copy of Windows 7 or later. Anything older will not work (please, if possible, buy a new system if you're using Window XP or Vista). If you're using Windows 7, write down the activation key (you may need this later). A free tool like NirSoft’s ProduKey will help you find it.  

2. This is a good stop to pause and back up anything you’d like to save on your current PC before continuing. Follow our Windows 10 backup instructions on how to do so. 

3. Visit the Windows 10 download page. This is an official Microsoft page that may allow you to upgrade for free. Once you're there, open the Windows 10 Media Creation Tool (press "download tool now") and choose "Upgrade this PC now." 

4. Accept the terms and choose the upgrade options that lets you keep your files and preferences. Again, having a backup ready at this point is very important so save everything to the cloud or to an SSD or USB. 

5. Reboot your computer and connect it to the internet. Open Settings and choose "Update & Security" and click "Activation." From here, you can see if the Windows 10 upgrade worked. If not, press an "Activate" button (if there is one); this will create a digital Windows 10 product key. Try using your Windows 7 or Windows 8 license key. 

Now that you know how to upgrade to Windows 10 for free, be sure to check out our other Windows 10 tutorials below, including tips on how to uninstall programs on Windows 10, how to find your MAC address in Windows 10, how to create a new folder in Windows 10 and more.

Источник: https://www.laptopmag.com/articles/upgrade-to-windows-10-free

Frequently asked questions about the Accellion data breach

The University of California Undergraduate Experience Survey (UCUES) solicits student opinions on a broad range of academic and co-curricular experiences, including instruction, advising and student services. UCUES provides information about student attitudes and behaviors including time use, academic engagement and community involvement. It assesses attitudes towards many different aspects of campus life including academic advising, campus climate, courses & instruction, and interaction with faculty. It documents students' self-perceptions and goals, political beliefs, and perceptions of the role of the research university. It also collects background demographic information, such as first language, family immigration background and social class.

+

Why does UC conduct the UCUES?

UCUES has been used extensively to guide the University on improving the undergraduate experience. Campuses also use UCUES to report on the quality of their academic programs to their academic senates. Some campuses have used UCUES data in their WASC accreditation self-studies. Other campuses, as well as the Council of Vice-Chancellors of Student Affairs, use UCUES to evaluate the quality and use of their student services. A number of campuses have used UCUES to report on campus climate and the impact of diversity on students' educational experiences.

UCUES data and results have been used in UC’s Annual Accountability Reports, UC Budget for Current Operations, and to inform regents' committees, such as the Long-Range Guidance Team, the Diversity Study Group, and Student Basic Needs Committee.

+

Was other survey data impacted by the Accellion FTA security event?

We have not identified any other impacted surveys.

+

What types of information from the UCUES survey were posted to the internet?

The impacted information includes participants’ full survey responses, which potentially include your name; email address; student ID; background and personal characteristics; academic engagement; educational experiences; personal development and mental health; the campus climate for diversity and inclusiveness; sexual misconduct situations; student life; and food and housing security, if you provided this information in response to the survey. A sample list of the questions from the survey can be found here.

The University used the Accellion FTA to transfer large files such as the survey results.  Unfortunately, perpetrators exploited a vulnerability in the application and attacked over 100 organizations including universities, government agencies, and private companies. When the University discovered the issue, we took the system offline and patched the Accellion vulnerability. We are in the process of transitioning to a more secure solution. The University cooperated with the FBI and worked with external cybersecurity experts to investigate this matter and determine what happened, what data was impacted, and to whom the data belongs.

When the University discovered the issue, it took the Accellion FTA offline and patched the vulnerability. There is no evidence that other University systems were impacted. The University is in the process of transitioning to a new file transfer system with enhanced security controls, deploying additional system monitoring broadly throughout its network, conducting a security health check of certain systems, and enhancing security controls, processes, and procedures.

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How does the University intend to protect the confidentiality of those that take the UCUES going forward?

When the University discovered that student responses gathered in the 2020 University of California Undergraduate Experiences Survey (UCUES) were, unfortunately, part of the data in the Accellion FTA at the time of the cyberattack and posted to the internet, it began reviewing the policies and procedures surrounding the biennial survey to better protect the personal data and privacy of the UC community. That process to strengthen these policies and procedures is ongoing.

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What resources does the University have if I’m concerned about my physical, mental or emotional well-being?

There are several mental and emotional health support and safety resources available across the University community:  

  • Counseling & Psychological Services– Confidential mental and emotional health support is available for students through the appropriate counseling and psychological services office (sometimes called CAPS) for your campus:  
  • Faculty & Staff Assistance Program– Each campus, medical center, and national laboratory within the University administers its own faculty and staff assistance program (sometimes called an Employee Assistance Program). Assistance programs offer free, confidential resources for emotional health, often available right on campus, with easy access to short-term counseling, assessment, and referral. For more information on assistance programs available at specific UC locations, click here. 
  • CARE– For survivors of sexual violence, intimate partner violence, or stalking, please contact a UC CARE Advocate for confidential, compassionate support and safety planning. For more information about your campus CARE office, click here. If you’re in danger or need help now, call 9-1-1.  

If you need support beyond the UC community, these offices can also provide information about potential local resources that are available.  

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I am a 2021-2022 applicant to a University of California campus. Was my information affected?

The contact information for individuals who started or completed the application process for the University of California for the 2021 – 2022 school year were impacted. That contact information is limited to names, email addresses, and phone numbers.

The University is separately notifying these individuals, and their notification will contain information on what precautions they may take.

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I am a 2020-2021 applicant to a University of California campus. Was my information affected?

Information from submitted applications for the University of California for the 2020-2021 school year were impacted. This information could include date of birth, gender identity, family household income level, ethnicity and/or tribal affiliation and first language, sexual orientation, academic information (GPA, test scores), and whether you have received foster care.

The University is separately notifying these individuals, and their notification contains information on what precautions they may take.

+

I am an applicant to the University of California (UC) system for the 2020-2021 and 2021-2022 academic year. What resources are available to me?

The University is separately notifying 2020-2021 and 2021-2022 student applicants. Their notification contains information on what precautions they may take. 

We ask that University community members remain vigilant against threats of identity theft or fraud.  Additionally, it is always a good idea to be on alert for “phishing” emails or phone calls by someone who acts like they know you or are part of a company that you may do business with, and requests sensitive information, such as passwords, Social Security numbers, or financial account information. You may report suspected phishing or social engineering attempts to communications@ucop.edu, or the following email addresses depending upon your campus:

We also recommend that you rotate passwords and use multifactor authentication for your online accounts when offered.

Источник: https://ucnet.universityofcalifornia.edu/data-security/updates-faq/index.html

Hi Guys, Today I am Going to Show You How To Remove or Uninstall Windows Activation/License key in Windows 10 & 11?

Are you Looking for the Commonly Searched Term “How to Remove Windows 10 Activation Key? ” (or) “How To Remove Windows Activation/License key Using Cmd?”.

Check Out This: How to Fix An Automated WordPress Update has failed to Complete – Please attempt the update again now Error?

Steps For How To Remove or Uninstall Windows Activation/License key in Windows 10 & 11?

Step 1: Right-click on the Start and Select Command Prompt ( Admin ) in Your Windows 10,11.

Step 2: Now Type the Command “slmgr /upk ” to uninstall the current product key from Windows.

Step 3: Now Type the Command “slmgr /cpky ” to remove the product key from the registry.

Step 4: Now Type the Command “slmgr /rearm ” to reset the Windows activation timers.

Restart Your PC.

That’s It. You’re Done. Have a Nice Day.

@@@ Leave Comments @@@

##Stay Safe Guys And Live Happily ##

Vasantharaj R N

Basically an Instrumentation Engineer But Very much Interested in Blogging. I'm a Passionate Blogger and an Intermediate in the Search Engine Optimization Process. I'll always try to Fix those Common Issues Which was Faced By Most of the users in the World.

Related Posts

Источник: https://letsmakeiteasy.tech/how-to-remove-or-uninstall-windows-activation-license-key-in-windows-10-11/

Hotfixes: November 1, 2021

Here you'll find a list of hotfixes that address various issues related to World of Warcraft: Shadowlands, Burning Crusade Classic and WoW Classic. Some of the hotfixes below take effect the moment they were implemented, while others may require scheduled realm restarts to go into effect. Please keep in mind that some issues cannot be addressed without a client-side patch update. This list will be updated as additional hotfixes are applied.

Hotfixes


November 1, 2021

Dungeons and Raids

  • Sanctum of Domination
    • Remnant of Ner’zhul
      • [With realm restarts] Remnant of Ner’zhul health reduced by 5% on Mythic difficulty.
      • [With realm restarts] Orb of Torment health reduced by 10% on Mythic difficulty.
      • [With realm restarts] Orbs of Torment should now trigger kill credit effects for abilities like Warlock's Shadowburn.
    • Soulrender Dormazain
      • [With realm restarts] Unleashed Tyranny damage reduced by 15% on Mythic difficulty.
      • [With realm restarts] Mawsworn Agonizer and Mawsworn Overlord health reduced by 5% on Mythic difficulty.
    • Painsmith Raznal
      • [With realm restarts] Spiked Balls have been removed from the first intermission on Mythic difficulty.
    • Sylvanas Windrunner
      • [With realm restarts] Reduced the damage of Ranger Shot by 15% on all difficulties.
      • [With realm restarts] Reduced the damage of Haunting Wave by 33% on Heroic difficulty.
      • [With realm restarts] Reduced the damage of Domination Chains by 15% on Heroic difficulty.
      • [With realm restarts] Reduced the radius of Veil of Darkness during Stage 2 to 8 yards on Heroic difficulty (was 10 yards).

Burning Crusade Classic

  • Fixed an issue with the quest "Helboar, the Other White Meat" that caused an extra Tainted Helboar Meat to be consumed.

October 22, 2021

Dungeons and Raids

  • Sanctum of Domination
    • Sylvanas Windrunner
      • Fixed an issue where the Death Knives warning aura could be accidentally removed by immunity effects, causing incalculable chaos.

Items and Rewards

  • Fixed an issue which sometimes caused the Shard of Dyz debuff to be applied incorrectly when damaging an ally.

October 21, 2021

Covenants

  • Venthyr
    • Fixed an issue that caused players to be teleported to the wrong instance of the Forgotten Chamber when repairing the mirror in The Shrouded Asylum.

Quests

  • Kael'thas Sunstrider should no longer be visible in chains if he is also by your side while in Sinfall for the quest “The “Unwelcome” Guests.”
  • Fixed an issue that caused Thenios to be missing for some players who were trying to turn in “Mysterious Soul Mirror.”

October 12, 2021

Dungeons and Raids

  • Sanctum of Domination
    • Eye of the Jailer
      • Resolved an issue that prevented Monk’s Faeline Stomp (Night Fae Ability) from consistently dealing damage.

Burning Crusade Classic

  • All "pre-made" groups may now queue for Battlegrounds. Grouped players will primarily face opponents who queued in groups of similar sizes.
    • Developers' note: With this change, the matchmaker will now match raid groups of 6 or more players against at least one group of 6 or more players. If the total number of players in your raid is smaller than the maximum size of the Battleground, the matchmaker will automatically fill your side with other groups or individuals. If there are no large pre-mades in the queue, party groups of 5 or fewer players will be placed against other parties of 5 or fewer players. Queuing alone or in small parties will not guarantee an opposing team with no large pre-mades.

WoW Classic

  • Restored the green face paint for male Trolls that had picked the corresponding hair color.

October 5, 2021

Dungeons and Raids

  • Sanctum of Domination
    • Fixed an issue where Highlord Bolvar Fordragon’s dialogue would sometimes not start if players were not in close proximity to him after defeating Kel’Thuzad.

WoW Classic

  • Fixed an issue where Guild Tabards weren't displaying textures.
  • Fixed an issue where the “Useable Items” checkbox in the Auction House was not correctly filtering items that taught spells, such as tradeskill recipes.

October 4, 2021

Burning Crusade Classic

  • Brewfest is again up and running on all realms, and will end at 23:59 server time tomorrow, October 5.
    • Developers’ note: We initially set up Brewfest 2021 in Burning Crusade Classic to run for the same duration as it ran in 2007 in original Burning Crusade, but we’ve decided to bring it back for another day.
  • Hunter
    • Feeding pets Sporeling Snack and Kibler's Bits no longer generates threat.

WoW Classic

  • Fixed an issue where some spells were missing visual effects.

October 1, 2021

Classes

  • Warlock
    • Demonology
      • Call Dreadstalkers should now be able to leap to Mueh'zala in De Other Side and use Dreadbite successfully.

Dungeons and Raids

  • Sanctum of Domination
    • Painsmith Raznal
      • Fixed an issue causing Painsmith to sometimes stop and cast the weapon throw of Cruciform Axe, Reverberating Hammer, and Dualblade Scythe during his transition.
      • Fixed an issue causing Shadowsteel Chains to persist into Stage Two if players were affected by Podtender (Dreamweaver Soulbind) during the transition.

WoW Classic

  • Fixed issues that caused the talents Permafrost, Camouflage, Amplify Curse, Improved Curse of Exhaustion, Improved Enslave Demon, and Pathfinding to not be applying all of their effects correctly.
  • Fixed an issue where the Battle Map could cause the User Interface to become non-responsive.
  • Fixed an issue with missing footsteps for Dwarves and when riding ram and horse mounts.
  • Fixed an issue that occurs when selecting a player in the Guild User Interface.
  • Fixed an issue that occurs when reordering global channels in Chat Settings.

September 28, 2021

Dungeons and Raids

  • Sanctum of Domination
    • Kel'Thuzad
      • Fixed an issue where Howling Blizzard ice patches would still explode after entering the Phylactery Phase.

Player versus Player

  • The amount of Conquest awarded has been increased from all activities by about 70%.

Burning Crusade Classic

  • Fixed an issue where Lady Vashj would sometimes evade when backing up into the shield generators around her encounter area.

September 27, 2021

Dungeons and Raids

  • Sanctum of Domination
    • Kel'Thuzad
      • Howling Blizzard ice patches are now immediately removed when pushing to his Phylactery Phase.
  • Theater of Pain
    • Fixed an issue where gladiators in the Halls of Might could sometimes remain immune to player abilities after finishing their duel.

Burning Crusade Classic

  • [With realm restarts] Spell Haste now lowers the global cooldown (GCD) to a minimum of 1.0 second (was 0.75 seconds).
    • Developers’ note: This hotfix is intended to bring the behavior of the GCD in line with version 2.4.0 of Burning Crusade, which the gameplay conditions of Burning Crusade Classic 2.5.2 are based on. Due to a bug in the original 2.4.0 code, players with high Spell Haste in original Burning Crusade were sometimes able to cast certain spells less than second apart, and they would also sometimes be delayed to over a second, based on how their actions were lining up with the server’s tick rate. We've decided that the fairest and most accurate thing we could do is to replicate the intent of the original game and enforce that Spell Haste cannot reduce the GCD below 1.0 second.

September 24, 2021

Achievements

  • On the Offensive now requires 6 of the covenant assault achievements to be completed (was 9).

Classes

  • Rogue
    • Fixed an issue which could cause a player to clip through the platform when using Shadowstep on Mueh'zala in De Other Side.

September 23, 2021

Burning Crusade Classic

  • Items that are disenchanted should now be available on the Item Restoration support page to self-restore, as long as the materials gained are still present.
  • Creatures and NPCs
    • Some missing NPCs around the world are now visible again.
  • Dungeons and Raids
    • Fixed an issue where enemies, such as Kael’thas Sunstrider and Lady Vashj, could wipe threat from their primary target after mind controlling players.
  • Quests
    • Fixed an issue preventing Druids in Flight Form from using Skyguard Bombs during the "Bombing Run" quest and using Skyguard Blasting Charges during the "Fires Over Skettis" quest.

September 22, 2021

Classes

  • Hunter
    • Beast Mastery
      • Fixed an issue that caused more pet abilities than intended to have their cooldown reduced by Kindred Beasts (PvP Talent).

Dungeons and Raids

  • Sanctum of Domination
    • Eye of the Jailer
      • Fixed an issue that sometimes caused Annihilating Glare to be cast on transition into Phase 2.
    • Painsmith Raznal
      • Fixed an issue causing players to be hit by two floor spikes in quick succession when moving through them at very high speeds.
    • Sylvanas Windrunner
      • Implemented additional performance improvements to the beginning of the encounter.

September 21, 2021

Dungeons and Raids

  • Tazavesh, the Veiled Market
    • Playing instruments in Myza's Oasis no longer cancels shapeshift forms.

Burning Crusade Classic

  • The Shartuul's teleporter event has been enabled once again.
  • Fixed an issue where some bosses in Serpentshrine Cavern and Tempest Keep were missing certain items from their loot table.
  • Fixed an issue where Horde characters weren't automatically barking when riding a ram through Orgrimmar for the Brewfest quests “Bark for T’chali’s Voodoo Brewery!” and “Bark for Drohn’s Distillery.”
  • Fixed an issue during “Terokk's Downfall” that prevented Skyguard Ace from casting Skyguard Flare.
  • Fixed an issue preventing some players from using Skyguard Bombs during the "Bombing Run" quest.

September 20, 2021

Achievements

  • The 9.1 world achievements On the Offensive and Breaking the Chains are now properly account-wide. Completing Breaking the Chains should properly award the Hand of Salaranga mount.

Dungeons and Raids

  • Sanctum of Domination
    • Painsmith Raznal
      • [With realm restarts] Reduced the distance between floor spike gaps during Stage Two on Mythic difficulty.
        • Developers’ note: The distance between safe locations should now be more consistent with this change.
      • [With realm restarts] Shadowsteel Chains periodic damage reduced by 15% on Mythic difficulty.
    • Fatescribe Roh-Kalo
      • [With realm restarts] Updated the rune locations to be more consistent with clockwise rotations and slightly less demanding with counterclockwise rotations on Normal and Heroic difficulties.
      • [With realm restarts] Players now have an additional 10 seconds on Raid Finder difficulty, 10 seconds on Normal difficulty, and 5 seconds on Heroic difficulty to realign their fate.
    • Kel'Thuzad
      • [With realm restarts] Kel’Thuzad health reduced by 5% on Mythic difficulty.
      • [With realm restarts] Remnant of Kel'Thuzad health reduced by 20% on Mythic difficulty.
      • [With realm restarts] Unstoppable Abomination health reduced by 20% on Mythic difficulty.
      • [With realm restarts] Soul Reaver health reduced by 20% on Mythic difficulty.
      • [With realm restarts] Frozen Destruction’s initial damage reduced by 40% on Mythic difficulty.
      • [With realm restarts] Frozen Destruction’s damage over time effect reduced by 10% and the duration reduced to 8 seconds (was 10 seconds) on Mythic difficulty.
      • [With realm restarts] Fixed an issue where Kel'Thuzad would cast abilities during Howling Blizzard on Mythic difficulty.
      • [With realm restarts] Howling Blizzard now inflicts stacking damage over the duration of the channel on Mythic difficulty.
        • Developers' note: As we saw the community strategies for defeating Kel'Thuzad on Mythic difficulty settle on a preferred approach that involved long stretches of time stalling, waiting for cooldowns to come back up, we started exploring ways of changing the encounter so that this no longer felt required. Players have been clear from the outset that this was frustrating and tedious gameplay, or lack thereof. But we also wanted to be careful to avoid increasing the difficulty of the encounter or introducing other issues and force guilds to re-learn the encounter. We internally tested a few different approaches, including just bypassing the waiting period by resetting cooldowns like we would at the start of an encounter (a portion of which was recently seen on the 9.1.5 Public Test Realm), but testing indicated that this benefited some specs much more than others, and caused worry that groups reaching the encounter now would feel pressure to stack those specs for an easier time. The changes we've settled on aim at making it impossible to stall indefinitely, while reducing the difficulty of key elements of the encounter to make it no longer feel required.
    • Sylvanas Windrunner
      • [With realm restarts] Domination Arrows health reduced by 15% on Mythic difficulty.
      • [With realm restarts] Dark Sentinels health reduced by 15% on Mythic difficulty.
      • [With realm restarts] Curse of Lethargy base duration reduced to 4 seconds on Mythic difficulty (was 6 seconds).
      • [With realm restarts] Decrepit Orb Detonation damage reduced by 10% on Mythic difficulty.
      • [With realm restarts] Veil of Darkness radius during Stage Two reduced to 12 yards on Mythic difficulty (was 15 yards).
      • [With realm restarts] Banshee's Fury unavoidable damage reduced by 15% on Mythic difficulty.
      • [With realm restarts] Ranger's Heartseeker, Banshee's Heartseeker, and Banshee's Blades damage reduced by 8% on Mythic difficulty.
      • Resolved an issue which could cause Ruin to unintentionally fail to inflict damage.
  • The Necrotic Wake
    • Surgeon Stitchflesh
      • [With realm restarts] Fixed an issue that caused the first Stitchflesh’s Creation to not increase its applications of Festering Rot.
      • [With realm restarts] Fixed an issue that sometimes caused two Stitchflesh’s Creations to be summoned in quick succession.

September 16, 2021

Classes

  • Monk
    • Fixed an issue that allowed Bonedust Brew (Necrolord Ability) to deal damage based on non-hostile damage events, such as Blessing of Sacrifice.

Dungeons and Raids

  • Sanctum of Domination
    • [With NA and EU realm restarts] Congratulations to the top 100 Horde and Alliance guilds for defeating Sylvanas on Mythic difficulty! With the next reset, cross realm groups can enter Sanctum of Domination on Mythic difficulty.
  • Theater of Pain
    • Falling from a platform in the Altars of Agony before Kul'tharok will now place the character's body on the platform they fell from.

Quests

  • The Shardhides for “Spill the Tea” should now be more plentiful.

Burning Crusade Classic

  • Fixed an issue that prevented the pop-up notice that is displayed when a Battlefield is ready from hiding when you leave the queue.
  • Fixed a sound issue when riding ram, horse, talbuk and deathcharger mounts.

September 15, 2021

Classes

  • Demon Hunter
    • Fixed an issue which could prevent some Demon Hunters from receiving Memory of a Burning Wound (Runecarving Power).
  • Priest
    • Shadow Word: Death will no longer apply the Shard of Dyz item effect when it damages the Priest.

Burning Crusade Classic

  • The Shartuul's Transporter event has been temporarily disabled, due to a bug.
    • Developers' note: We expect to have it fixed in a few days, and we'll post an update here when we do.

September 13, 2021

Classes

  • Warlock
    • Demonic Circle can no longer be placed with the Kilrogg's Cunning conduit while Eye of Kilrogg is off the ground.
  • Warrior
    • Arms
      • Fixed an issue causing Warbreaker (Talent) to not apply the Colossus Smash debuff to enemies if it was used while the Warrior was Disarmed.

Dungeons and Raids

  • Sanctum of Domination
    • Sylvanas Windrunner
      • [With realm restarts] Optimized game performance at the initialization of the first two phases of the encounter.
        • Developers' note: Thanks to community reports, we discovered a way to optimize the processes that caused performance drops at the beginning of the fight and at the beginning of the second phase of the fight (the bridge scene).
      • Fixed an issue where Mistweaver Monks could be preferentially targeted by Wailing Arrow in Stage 3.
      • Fixed an issue where both Tank-specialized players could be targeted with the same Black Arrow cast.
      • Fixed an issue where Dark Sentinels could cast Rage on targets struck by a very recent Black Arrow.
  • Theater of Pain
    • [With realm restarts] The Mythic+ completion timer has been increased to 38 minutes (was 37 minutes).

September 7, 2021

Covenants

  • Conduit Energy now refills at a rate of 10 per day (was 1 per day).
    • Developers' note: We are entirely removing Conduit Energy as a system in the upcoming 9.1.5 patch, but in the meantime, we wanted to hotfix in a stopgap measure that should effectively remove it as a meaningful constraint.

Items and Rewards

  • The Trueheart Spear debuff can no longer be applied more than once on a target.

September 2, 2021

Dungeons and Raids

  • Sanguine Depths
    • Fixed an issue where Gluttonous Ticks were not exploding upon death.

Items and Rewards

  • The covenant cosmetic armor that can show up on Korthia Dailies should now show up more often.
  • Fixed an issue that would prevent players who switched covenants from being able to upgrade their Korthia gear to Tier 5.

WoW Companion App

  • Fixed a Login UX issue for players with multiple WoW accounts.
  • Fixed an issue with news articles not showing anything or duplicating text.

August 30, 2021

Classes

  • [With regional restarts] Condensed Anima Sphere (Conduit) effectiveness reduced by 50% in PvP combat for all classes.
  • Death Knight
    • Unholy
      • Fixed an issue where Defile (Talent) would activate Kevin's Oozeling (Necrolord Soulbind).
  • Druid
    • Restoration
      • [With regional restarts] Mana regeneration reduced by 60% in PvP combat (was 55%).
  • Monk
    • Fixed an issue where Bonedust Brew (Necrolord Ability) caused Kevin's Oozeling (Necrolord Soulbind) to stay too long.
  • Shaman
    • Restoration
      • [With regional restarts] Mana regeneration reduced by 55% in PvP combat (was 50%).

Items and Rewards

  • The maximum value the Anima Reservoir can hold has been greatly increased to 200,000 (was 35,000).
    • Developers’ note: We'll be introducing a way for characters who have fully upgraded a Covenant Sanctum to transfer anima, either to their alts or to other covenants on the same character, and so we're increasing the anima cap in anticipation of this change.
  • Shards of Domination
    • [With regional restarts] All Domination gear now activate a gem set bonus.
    • [With regional restarts] Sanctum of Domination Legs for all armor types now activate a gem set bonus.
      • Cloth: Legs – Blood, Bracers – Frost, Belt – Unholy
      • Leather: Legs – Frost, Gloves – Unholy, Boots – Blood
      • Mail: Legs – Blood, Belt – Unholy, Boots – Frost
      • Plate: Legs – Frost, Bracers – Unholy, Gloves – Blood
      • Developers’ note: Requiring a specific slot from the raid to take advantage of the set bonus is proving to be too elusive for some players even with some assistance from the Great Vault. If you have previously acquired an item affected by this change but have destroyed it, you can use the Item Restoration service to recreate it after the hotfix goes live with this week’s maintenance. Please note, there is no benefit from having the activation spell twice.
    • [With regional restarts] Shard of Kyr effectiveness reduced by 75% in PvP combat (was 50%).
  • Players should now correctly see the Mastercraft Gravewing in the Mounts tab of their Collections window.

Korthia and the Maw

  • Player abilities that have restricted use indoors such as Heroic Leap and Demonic Gateway are now easier to use in Korthia and the Maw.

August 26, 2021

Covenants

  • Necrolord
    • Plague Deviser Marileth
      • Resolved an issue where Kevin's Oozeling would last longer than it should.
      • Resolved an issue where Kevin's Oozeling would remain after swapping Soulbinds.

Dungeons and Raids

  • Sanctum of Domination
    • Painsmith Raznal
      • Fixed an issue that caused players affected by Priest’s Spirit of Redemption to trigger Flameclasp Traps.
    • Sylvanas Windrunner
      • Fixed an issue causing Rage to cancel the channel effect of Shaman Fae Transfusion.

August 24, 2021

Achievements

  • Players can now continue to give Rendle hats to complete Rendle's Big Day after becoming his best friend.

Classes

  • Priest
    • Fixed an issue where Kevin's Oozeling (Necrolord Soulbind) would not activate when Unholy Nova (Necrolord Ability) does not heal.

Dungeons and Raids

  • Sanctum of Domination
    • Kel'Thuzad
      • Glacial Spikes now properly kill themselves and apply Frozen Destruction even if they receive no damage from the players.

Items and Rewards

  • Runecarving memories which required reputation with a faction to use now instead require the reputation in order to purchase, allowing them to be used when obtained by Chronicle of Lost Memories without having the required reputation.
  • Fixed an issue that caused the Reinforced Stygian Shoulders to drop for non-plate classes when opening the Escaped Wilderlings' Talon-Pierced Mawsworn Lockbox.
  • Credit for feeding Darkmaul will now be granted while in a raid group.

Quests

  • “A Suitable Demise” can now be completed while the Kyrian assault is active.

August 19, 2021

Classes

  • Mage
    • Fixed and issue with Harmonic Echo (Runecarving Power) not damaging nearby enemies on the 4th stack of Radiant Spark Vulnerability (Kyrian Ability).
    • Fire
      • Fixed an issue with Sun King's Blessing (Runecarving Power) triggering after consuming 9 Hot Streaks instead of the intended 8.
      • Fixed and issue with Sun King's Blessing (Runecarving Power) not granting the buff when Hot Streak is consumed by Flamestrike.
  • Monk
    • Fixed an issue with Call to Arms (Runecarving Power) not correctly tracking Xuen's empowered lightning damage when activated by Weapons of Order (Kyrian Ability).

Creatures and NPCs

  • Fleshwing should now always correctly fly to the ground, even if its initial flight down is interrupted by combat.

Dungeons and Raids

  • Sanctum of Domination
    • Eye of the Jailer
      • Fixed an issue where a debuff was not appearing on players targeted by Desolation Beam on Normal and Heroic difficulties.
    • Painsmith Raznal
      • Fixed an issue causing players to sometimes be hit twice by the Physical damage of Shadowsteel Chains.
    • Guardian of the First Ones
      • Resolved an issue where several abilities could damage pets.
  • Halls of Atonement
    • Depraved Obliterator’s Wicked Bolt cast time has increased to 2 seconds (was 1.5 seconds).

Quests

  • The mirrors in Revendreth related to the assault should now always be visible, regardless of any other quests that you have active in the area.
  • The clickable quest items for “Continued Efforts: Seeker's Quorum” now grant credit to party members.

Torghast, Tower of the Damned

  • Anima Powers
    • Death Knight
      • Engorged Limb should now trigger from all rune spending abilities.

August 17, 2021

Classes

  • Warlock
    • The Demonic Momentum conduit will now grant the correct amount of movement speed at item level 252.

Dungeons and Raids

  • Characters must now be level 60 to list Group Finder groups for Mythic+ dungeons or Shadowlands raids.
  • Sanctum of Domination
    • Fatescribe Roh-Kalo
      • Fixed an issue where players who have Forgeborne Reveries (Bonesmith Heirmir Soulbind) could be targeted for Grim Portent and Runic Affinity.
  • Sanguine Depths
    • Fixed an issue that unintentionally allowed players to leave the dungeon with the Sinfall Boon aura.

Items and Rewards

  • The Soultwining Crescent and Death-Bound Shard should now grant conduits by your current specialization instead of by your class.
    • Developers’ note: Players will need to switch their specialization to get conduits for the other specs, just changing your Loot Specialization will not work.
  • The Death-Bound Shard is more likely to appear on completion of the Adamant Vaults in Torghast, Tower of the Damned.
  • The Chronicle of Lost Memories item is now also available for 2000 Cataloged Research from Archivist Roh-Suir when you have Tier 3 Research with The Archivists' Codex.
    • Developers’ note: Thank you for all of your feedback on alts and how difficult it can be to acquire some legendary patterns, especially from Castle Nathria now that Sanctum of Domination is out. We hope that this change can give players a new way to acquire their last few legendaries by engaging with the newer Korthia content.
  • Increased the amount of Korthite Crystals rewarded in the Maw Assault box, Korthia weekly box, and Broker daily quests.
  • Shards of Domination
    • Shard of Zed is now affected by the caster's Versatility, rather than the target’s Versatility.
    • Fixed an issue where Shard of Zed could deal more damage than intended when applied to specific pets.

Quests

  • Resolved an issue with gromits during the “Think of the Critters” quest in Korthia. Hungry Gromits now anxiously await your delicious treats!

August 16, 2021

Covenants

  • Kyrian
    • Forgelite Prime Mikanikos
      • Fixed an issue where Bron’s Call to Action would gain 2 stacks for some projectile-based abilities and spells.
      • Fixed an issue where some abilities were not correctly adding stacks of Bron’s Call to Action.

Items and Rewards

  • Shards of Domination
    • Blood Link should now be more responsive to damage.

August 13, 2021

Classes

  • Monk
    • Windwalker
      • Resolved an issue where Storm, Earth, and Fire spirits could deal increased damage with their abilities during the small window of time while they are returning to your Monk after Storm, Earth, and Fire’s duration has expired.

Dungeons and Raids

  • Sanctum of Domination
    • Sylvanas Windrunner
      • Resolved an issue that could cause Veil of Darkness to not strike any targets in Stage 3.

Items and Rewards

  • Some leather and mail covenant armor should now show up properly on the Kyrian and Necrolord Renown Quartermasters with the default filters set.

August 12, 2021

Classes

  • Priest
    • Glyph of the Sha will now benefit from the Rabid Shadows conduit.

Torghast, Tower of the Damned

  • Anima Powers
    • Priest
      • Fallen Priest's Blessing will now grant more damage to Devouring Plague, Penance, and Holy Word: Chastise when acquiring multiple stacks of the power.
      • Discipline
        • Fallen Priest's Blessing will no longer gain stacks when Purge the Wicked (Talent) deals damage.

August 11, 2021

Achievements

  • Death's Advance, The Archivists' Codex, Ve'nari, and The Avowed reputations should now count towards the Exalted Reputation achievements.
    • Developers’ note: Some players who have already capped out their reputation with these factions may not see these update until next week’s restarts. We have a code change coming with restarts that will fix those players, but we want to get the data updated to prevent new players from running into the issue.

Classes

  • Warlock
    • Fixed an issue where Decaying Soul Satchel and Wrath of Consumption Runecarving effects would persist after the items were removed.

Dungeons and Raids

  • Sanctum of Domination
    • Fatescribe Roh-Kalo
      • The Loom of Fates should more easily maintain counterclockwise rotation without interruption.
  • Mists of Tirna Scithe
    • Ingra Maloch
      • Repulsive Visage will no longer be cast when Droman Oulfarran is at 25% HP or less.
        • Developers’ note: Currently it's possible to get Oulfarran to 20% just as Maloch begins casting Repulsive Visage, and this can feel frustrating and difficult to control when it happens. The goal of this change is to give players a small buffer so they can play around this ability more reliably.

Quests

  • Fixed an issue in the "The Power of Elune" quest where Shandris Feathermoon would sometimes use Sentinel's Ward at improper times.

August 10, 2021

Korthia and the Maw

  • A new set of grapple points were added to connect the southwest part of the Seeker's Quorum to the Vault of Secrets island to the south.
    • Developers’ note: This is available once your character has completed Chapter 3 in Korthia and should allow players close to the Vault to get across without having to go back to town and take the flayedwing flight.
  • The Tormentors of Torghast will now arrive at their destination in the Maw 5 minutes after the event announcement is broadcast.

Player versus Player

  • Brawls
    • Enemies in Comp Stomp are now stronger.

Quests

  • Fixed an issue where the quest “Tazavesh: A Hard Bargain” could not be turned in if the instance was allowed to reset after completing Myza's Oasis.
  • Thrall and Jaina are now available to turn in “Doorway in the Dark” after the cutscene completes.

August 9, 2021

Classes

  • Death Knight
    • The Runecarver continues to hone his craft and can now forge Death's Certainty as a necklace.
    • Blood
      • Fixed an issue where Dancing Rune Weapon would not mimic the caster's abilities while Mnemonic Equipment (Bonesmith Heirmir Soulbind) is active.
  • Demon Hunter
    • Fodder to the Flame (Necrolord Ability) no longer causes Kevin's Oozeling (Plague Deviser Marileth Soulbind) to last indefinitely.
  • Druid
    • Fixed an issue where applying Kindred Spirits (Kyrian Ability) triggered Combat Meditation (Pelagos Soulbind).
  • Monk
    • Windwalker
      • Fists of Fury will now count towards Bron's Call to Action (Forgelite Prime Mikanikos Soulbind).

Dungeons and Raids

  • Sanctum of Domination
    • Painsmith Raznal
      • [With regional restarts] A gap now appears in every row of spikes during Stage Two on Mythic difficulty.
      • [With regional restarts] Health of Painsmith Raznal, Spiked Balls, and Shadowsteel Horrors reduced by 10% on Mythic difficulty.
  • Mythic+
    • De Other Side
      • [With regional restarts] Enraged Spirit’s Rage duration reduced to 5 seconds (was 6 seconds).
    • Halls of Atonement
      • [With regional restarts] The completion timer has been increased to 32 minutes (was 31 minutes).
      • Echelon
        • [With regional restarts] Stone Shattering Leap damage reduced by 15% in Mythic and Mythic+ difficulties.
    • Mists of Tirna Scithe
      • Ingra Maloch
        • [With regional restarts] The duration of Droman's Wrath has been increased to 15 seconds (was 12 seconds).
    • Plaguefall
      • [With regional restarts] Plaguebelcher’s summoned Slimy Morsels have had their health reduced by 50%.
      • Globgrog
        • [With regional restarts] Slimy Morsel health reduced by 30%.
    • Sanguine Depths
      • [With regional restarts] Gluttonous Tick should now lose any stacks of Engorge when they leave combat.
      • Infused Quill-feathers no longer trigger on death affixes such as Bolstering, Sanguine, etc.
      • Kryxis the Voracious
        • [With regional restarts] Juggernaut Rush damage reduced by 20%.
    • The Necrotic Wake
      • Surgeon Stitchflesh
        • [With regional restarts] Health reduced by 10%.
    • Theater of Pain
      • Affront of Challengers
        • [With regional restarts] Sathel the Accursed's One With Death now absorbs 20% of their maximum health (was 30%).
        • [With regional restarts] Dessia the Decapitator's Slam damage reduced by 40%.

Items and Rewards

  • Increased the Stygia that can be rewarded from Maw daily quests by 2x. Additionally, the chance for Stygia to be picked as the reward increased by 15%.
  • Fixed an issue that was caused The Shaded Judgement Stone and the Stolen Korthian Supplies to not drop from all creatures in the Korthia and Maw Rifts.

Player versus Player

  • Death Knight
    • [With regional restarts] Rune of the Fallen Crusader no longer has its Strength bonus reduced in PvP situations (was reduced by 33%).
    • Unholy
      • [With regional restarts] Necrotic Wounds (PvP Talent) debuff duration increased to 15 seconds (was 12 seconds).
  • Hunter
    • [With regional restarts] Arcane Shot damage increased by 9% in PvP situations.
    • Marksmanship
      • [With regional restarts] Aimed Shot PvP damage increased by 10% in PvP situations.
  • Monk
    • Mistweaver
      • [With regional restarts] Mana regeneration reduced by 30% in PvP situations (was 40%).
      • [With regional restarts] Renewing Mist healing increased by 10% in PvP situations.
      • [With regional restarts] Vivify healing increased by 10% in PvP situations. Brewmaster and Windwalker Vivify healing unchanged.
  • Warlock
    • [With regional restarts] Demon Armor (PvP Talent) maximum health bonus increased to 10% (was 5%).
    • Affliction
      • [With regional restarts] Agony PvP damage increased by 15% in PvP situations.
      • [With regional restarts] Corruption PvP damage increased by 15% in PvP situations.
      • [With regional restarts] Siphon Life (Talent) PvP damage increased by 15% in PvP situations.
      • [With regional restarts] Shadow Bolt damage increased by 10% in PvP situations.

August 6, 2021

Classes

  • Demon Hunter
    • Resolved an issue that caused Blood Moon (PvP Talent) to dispel two Magic effects from the initial target.
  • Druid
    • Fixed an issue where Lone Empowerment (Kyrian Ability) was not granting additional Mastery via Kindred Affinity (Runecarving Effect).
  • Monk
    • Resolved an issue that allowed Monks to activate Transcendence: Transfer while crowd-controlled by certain types of effects.

Dungeons and Raids

  • Timewalking
    • Increased experience earned from Timewalking dungeon completion by 50%.
      • Developers’ note: There was a bug introduced in 9.1 that caused Timewalking to give much more completion experience than the UI advertised, ramping up more the lower-level the base expansion was, which is why this wasn’t noticed with Warlords of Draenor Timewalking a few weeks ago. The intent is for all Timewalking weeks to give comparable experience – we put in a quick fix last night and have deployed the proper fix today. We also took the opportunity to recalibrate Timewalking experience and increase it.

Items and Rewards

  • Shards of Domination
    • The tooltip for Shards of Domination bonuses have been updated to more clearly indicate that the Rune Words are only active in the Maw or related areas. This is a tooltip change only.

Burning Crusade Classic

  • The Midsummer Fire Festival has been configured to run for 16 days, in order to give players a little extra time to complete its many quests. This means that Burning Blossoms, which expire after being held for 14 days, may disappear if they were collected in the first two days of the event and then never spent.

August 5, 2021

Classes

  • Demon Hunter
    • Fixed an issue that caused Blood Moon (PvP Talent) to fail to grant the Demon Hunter leech.
    • Fixed an issue that could prevent the Demon Hunter from gaining Fury/Pain with Consume Magic.
  • Monk
    • Windwalker
      • Earth and Fire spirits now properly remove themselves from crowd-control effects when the Storm spirit activates effects such as Gladiator's Medallion.
  • Rogue
    • Serrated Bone Spike (Necrolord Ability) will no longer remove itself after a short duration on some targets such as target dummies.
    • Fixed an issue that prevented Serrated Bone Spike (Necrolord Ability) from refunding a charge when targets die after being affected by the ability multiple times.
    • Assassination
      • Fixed an issue that prevented Echoing Reprimand (Kyrian Ability) from granting the proper duration to Envenom when consumed.

Dungeons and Raids

  • Sanctum of Domination
    • Added death gates to assist in traversing through the Sanctum of Domination.
Источник: https://worldofwarcraft.com/en-us/news/23691036/hotfixes-november-1-2021

How to bypass activation lock (iOS 12.4.8 to iOS 14.6)

Apple products are dominating the market for a fairly good reason, because the iOS system is extremely accessible for anybody. On the other hand it is equipped with a good amount of security measures, that helps against possible theft or loss. But such security barriers can be sometimes pretty problematic even for the legit user. You never know, you can always forget your Apple ID password, set-up bought second-hand phone or just handle your hacked Apple ID account. Thanks to UltFone Activation Unlocker you can do all that with one very simple and handy software tool coming from UltFone.

iCloud lock can be a hassle

 

UltFone Activation Unlocker specializes in removing the Activation lock (aka iCloud lock) in the emergency cases. This lock feature is a special security tool, which prevents anybody else from using your iDevice. Even if they would fully erase the iDevice without signing out of iCloud, the activation lock would still stay in place. But as mentioned before, even as the rightful owner you can get to tricky situation and could need it removed. There are ways to solve it with pretty complex solutions (like depicted in this Best Solutions to iCloud DNS Bypass Not Working Issue article), but using UltFone Activation Unlocker is much easier and with a guaranteed success.

Solution for most iOS devices

After removal of the iCloud activation lock you will be once again in control of your phone. You could just sign in with a new Apple ID, without any worries about being tracked by the previous owner. Or even without the fear of being locked out again. And with wide range of supported iOS devices, ranging from iOS 12 to iOS 14. You can also turn off Find my iPhone function without knowing the password and set-up and use the device as brand new. This works only on selected devices though, running iOS 13 to iOS 14.

Easy software tool for anybody

Using the UltFone Activation Unlocker is extremely simple and you don’t need to posses any extensive technical knowledge. Just downloading the software tool and following the detailed guide is enough and in short you need just to go through these main steps :

  1. Launch the UltFone Activation Unlocker, select Remove iCloud Activation Lock and start the process. Then connect your iDevice via USB cable and the program will automatically detect it.
  2. Then it will download the jailbreak tool for you and you will need to burn the jailbreak environemtn to a USB flash drive if on Windows. Macs have it much simpler, just download the tool and follow the prompts. On Windows you have to boot from the USB drive with the jailbreak. But there is a clear tutorial guide to follow.
  3. After a successful jailbreak you can just click Start to remove the iCloud activation lock and confirm with Done later.
  4. With all that out of the way you can start setting up your device without the iCloud activation lock in place.

Test if for free with a trial version

UltFone Activation Unlocker is available for both Windows and Mac platforms and you can downlod the trial version for free to test it. But for the full functionality and features you need to get it activated with a licence. These licences always work for 5 devices and 1 computer, while you have the choice of a monthly, yearly or even a full lifetime licence option. And you can maybe even get lucky and find some extra summer discount coupon there right now…

Источник: https://www.gizchina.com/2021/07/12/how-to-bypass-activation-lock-ios-12-4-8-to-ios-14-6/

: July 12, 2021 - Free Activators

July 12, 2021 - Free Activators
July 12, 2021 - Free Activators
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Hotfixes: November 1, 2021

Here you'll find a list of hotfixes that address various issues related to World of Warcraft: Shadowlands, Burning Crusade Classic and WoW Classic. Some of the hotfixes below take effect the moment they were implemented, while others may require scheduled realm restarts to go into effect. Please keep in mind that some issues cannot be addressed without a client-side patch update. This list will be updated as additional hotfixes are applied.

Hotfixes


November 1, 2021

Dungeons and Raids

  • Sanctum of Domination
    • Remnant of Ner’zhul
      • [With realm restarts] Remnant of Ner’zhul health reduced by 5% on Mythic difficulty.
      • [With realm restarts] Orb of Torment health reduced by 10% on Mythic difficulty.
      • [With realm restarts] Orbs of Torment should now trigger kill credit effects for abilities like Warlock's Shadowburn.
    • Soulrender Dormazain
      • [With realm restarts] Unleashed Tyranny damage reduced by 15% on Mythic difficulty.
      • [With realm restarts] Mawsworn Agonizer and Mawsworn Overlord health reduced by 5% on Mythic difficulty.
    • Painsmith Raznal
      • [With realm restarts] Spiked Balls have been removed from the first intermission on Mythic difficulty.
    • Sylvanas Windrunner
      • [With realm restarts] Reduced the damage of Ranger Shot by 15% on all difficulties.
      • [With realm restarts] Reduced the damage of Haunting Wave by 33% on Heroic difficulty.
      • [With realm restarts] Reduced the damage of Domination Chains by 15% on Heroic difficulty.
      • [With realm restarts] Reduced the radius of Veil of Darkness during Stage 2 to 8 yards on Heroic difficulty (was 10 yards).

Burning Crusade Classic

  • Fixed an issue with the quest "Helboar, the Other White Meat" that caused an extra Tainted Helboar Meat to be consumed.

October 22, 2021

Dungeons and Raids

  • Sanctum of Domination
    • Sylvanas Windrunner
      • Fixed an issue where the Death Knives warning aura could be accidentally removed by immunity effects, causing incalculable chaos.

Items and Rewards

  • Fixed an issue which sometimes caused the Shard of Dyz debuff to be applied incorrectly when damaging an ally.

October 21, 2021

Covenants

  • Venthyr
    • Fixed an issue that caused players to be teleported to the wrong instance of the Forgotten Chamber when repairing the mirror in The Shrouded 2021 - Free Activators Sunstrider should no longer be visible in chains if he is also by your side while in Sinfall for the quest “The “Unwelcome” Guests.”
    • Fixed an issue that caused Thenios to be missing for some players who were trying to turn in “Mysterious Soul Mirror.”

    October 12, 2021

    Dungeons and Raids

    • Sanctum of Domination
      • Eye of the Jailer
        • Resolved an issue that prevented Monk’s Faeline Stomp (Night Fae Ability) from consistently dealing damage.

    Burning Crusade Classic

    • All "pre-made" groups may now queue for Battlegrounds. Grouped players will primarily face opponents who queued in groups of similar sizes.
      • Developers' note: With this change, the matchmaker will now match raid groups of 6 or more players against at least one group of 6 or more players. If the total number of players in your raid is smaller than the maximum size of the Battleground, the matchmaker will automatically fill your side with other groups or individuals. If there are no large pre-mades in the queue, party groups of 5 or fewer players will be placed against other parties of 5 or fewer players. Queuing alone or in small parties will not guarantee an opposing team with no large pre-mades.

    WoW Classic

    • Restored the green face paint for male Trolls that had picked the corresponding hair color.

    October 5, 2021

    Dungeons and Raids

    • Sanctum of Domination
      • Fixed an issue where Highlord Bolvar Fordragon’s dialogue would sometimes not start if players were not in close proximity to him after defeating Kel’Thuzad.

    WoW Classic

    • Fixed an issue where Guild Tabards weren't displaying textures.
    • Fixed an issue where the “Useable Items” checkbox in the Auction House was not correctly filtering items that taught spells, such as tradeskill recipes.

    October 4, 2021

    Burning Crusade Classic

    • Brewfest is again up and running on all realms, and will end at 23:59 server time tomorrow, October 5.
      • Developers’ note: We initially set up Brewfest 2021 in Burning Crusade Classic to run for the same duration as it ran in 2007 in original Burning Crusade, but we’ve decided to bring it back for another day.
    • Hunter
      • Feeding pets Sporeling Snack and Kibler's Bits no longer generates threat.

    WoW Classic

    • Fixed an issue where some spells were missing visual effects.

    October 1, 2021

    Classes

    • Warlock
      • Demonology
        • Call Dreadstalkers should now be able to leap to Mueh'zala in De Other Side and use Dreadbite successfully.

    Dungeons and Raids

    • Sanctum of Domination
      • Painsmith Raznal
        • Fixed an issue causing Painsmith to sometimes stop and cast the weapon throw of Cruciform Axe, Reverberating Hammer, and Dualblade Scythe during his transition.
        • Fixed an issue causing Shadowsteel Chains to persist into Stage Two if players were affected by Podtender (Dreamweaver Soulbind) during the transition.

    WoW Classic

    • Fixed issues that caused the talents Permafrost, Camouflage, Amplify Curse, Improved Curse of Exhaustion, Improved Enslave Demon, and Pathfinding to not be applying all of their effects correctly.
    • Fixed an issue where the Battle Map could cause the User Interface to become non-responsive.
    • Fixed an issue with missing footsteps for Dwarves and when riding ram and horse mounts.
    • Fixed an issue that occurs when selecting a player in the Guild User Interface.
    • Fixed an issue that occurs when reordering global channels in Chat Settings.

    September 28, 2021

    Dungeons and Raids

    • Sanctum of Domination
      • Kel'Thuzad
        • Fixed an issue where Howling Blizzard ice patches would still explode after entering the Phylactery Phase.

    Player versus Player

    • The amount of Conquest awarded has been increased from all activities by about 70%.

    Burning Crusade Classic

    • Fixed an issue where Lady Vashj would sometimes evade when backing up into the shield generators around her encounter area.

    September 27, 2021

    Dungeons and Raids

    • Sanctum of Domination
      • Kel'Thuzad
        • Howling Blizzard ice patches are now immediately removed when pushing to his Phylactery Phase.
    • Theater of Pain
      • Fixed an issue where gladiators in the Halls of Might could sometimes remain immune to player abilities after finishing their duel.

    Burning Crusade Classic

    • [With realm restarts] Spell Haste now lowers the global cooldown (GCD) to a minimum of 1.0 second (was 0.75 seconds).
      • Developers’ note: This hotfix is intended to bring the behavior of the GCD in line with version 2.4.0 of Burning Crusade, which the gameplay conditions of Burning Crusade Classic 2.5.2 are based on. Due to a bug in the original 2.4.0 code, players with high Spell Haste in original Burning Crusade were sometimes able to cast certain spells less than second apart, and they would also sometimes be delayed to over a second, based on how their actions were lining up with the server’s tick rate. We've decided that the fairest and most accurate thing we could do is to replicate the intent of the original game and enforce that Spell Haste cannot reduce the GCD below 1.0 second.

    September 24, 2021

    Achievements

    • On the Offensive now requires 6 of the covenant assault achievements to be completed (was 9).

    Classes

    • Rogue
      • Fixed an issue which could cause a player to clip through the platform when using Shadowstep on Mueh'zala in De Other Side.

    September 23, 2021

    Burning Crusade Classic

    • Items that are disenchanted should now be available on the Item Restoration support page to self-restore, as long as the materials gained are still present.
    • Creatures and NPCs
      • Some missing NPCs around the world are now visible again.
    • Dungeons and Raids
      • Fixed an issue where enemies, such as Kael’thas Sunstrider and Lady Vashj, could wipe threat from their primary 2021 - Free Activators after mind controlling players.
    • Quests
      • Fixed an issue preventing Druids in Flight Form from using Skyguard Bombs during the "Bombing Run" quest and using Skyguard Blasting Charges during the "Fires Over Skettis" quest.

    September 22, 2021

    Classes

    • Hunter
      • Beast Mastery
        • Fixed an issue that caused more pet abilities than intended to have their cooldown reduced by Kindred Beasts (PvP Talent).

    Dungeons and Raids

    • Sanctum of Domination
      • Eye of the Jailer
        • Fixed an issue that sometimes caused Annihilating Glare to be cast on transition into Phase 2.
      • Painsmith Raznal
        • Fixed an issue causing players to be hit by two floor spikes in quick succession when moving through them at very high speeds.
      • Sylvanas Windrunner
        • Implemented additional performance improvements to the beginning of the encounter.

    September 21, 2021

    Dungeons Video Downloader Raids

    • Tazavesh, the Veiled Market
      • Playing instruments in Myza's Oasis no longer cancels shapeshift forms.

    Burning Crusade Classic

    • The Shartuul's teleporter event has been enabled once again.
    • Fixed an issue where some bosses in Serpentshrine Cavern and Tempest Keep were missing certain items from their loot table.
    • Fixed an issue where Horde characters weren't automatically barking when riding a ram through Orgrimmar for the Brewfest quests “Bark for T’chali’s Voodoo Brewery!” and “Bark for Drohn’s Distillery.”
    • Fixed an issue during “Terokk's Downfall” that prevented Skyguard Ace from casting Skyguard Flare.
    • Fixed an issue preventing some players from using Skyguard Bombs during the "Bombing Run" quest.

    September 20, 2021

    Achievements

    • The 9.1 world achievements On the Offensive and Breaking the Chains are now properly account-wide. Completing Breaking the Chains should properly award the Hand of Salaranga mount.

    Dungeons and Raids

    • Sanctum of Domination
      • Painsmith Raznal
        • [With realm restarts] Reduced the distance between floor spike gaps during Stage Two on Mythic difficulty.
          • Developers’ note: The distance between safe locations should now be more consistent with this change.
        • [With realm restarts] Shadowsteel Chains periodic damage reduced by 15% on Mythic difficulty.
      • Fatescribe Roh-Kalo
        • [With realm restarts] Updated the rune locations to be more consistent with clockwise rotations and slightly less demanding with counterclockwise rotations on Normal and Heroic difficulties.
        • [With realm restarts] Players now have an additional 10 seconds on Raid Finder difficulty, 10 seconds on Normal difficulty, and 5 seconds on Heroic difficulty to realign their fate.
      • Kel'Thuzad
        • [With realm restarts] Kel’Thuzad health reduced by 5% on Mythic difficulty.
        • [With realm restarts] Remnant of Kel'Thuzad health reduced by 20% on Mythic difficulty.
        • [With realm restarts] Unstoppable Abomination health reduced by 20% on Mythic difficulty.
        • [With realm restarts] Soul Reaver health reduced by 20% on Mythic difficulty.
        • [With realm restarts] Frozen Destruction’s initial damage reduced by 40% on Mythic difficulty.
        • [With realm restarts] Frozen Destruction’s damage over time effect reduced by 10% and the duration reduced to 8 seconds (was 10 seconds) on Mythic difficulty.
        • [With realm restarts] Fixed an issue where Kel'Thuzad would cast abilities during Howling Blizzard on Mythic difficulty.
        • [With realm restarts] Howling Blizzard now inflicts stacking damage over the duration of the channel on Mythic difficulty.
          • Developers' note: As we saw the community strategies for defeating Kel'Thuzad on Mythic difficulty settle on a preferred approach that involved long stretches of time stalling, waiting for cooldowns to come back up, we started exploring ways of changing the encounter so that this no longer felt required. Players have been clear from the outset that this was frustrating and tedious gameplay, or lack thereof. But we also wanted to be careful to avoid increasing the difficulty of the encounter or introducing other issues and force guilds to re-learn the encounter. We internally tested a few different approaches, including just bypassing the waiting period by resetting cooldowns like we would at the start of an encounter (a portion of which was recently seen on the 9.1.5 Public Test Realm), but testing indicated that this benefited some specs much more than others, and caused worry that groups reaching the encounter now would feel pressure to stack those specs for an easier time. The changes we've settled on aim at making it impossible to stall indefinitely, while reducing the difficulty of key elements of the encounter to make it no longer feel required.
      • Sylvanas Windrunner
        • [With realm restarts] Domination Arrows health reduced by 15% on Mythic difficulty.
        • [With realm restarts] Dark Sentinels health reduced by 15% on Mythic difficulty.
        • [With realm restarts] Curse of Lethargy base duration reduced to 4 seconds on Mythic difficulty (was 6 seconds).
        • [With realm restarts] Decrepit Orb Detonation damage reduced by 10% on Mythic difficulty.
        • [With realm restarts] Veil of Darkness radius during Stage Two reduced to 12 yards on Mythic difficulty (was 15 yards).
        • [With realm restarts] Banshee's Fury unavoidable damage reduced by 15% on Mythic difficulty.
        • [With realm restarts] Ranger's Heartseeker, Banshee's Heartseeker, and Banshee's Blades damage reduced by 8% on Mythic difficulty.
        • Resolved an issue which could cause Ruin to unintentionally fail to inflict damage.
    • The Necrotic Wake
      • Surgeon Stitchflesh
        • [With realm restarts] Fixed an issue that caused the first Stitchflesh’s Creation to not increase its applications of Festering Rot.
        • [With realm restarts] Fixed an issue that sometimes caused two Stitchflesh’s Creations to be summoned in quick succession.

    September 16, 2021

    Classes

    • Monk
      • Fixed an issue that allowed Bonedust Brew (Necrolord Ability) to deal damage based on non-hostile damage events, such as Blessing of Sacrifice.

    Dungeons and Raids

    • Sanctum of Domination
      • [With NA and EU realm restarts] Congratulations to the top 100 Horde and Alliance guilds for defeating Sylvanas on Mythic difficulty! With the next reset, cross realm groups can enter Sanctum of Domination on Mythic difficulty.
    • Theater of Pain
      • Falling from a platform in the Altars of Agony before Kul'tharok will now place the character's body on the platform they fell from.

    Quests

    • The Shardhides for “Spill the Tea” should now be more plentiful.

    Burning Crusade Classic

    • Fixed an issue that prevented the pop-up notice that is displayed when a Battlefield is ready from hiding when you leave the queue.
    • Fixed a sound issue when riding ram, horse, talbuk and deathcharger mounts.

    September 15, 2021

    Classes

    • Demon Hunter
      • Fixed an issue which could prevent some Demon Hunters from receiving Memory of a Burning Wound (Runecarving Power).
    • Priest
      • Shadow Word: Death will no longer apply the Shard of Dyz item effect when it damages the Priest.

    Burning Crusade Classic

    • The Shartuul's Transporter event has been temporarily disabled, due to a bug.
      • Developers' note: We expect to have it fixed in a few days, and we'll post an update here when we do.

    September 13, 2021

    Classes

    • Warlock
      • Demonic Circle can no longer be placed with the Kilrogg's Cunning conduit while Eye of Kilrogg is off the ground.
    • Warrior
      • Arms
        • Fixed an issue causing Warbreaker (Talent) to not apply the Colossus Smash debuff to enemies if it was used while the Warrior was Disarmed.

    Dungeons and Raids

    • Sanctum of Domination
      • Sylvanas Windrunner
        • [With realm restarts] Optimized game performance at the initialization of the first two phases of the encounter.
          • Developers' note: Thanks to community reports, we discovered a way to optimize the processes that caused performance drops at the beginning of the fight and at the beginning of the second phase of the fight (the bridge scene).
        • Fixed an issue where Mistweaver Monks could be preferentially targeted by Wailing Arrow in Stage 3.
        • Fixed an issue where both Tank-specialized players could be targeted with the same Black Arrow cast.
        • Fixed an issue where Dark Sentinels could cast Rage on targets struck by a very recent Black Arrow.
    • Theater of Pain
      • [With realm restarts] The Mythic+ completion timer has been increased to 38 minutes (was 37 minutes).

    September 7, 2021

    Covenants

    • Conduit Energy now refills at a rate of 10 per day (was 1 per day).
      • Developers' note: We are entirely removing Conduit Energy as a system in the upcoming 9.1.5 patch, but in the meantime, we wanted to hotfix in a stopgap measure that should effectively remove it as a meaningful constraint.

    Items and Rewards

    • The Trueheart Spear debuff can no longer be applied more than once on a target.

    September 2, 2021

    Dungeons and Raids

    • Sanguine Depths
      • Fixed an issue where Gluttonous Ticks were not exploding upon death.

    Items and Rewards

    • The covenant cosmetic armor that can show up on Korthia Dailies should now show up more often.
    • Fixed an issue that would prevent players who switched covenants from being able to upgrade their Korthia gear to Tier 5.

    WoW Companion App

    • Fixed a Login UX issue for players with multiple WoW accounts.
    • Fixed an issue with news articles not showing anything or duplicating text.

    August 30, 2021

    Classes

    • [With regional restarts] Condensed Anima Sphere (Conduit) effectiveness reduced by 50% in PvP combat for all classes.
    • Death Knight
      • Unholy
        • Fixed an issue where Defile (Talent) would activate Kevin's Oozeling (Necrolord Soulbind).
    • Druid
      • Restoration
        • [With regional restarts] Mana regeneration reduced by 60% in PvP combat (was 55%).
    • Monk
      • Fixed an issue where Bonedust Brew (Necrolord Ability) caused Kevin's Oozeling (Necrolord Soulbind) to stay too long.
    • Shaman
      • Restoration
        • [With regional restarts] Mana regeneration reduced by 55% in PvP combat (was 50%).

    Items and Rewards

    • The maximum value the Anima Reservoir can hold has been greatly increased to 200,000 (was 35,000).
      • Developers’ note: We'll be introducing a way for characters who have fully upgraded a Covenant Sanctum to transfer anima, either to their alts or to other covenants on the same character, and so we're increasing the anima cap in anticipation of this change.
    • Shards of Domination
      • [With regional restarts] All Domination gear now activate a gem set bonus.
      • [With regional restarts] Sanctum of Domination Legs for all armor types now activate a gem set bonus.
        • Cloth: Legs – Blood, Bracers – Frost, Belt – Unholy
        • Leather: Legs – Frost, Gloves – Unholy, Boots – Blood
        • Mail: Legs – Blood, Belt – Unholy, Boots – Frost
        • Plate: Legs – Frost, Bracers – Unholy, Gloves – Blood
        • Developers’ note: Requiring a specific slot from the raid to take advantage of the set bonus is proving to be too elusive for some players even with some assistance from the Great Vault. If you have previously acquired an item affected by this change but have destroyed it, you can use the Item Restoration service to recreate it after the hotfix goes live with this week’s maintenance. Please note, there is no benefit from having the activation spell twice.
      • [With regional restarts] Shard of Kyr effectiveness reduced by 75% in PvP combat (was 50%).
    • Players should now correctly see the Mastercraft Gravewing in the Mounts tab of their Collections window.

    Korthia and the Maw

    • Player abilities that have restricted use indoors such as Heroic Leap and Demonic Gateway are now easier to use in Korthia and the Maw.

    August 26, 2021

    Covenants

    • Necrolord
      • Plague Deviser Marileth
        • Resolved an issue where Kevin's Oozeling would last longer than it should.
        • Resolved an issue where Kevin's Oozeling would remain after swapping Soulbinds.

    Dungeons and Raids

    • Sanctum of Domination
      • Painsmith Raznal
        • Fixed an issue that caused players affected by Priest’s Spirit of Redemption to trigger Flameclasp Traps.
      • Sylvanas Windrunner
        • Fixed an issue causing Rage to cancel the channel effect of Shaman Fae Transfusion.

    August 24, 2021

    Achievements

    • Players can now continue to give Rendle hats to complete Rendle's Big Day after becoming his best friend.

    Classes

    • Priest
      • Fixed an issue where Kevin's Oozeling (Necrolord Soulbind) would not activate when Unholy Nova (Necrolord Ability) does not heal.

    Dungeons and Raids

    • Sanctum of Domination
      • Kel'Thuzad
        • Glacial Spikes now properly kill themselves and apply Frozen Destruction even if they receive no damage from the players.

    Items and Rewards

    • Runecarving memories which required reputation with a faction to use now instead require the reputation in order to purchase, allowing them to be used when obtained by Chronicle of Lost Memories without having the required reputation.
    • Fixed an issue that caused the Reinforced Stygian Shoulders to drop for non-plate classes when opening the Escaped Wilderlings' Talon-Pierced Mawsworn Lockbox.
    • Credit for feeding Darkmaul will now be granted while in a raid group.

    Quests

    • “A Suitable Demise” can now be completed while the Kyrian assault is active.

    August 19, 2021

    Classes

    • Mage
      • Fixed and issue with Harmonic Echo (Runecarving Power) not damaging nearby enemies on the 4th stack of Radiant Spark Vulnerability (Kyrian Ability).
      • Fire
        • Fixed an issue with Sun King's Blessing (Runecarving Power) triggering after consuming 9 Hot Streaks instead of the intended 8.
        • Fixed and issue with Sun King's Blessing (Runecarving Power) not granting the buff when Hot Streak is consumed by Flamestrike.
    • Monk
      • Fixed an issue with Call to Arms (Runecarving Power) not correctly tracking Xuen's empowered lightning damage when activated by Weapons of Order (Kyrian Ability).

    Creatures and NPCs

    • Fleshwing should now always correctly fly to the ground, even if its initial flight down is interrupted by combat.

    Dungeons and Raids

    • Sanctum of Domination
      • Eye of the Jailer
        • Fixed an issue where a debuff was not appearing on players targeted by Desolation Beam on Normal and Heroic difficulties.
      • Painsmith Raznal
        • Fixed an issue causing players to sometimes be hit twice by the Physical damage of Shadowsteel Chains.
      • Guardian of the First Ones
        • Resolved an issue where several abilities could damage pets.
    • Halls of Atonement
      • Depraved Obliterator’s Wicked Bolt cast time has increased to 2 seconds (was 1.5 seconds).

    Quests

    • The mirrors in Revendreth related to the assault should now always be visible, regardless of any other quests that you have active in the area.
    • The clickable quest items for “Continued Efforts: Seeker's Quorum” now grant credit to party members.

    Torghast, Tower of the Damned

    • Anima Powers
      • Death Knight
        • Engorged Limb should now trigger from all rune spending abilities.

    August 17, 2021

    Classes

    • Warlock
      • The Demonic Momentum conduit will now grant the correct amount of movement speed at item level 252.

    Dungeons and Raids

    • Characters must now be level 60 to list Group Finder groups for Mythic+ dungeons or Shadowlands raids.
    • Sanctum of Domination
      • Fatescribe Roh-Kalo
        • Fixed an issue where players who have Forgeborne Reveries (Bonesmith Heirmir Soulbind) could be targeted for Grim Portent and Runic Affinity.
    • Sanguine Depths
      • Fixed an issue that unintentionally allowed players to leave the dungeon with the Sinfall Boon aura.

    Items and Rewards

    • The Soultwining Crescent and Death-Bound Shard should now grant conduits by your current specialization instead of by your class.
      • Developers’ note: Players will need to switch their specialization to get conduits for the other specs, just changing your Loot Specialization will not work.
    • The Death-Bound Shard is more likely to appear on completion of the Adamant Vaults in Torghast, Tower of the Damned.
    • The Chronicle of Lost Memories item is now also available for 2000 Cataloged Research from Archivist Roh-Suir when you have Tier 3 Research with The Archivists' Codex.
      • Developers’ note: Thank you for all of your feedback on alts and how difficult it can be to acquire some legendary patterns, especially from Castle Nathria now that Sanctum of Domination is out. We hope that this change can give players a new way to acquire their last few legendaries by engaging with the newer Korthia content.
    • Increased the amount of Korthite Crystals rewarded in the Maw Assault box, Korthia weekly box, and Broker daily quests.
    • Shards of Domination
      • Shard of Zed is now affected by the caster's Versatility, rather than the target’s Versatility.
      • Fixed an issue where Shard of Zed could deal more damage than intended when applied to specific pets.

    Quests

    • Resolved an issue with gromits during the “Think of the Critters” quest in Korthia. Hungry Gromits now anxiously await your delicious treats!

    August 16, 2021

    Covenants

    • Kyrian
      • Forgelite Prime Mikanikos
        • Fixed an issue where Bron’s Call to Action would gain 2 stacks for some projectile-based abilities and spells.
        • Fixed an issue where some abilities were not correctly adding stacks of Bron’s Call to Action.

    Items and Rewards

    • Shards of Domination
      • Blood Link should now be more responsive to damage.

    August 13, 2021

    Classes

    • Monk
      • Windwalker
        • Resolved an issue where Storm, Earth, and Fire spirits could deal increased damage with their abilities during the small window of time while they are returning to your Monk after Storm, Earth, and Fire’s duration has expired.

    Dungeons and Raids

    • Sanctum of Domination
      • Sylvanas Windrunner
        • Resolved an issue that could cause Veil of Darkness to not strike any targets in Stage 3.

    Items and Rewards

    • Some leather and mail covenant armor should now show up properly on the Kyrian and Necrolord Renown Quartermasters with the default filters set.

    August 12, 2021

    Classes

    • Priest
      • Glyph of the Sha will now benefit from the Rabid Shadows conduit.

    Torghast, Tower of the Damned

    • Anima Powers
      • Priest
        • Fallen Priest's Blessing will now grant more damage to Devouring Plague, Penance, and Holy Word: Chastise when acquiring multiple stacks of the power.
        • Discipline
          • Fallen Priest's Blessing will no longer gain stacks when Purge the Wicked (Talent) deals damage.

    August 11, 2021

    Achievements

    • Death's Advance, The Archivists' Codex, Ve'nari, and The Avowed reputations should now count towards the Exalted Reputation achievements.
      • Developers’ note: Some players who have already capped out their reputation with these factions may not see these update until next week’s restarts. We have a code change coming with restarts that will fix those players, but we want to get the data updated to prevent new players from running into the issue.

    Classes

    • Warlock
      • Fixed an issue where Decaying Soul Satchel and Wrath of Consumption Runecarving effects would persist after the items were removed.

    Dungeons and Raids

    • Sanctum of Domination
      • Fatescribe Roh-Kalo
        • The Loom of Fates should more easily maintain counterclockwise rotation without interruption.
    • Mists of Tirna Scithe
      • Ingra Maloch
        • Repulsive Visage will no longer be cast when Droman Oulfarran is at 25% HP or less.
          • Developers’ note: Currently it's possible to get Oulfarran to 20% just as Maloch begins casting Repulsive Visage, and this can feel frustrating and difficult to control when it happens. The goal of this change is to give players a small buffer so they can play around this ability more reliably.

    Quests

    • Fixed an issue in the "The Power of Elune" quest where Shandris Feathermoon would sometimes use Sentinel's Ward at improper times.

    August 10, 2021

    Korthia and the Maw

    • A new set of grapple points were added to connect the southwest part of the Seeker's Quorum to the Vault of Secrets island to the south.
      • Developers’ note: This is available once your character has completed Chapter 3 in Korthia and should allow players close to the Vault to get across without having to go back to town and take the flayedwing flight.
    • The Tormentors of Torghast will now arrive at their destination in the Maw 5 minutes after the event announcement is broadcast.

    Player versus Player

    • Brawls
      • Enemies in Comp Stomp are now stronger.

    Quests

    • Fixed an issue where the quest “Tazavesh: A Hard Bargain” could not be turned in if the instance was allowed to reset after completing Myza's Oasis.
    • Thrall and Jaina are now available to turn in “Doorway in the Dark” after the cutscene completes.

    August 9, 2021

    Classes

    • Death Knight
      • The Runecarver continues to hone his craft and can now forge Death's Certainty as a necklace.
      • Blood
        • Fixed an issue where Dancing Rune Weapon would not mimic the caster's abilities while Mnemonic Equipment (Bonesmith Heirmir Soulbind) is active.
    • Demon Hunter
      • Fodder to the Flame (Necrolord Ability) no longer causes Kevin's Oozeling (Plague Deviser Marileth Soulbind) to last indefinitely.
    • Druid
      • Fixed an issue where applying Kindred Spirits (Kyrian Ability) triggered Combat Meditation (Pelagos Soulbind).
    • Monk
      • Windwalker
        • Fists of Fury will now count towards Bron's Call to Action (Forgelite Prime Mikanikos Soulbind).

    Dungeons and Raids

    • Sanctum of Domination
      • Painsmith Raznal
        • [With regional restarts] A gap now appears in every row of spikes during Stage Two on Mythic difficulty.
        • [With regional restarts] Health of Painsmith Raznal, Spiked Balls, and Shadowsteel Horrors reduced by 10% on Mythic difficulty.
    • Mythic+
      • De Other Side
        • [With regional restarts] Enraged Spirit’s Rage duration reduced to 5 seconds (was 6 seconds).
      • Halls of Atonement
        • [With regional restarts] The completion timer has been increased to 32 minutes (was 31 minutes).
        • Echelon
          • [With regional restarts] Stone Shattering Leap damage reduced by 15% in Mythic and Mythic+ difficulties.
      • Mists of Tirna Scithe
        • Ingra Maloch
          • [With regional restarts] The duration of Droman's Wrath has been increased to 15 seconds (was 12 seconds).
      • Plaguefall
        • [With regional restarts] Plaguebelcher’s summoned Slimy Morsels have had their health reduced by 50%.
        • Globgrog
          • [With regional restarts] Slimy Morsel health reduced by 30%.
      • Sanguine Depths
        • [With regional restarts] Gluttonous Tick should now lose any stacks of Engorge when they leave combat.
        • Infused Quill-feathers no longer trigger on death affixes such as Bolstering, Sanguine, etc.
        • Kryxis the Voracious
          • [With regional restarts] Juggernaut Rush damage reduced by 20%.
      • The Necrotic Wake
        • Surgeon Stitchflesh
          • [With regional restarts] Health reduced by 10%.
      • Theater of Pain
        • Affront of Challengers
          • [With regional restarts] Sathel the Accursed's One With Death now absorbs 20% of their maximum health (was 30%).
          • [With regional restarts] Dessia the Decapitator's Slam damage reduced by 40%.

    Items and Rewards

    • Increased the Stygia that can be rewarded from Maw daily quests by 2x. Additionally, the chance for Stygia to be picked as the reward increased by 15%.
    • Fixed an issue that was caused The Shaded Judgement Stone and the Stolen Korthian Supplies to not drop from all creatures in the Korthia and Maw Rifts.

    Player versus Player

    • Death Knight
      • [With regional restarts] Rune of the Fallen Crusader no longer has its Strength bonus reduced in PvP situations (was reduced by 33%).
      • Unholy
        • [With regional restarts] Necrotic Wounds (PvP Talent) debuff duration increased to 15 seconds (was 12 seconds).
    • Hunter
      • [With regional restarts] Arcane Shot damage increased by 9% in PvP situations.
      • Marksmanship
        • [With regional restarts] Aimed Shot PvP damage increased by 10% in PvP situations.
    • Monk
      • Mistweaver
        • [With regional restarts] Mana regeneration reduced by 30% 2021 - Free Activators PvP situations (was 40%).
        • [With regional restarts] Renewing Mist healing increased by 10% in PvP situations.
        • [With regional restarts] Vivify healing increased by 10% in PvP situations. Brewmaster and Windwalker Vivify healing unchanged.
    • Warlock
      • [With regional restarts] Demon Armor (PvP Talent) maximum health bonus increased to 10% (was 5%).
      • Affliction
        • [With regional restarts] Agony PvP damage increased by 15% in PvP situations.
        • [With regional restarts] Corruption PvP damage increased by 15% in PvP situations.
        • [With regional restarts] Siphon Life (Talent) PvP damage increased by 15% in PvP situations.
        • [With regional restarts] Shadow Bolt damage increased by 10% in PvP situations.

    August 6, 2021

    Classes

    • Demon Hunter
      • Resolved an issue that caused Blood Moon (PvP Talent) to dispel two Magic effects from the initial target.
    • Druid
      • Fixed an issue where Lone Empowerment (Kyrian Ability) was not granting additional Mastery via Kindred Affinity (Runecarving Effect).
    • Monk
      • Resolved an issue that allowed Monks to activate Transcendence: Transfer while crowd-controlled by certain types of effects.

    Dungeons and Raids

    • Timewalking
      • Increased experience earned from Timewalking dungeon completion by 50%.
        • Developers’ note: There was a bug introduced in 9.1 that caused Timewalking to give much more completion experience than the UI advertised, ramping up more the lower-level the base expansion was, which is why this wasn’t noticed with Warlords of Draenor Timewalking a few weeks ago. The intent is for all Timewalking weeks to give comparable experience – we put in a quick fix last night and have deployed the proper fix today. We also took the opportunity to recalibrate Timewalking experience and increase it.

    Items and Rewards

    • Shards of Domination
      • The tooltip for Shards of Domination bonuses have been updated to more clearly indicate that the Rune Words are only active in the Maw or related areas. This is a tooltip change only.

    Burning Crusade Classic

    • The Midsummer Fire Festival has been configured to run for 16 days, in order to give players a little extra time to complete its many quests. This means that Burning Blossoms, which expire after being held for 14 days, may disappear if they were collected in the first two days of the event and then never spent.

    August 5, 2021

    Classes

    • Demon Hunter
      • Fixed an issue that caused Blood Moon (PvP Talent) to fail to grant the Demon Hunter leech.
      • Fixed an issue that could prevent the Demon Hunter from gaining Fury/Pain with Consume Magic.
    • Monk
      • Windwalker
        • Earth and Fire spirits now properly remove themselves from crowd-control effects when the Storm spirit activates effects such as Gladiator's Medallion.
    • Rogue
      • Serrated Bone Spike (Necrolord Ability) will no longer remove itself after a short duration on some targets such as target dummies.
      • Fixed an issue that prevented Serrated Bone Spike (Necrolord Ability) from refunding a charge when targets die after being affected by the ability multiple times.
      • Assassination
        • Fixed an issue that prevented Echoing Reprimand (Kyrian Ability) from granting the proper duration to Envenom when consumed.

    Dungeons and Raids

    • Sanctum of Domination
      • Added death gates to assist in traversing through the Sanctum of Domination.
Источник: https://worldofwarcraft.com/en-us/news/23691036/hotfixes-november-1-2021

Hi Guys, Today I am Going to Show You How To Remove or Uninstall Windows Activation/License key in Windows 10 & 11?

Are you Looking for the Commonly Searched Term “How to Remove Windows 10 Activation Key? ” (or) “How To Remove Windows Activation/License key Using Cmd?”.

Check Out This: How to Fix An Automated WordPress Update has failed to Complete – Please attempt the update again now Error?

Steps For How To Remove or Uninstall Windows Activation/License key in Windows 10 & 11?

Step 1: Right-click on the Start and Select Command Prompt ( Admin ) in Your Windows 10,11.

Step 2: 2021 - Free Activators Type the Command “slmgr /upk ” to uninstall the current product key from Windows.

Step 3: Now Type the Command “slmgr /cpky ” to remove the product key from the registry.

Step 4: Now Type the Command “slmgr /rearm ” to reset the Windows activation timers.

Restart Your PC.

That’s It. You’re Done. Have a Nice Day.

@@@ Leave Comments @@@

##Stay Safe Guys And Live Happily ##

Vasantharaj R N

Basically an Instrumentation Engineer But Very much Interested in Blogging. I'm a Passionate Blogger and an Intermediate in the Search Engine Optimization Process. I'll always try to Fix those Common Issues Which was Faced By Most of the users in the World.

Related Posts

Источник: https://letsmakeiteasy.tech/how-to-remove-or-uninstall-windows-activation-license-key-in-windows-10-11/

Frequently asked questions about the Accellion data breach

The University of California Undergraduate Experience Survey (UCUES) solicits student opinions on a broad range of academic and co-curricular experiences, including instruction, advising and student services. UCUES provides information about student attitudes and behaviors including time use, academic engagement and community involvement. It assesses attitudes towards many different aspects of campus life including academic advising, campus climate, courses & instruction, and interaction with faculty. It documents students' self-perceptions and goals, political beliefs, and perceptions of the role of the research university. It also collects background demographic information, such as first language, family immigration background and social class.

+

Why does UC conduct the UCUES?

UCUES has been used extensively to guide the University on improving the undergraduate experience. Campuses also use UCUES to report on the quality of their academic programs to their academic senates. Some campuses have used UCUES data in their WASC accreditation self-studies. Other campuses, as well as the Council of Vice-Chancellors of Student Affairs, use UCUES to evaluate the quality and use of their student services. A number of campuses have used UCUES to report on campus climate and the impact of diversity on students' educational experiences.

UCUES data and results have been used in UC’s Annual Accountability Reports, UC Budget for Current Operations, and to inform regents' committees, such as the Long-Range Guidance Team, the Diversity Study Group, and Student Basic Needs Committee.

+

Was other survey data impacted by the Accellion FTA security event?

We have not identified any other impacted surveys.

+

What types of information from the UCUES survey were posted to the internet?

The impacted information includes participants’ full survey responses, which potentially include your name; email address; student ID; background and personal characteristics; academic engagement; educational experiences; personal development and mental health; the campus climate for diversity and inclusiveness; sexual misconduct situations; student life; and food and housing security, if you provided this information in response to the survey. A sample list of the questions from the survey can be found here.

The University used the Accellion FTA to transfer large files such as the survey results.  Unfortunately, perpetrators exploited a vulnerability in the application and attacked over 100 organizations including universities, government agencies, and private companies. When the University discovered the issue, we took the system offline and patched the Accellion vulnerability. We are in the process of transitioning to a more secure 2021 - Free Activators. The University cooperated with the FBI and worked with external cybersecurity experts to investigate this matter and determine what happened, what data was impacted, and to whom the data belongs.

When the University discovered the issue, it took the Accellion FTA offline and patched the vulnerability. There is no evidence that other University systems were impacted. The University is in the process of transitioning to a new file transfer system with enhanced security controls, deploying additional system monitoring broadly throughout its network, conducting a security health check of certain systems, and enhancing security controls, processes, and procedures.

+

How does the University intend to protect the confidentiality of those that take the UCUES going forward?

When the University discovered that student responses gathered in the 2020 University of California Undergraduate Experiences Survey (UCUES) were, unfortunately, part of the data in the Accellion FTA at the time of the microsoft office accounting 2016 - Crack Key For U and posted to the internet, it began reviewing the policies and procedures surrounding the biennial survey to better protect the personal data and privacy of the UC community. That process to strengthen these policies and procedures is ongoing.

+

What resources does the University have if I’m concerned about my physical, mental or emotional well-being?

There are several mental and emotional health support and safety resources available across the University community:  

  • Counseling & Psychological Services– Confidential mental and emotional health support is available for students through the appropriate counseling and psychological services office (sometimes called CAPS) for your campus:  
  • Faculty & Staff Assistance Program– Each campus, medical center, and national laboratory within the University administers its own faculty and staff assistance program (sometimes called an Employee Assistance Program). Assistance programs offer free, confidential resources for emotional health, often available right on campus, with easy access to short-term counseling, assessment, and referral. For more information on assistance programs available at specific UC locations, click here. 
  • CARE– For survivors of sexual violence, intimate partner violence, or stalking, please contact a UC CARE Advocate for confidential, compassionate support and safety planning. For usb installer windows 7 - Free Activators information about your campus CARE office, click here. If you’re in danger or need help now, call 9-1-1.  

If you need support beyond the UC community, these offices can also provide information about potential local resources that are available.  

+

I am a 2021-2022 applicant to a University of California campus. Was my information affected?

The contact information for individuals who started or completed the application process for the University of California for the 2021 – 2022 school year were impacted. That contact information is limited to names, email addresses, and phone numbers.

The University is separately notifying these individuals, and their notification will contain information on what precautions they may take.

+

I am a 2020-2021 applicant to a University of California campus. Was my information affected?

Information from submitted applications for the University of California for the 2020-2021 school year were impacted. This information could include date of birth, gender identity, family household income level, ethnicity and/or tribal affiliation and first language, sexual orientation, academic information (GPA, test scores), and whether you have received foster care.

The University is separately notifying these individuals, and their notification contains information on what precautions they may take.

+

I am an applicant to the University of California (UC) system for the 2020-2021 and 2021-2022 academic year. What resources are available to me?

The University is separately notifying 2020-2021 and 2021-2022 student applicants. Their notification contains information on what precautions they may take. 

We ask that University community members remain vigilant against threats of identity theft or fraud.  Additionally, it is always a good idea to be on alert for “phishing” emails or phone calls by someone who acts like they know you or are part of a company that you may do business with, and requests sensitive information, such as passwords, Social Security numbers, or financial account information. You may report suspected phishing or social engineering attempts to communications@ucop.edu, or the following email addresses depending upon your campus:

We also recommend that you rotate passwords and use multifactor authentication for your online accounts when offered.

Источник: https://ucnet.universityofcalifornia.edu/data-security/updates-faq/index.html

Summary

Learn more about this security update, including improvements and fixes, any known issues, and how to get the update.

Important: Windows Server 2008 Service Pack 2 (SP2) has reached the end of mainstream support and is now in extended support. Starting in July 2020, there will no longer be optional, non-security releases (known as "C" releases) for this operating system. Operating systems in extended support have only cumulative monthly security updates (known as the "B" or Update Tuesday release).

Verify thatyou have installed the required updates listed in the How to get this update section before installing this update. 

For information about the various types of Windows updates, such as critical, security, driver, service packs, and so on, please see the following article. To view other notes and messages, see the Windows Server 2008 Service Pack 2 update history home page.

Improvements and fixes

This security update includes improvements and fixes that were a part of update KB5005606 (released September 14, 2021) and addresses the following issues:

  • Addresses an issue in which an Internet print server cannot package the driver to send to the client.

  • Implements a Group Policy setting for the following registry value:

    • Registry location: HKEY_LOCAL_MACHINE\Software\Policies\Microsoft\Windows NT\Printers\PointAndPrint

    • Value name: RestrictDriverInstallationToAdministrators

    • Value data: 1

    For more information, see KB5005652.

  • Adds the ability to configure period or dot (.) delimited IP addresses interchangeably with fully qualified host names in the following Group Policy settings:

  • Addresses an issue in which Security Account Manager (SAM) events are not displayed properly in the Event Viewer.

  • Addresses a known issue that might prevent devices from downloading and installing printer drivers when the devices attempt to connect to a network printer for the first time. We have observed this issue on devices that access printers using a print server that uses HTTP connections.

  • Addresses a known issue that might ask for administrative credentials every time you attempt to print. This occurs in environments in which the print server and print client are in different times zones.

For more information about the resolved security vulnerabilities, please refer to the new Security Update Guide website and the October 2021 Security Updates.

Known issues in this update

Symptom

Workaround

After installing this update and restarting your device, you might receive the error, “Failure to configure Windows updates. Reverting Changes. Do not turn off your computer”, and the update might show as Failed in Update History.

This is expected in the following circumstances:

  • If you are installing this update on a device that is running an edition that is not supported for ESU. For a complete list of which editions are supported, see KB4497181.

  • If you do not have an ESU MAK add-on key installed and activated.

If Glary Utilities Pro 5.172.0.200 Crack+ License Key Free Download 2021 have purchased an ESU key and have encountered this issue, please verify you have applied all prerequisites and that your key is activated. For information on activation, please see this blog post. For information on the prerequisites, see the "How to get this update" section of this article.

Certain operations, such as rename, that you perform on files or folders that are on a Cluster Shared Volume (CSV) may fail with the error, “STATUS_BAD_IMPERSONATION_LEVEL (0xC00000A5)”. This occurs when you perform the operation on a CSV owner node from a process that doesn’t have administrator privilege.

Do one of the following:

  • Perform the operation from a process that has administrator 2021 - Free Activators the operation from a node that doesn’t have CSV ownership.

Microsoft is working on a resolution and will provide an update in an upcoming release.

After installing this update, Windows print clients might encounter the following errors when connecting to a remote printer shared on a Windows print server:

  • 0x000006e4 (RPC_S_CANNOT_SUPPORT)

  • 0x0000007c (ERROR_INVALID_LEVEL)

  • 0x00000709 (ERROR_INVALID_PRINTER_NAME)

Note The printer connection issues described in this issue are specific to print servers and are not commonly observed in devices designed for home use. Printing environments affected by this issue are more commonly found in enterprises and organizations.

For workarounds and the latest status for this issue, please see Windows release health.

We are presently investigating and will provide an update in an upcoming release.

How to get this update

Before installing this update

IMPORTANT Customers who have purchased the Extended Security Update (ESU) for on-premises versions of these operating systems must follow the procedures in KB4522133 to continue receiving security updates after extended support ends on January 14, 2020.

For more information about ESU and which editions are supported, power iso free download full version for win7 - Crack Key For U must install the updates listed below and restart your device before installing the latest Rollup. Installing these updates improves the reliability of the update process and mitigates potential issues while installing the Rollup and applying Microsoft security fixes.

  1. The April 9, 2019 servicing stack update (SSU) (KB4493730). To get the standalone package for this SSU, search for it in the Microsoft Update Catalog. This update is required to install updates that are only SHA-2 signed.

  2. The latest SHA-2 update (KB4474419) released October 8, 2019. If you are using Windows Update, the latest SHA-2 update will be offered to you automatically. This update is required to install updates that are only SHA-2 signed. For more information on SHA-2 updates, see 2019 SHA-2 Code Signing Support requirement for Windows and WSUS.

  3. The Extended Security Updates (ESU) Licensing Preparation Package (KB4538484) or the Update for the Extended Security Updates (ESU) Licensing Preparation Package (KB4575904). The ESU licensing preparation package will be offered to you from WSUS. To get the standalone package for ESU licensing preparation package, search for it in the Microsoft Update Catalog.

After installing the items above, Microsoft strongly recommends that you install the latest SSU (KB5006750). If you are using Windows Update, the latest SSU will be offered to you automatically if you are an ESU customer. To get the standalone package for the latest SSU, search for it in the Microsoft Update Catalog. For general information about SSUs, see Servicing stack updates and Servicing Stack Updates (SSU): Frequently Asked Questions.

Install this update

Release Channel

Available

Next Step

Windows Update and Microsoft Update

Yes

None. This update will be downloaded and installed automatically from Windows Update if you are an ESU customer.

Microsoft Update Catalog

Yes

To get the standalone package for this update, go to the Microsoft Update Catalog website.

Windows Server Update Services (WSUS)

Yes

This update will automatically sync with WSUS if you configure Products and Classifications as follows:

Product:  Windows Server 2008 Service Pack 2

Classification: Security Updates

File information

For a list of the files that are provided in this update, download the file information for update 5006736.

Источник: https://support.microsoft.com/en-us/topic/october-12-2021-kb5006736-monthly-rollup-c5fc0c8f-92dd-40ad-9e4a-b13528b78ca5

How to upgrade to Windows 10 for free in 2021

Editors Note: Windows 11 arrives this fall. Before getting too excited, see our Windows 11 system requirements guide to see if your laptop or desktop is compatible. Windows 11 will be a free upgrade, much like Windows 10. If you can't wait to see the new OS, you can download a Windows 11 preview build. Be cautious though, we recommend doing this only on a system that doesn't contain valuable data. 

Microsoft shut down its free Windows 10 upgrade program in November 2017. If you didn’t get your free version of its best operating system to date, you were pretty much out of luck. Or, so we thought. It turns out, you can still upgrade to Windows 10 without spending a dime. 

It turns out there are several methods of upgrading from older versions of Windows (Windows 7, Windows 8, Windows 8.1) to Windows 10 Home without paying the $139 fee for the latest operating system. 

Keep in mind that this workaround won't necessarily work all the time. If it doesn't, you'll need to pay the Windows 10 Home license fee or, if your system is older than 4 years, you might want to buy a new one (all new PCs run on some version of Windows 10). You will certainly need to upgrade from Windows 7 or Windows 8 if you are still running those legacy operating systems as Microsoft no longer supports them. 

How to Upgrade to Windows 10 for free

1. Ensure you're using a genuine copy of Windows 7 or later. Anything older will not work (please, if possible, buy a new system if you're using Window XP or Vista). If you're using Windows 7, write down the activation key (you may need this later). A free tool like NirSoft’s ProduKey will help you find it.  

2. This is a good stop to pause and back up anything you’d like to save on your current PC before continuing. Follow our Windows 10 backup instructions on how to do so. 

3. Visit the Windows 10 download page. This is an official Microsoft page that may allow you to upgrade for free. Once you're there, open the Windows 10 Media Creation Tool (press "download tool now") and choose "Upgrade this PC now." 

4. Accept the terms and choose the upgrade options that lets you keep your files and preferences. Again, having a backup ready at this point is very important so save everything to the cloud or to an SSD or USB. 

5. Reboot your computer and connect it to the internet. Open Settings and choose "Update & Security" and click "Activation." From here, you can see if the Windows 10 upgrade worked. If not, press an "Activate" button July 12 there is one); this will create a digital Windows 10 product key. Try using your Windows 7 or Windows 8 license key. 

Now that you know how to upgrade to Windows 10 for free, be sure to check out our other Windows 10 tutorials below, including tips on how to uninstall programs on Windows 10, how to find your MAC address in Windows 10, how to create a new folder in Windows 10 and more.

Источник: https://www.laptopmag.com/articles/upgrade-to-windows-10-free

How To Activate Windows 10 Pro for free ( No Product Key Needed)

How To Activate Windows 10 Pro for free ( No Software Needed), In this article, I am going to show you how to activate Windows 10 Pro for free without any additional software. Just follow some easy steps and you will be able to activate Windows 10 Pro. first, let’s have some information about Windows 10 and its other versions, then, we will compare Windows 10 Pro to Windows 10 Home, which is another version of Windows 10. activate Windows 10 Pro

Windows 10

Meanwhile, Windows 10 is a personal computer operating system developed and produced by Microsoft and the successor of Windows 8.1. furthermore, Windows 10 has twelve editions, all with different features. in fact, all Windows 10 Pro and Windows 10 Home are notable. in the meantime, Windows 10 Home is the basic variant of Windows 10 and is basically designed for use PCs, tablets, and 2-in-1 PCs and Windows 10 Pro has all the features of Windows 10. But, it has introduced some extra features for business environments. Such as a bit locker and remote desktop.

Features of Windows 10 Pro

Windows 10 Pro has more features unlike Windows 7 and 8.1. So here are the features of Windows 10 Pro. these features are mainly designed for business environments.

  • BitLocker
  • Remote desktop connection
  • Windows update for business
  • Hyper-V
  • Group policy management
  • Trusted Boot
  • Assigned access

Also Read:

How to Activate Office 365 Pro Plus for Free

How to Activate Windows 11 for Free

The main differences between Windows 10 Pro and Home

Meanwhile, both Windows 10 versions ( Pro and Home) provide similar features. But on the other hand, Windows 10 Pro comes with some new features, which are actually designed for business environments. However, this doesn’t mean that Windows 10 Pro is better than the Home version. Here are the main differences in the table below. activate Windows 10 Pro

FeaturesWindows 10 HomeWindows 10 Pro
Group policy managementNoYes
BitLockerNoYes
Hyper-VNoYes
Remote desktopNoYes
Assigned AccessNoYes
Create and join a domain (work network)NoYes
Enterprise Mode Internet ExplorerNoYes
Trusted BootNoYes
Windows Update for businessNoYes
Windows Store for businessNoYes
Maximum supported RAM128GB ( Gigabyte)2TB (Terabyte)
Common Features of Windows 10 Pro and Windows 10 Home

However, there is not much difference between the two versions of Windows 10. here are the common features of Windows 10 Pro and Windows 10 Home in the table below. activate Windows 10 Pro

Read More: How to Activate Windows 10 Home without Product Key for Free

FeaturesWindows 10 HomeWindows 10 Pro
Start MenuYesYes
CortanaYesYes
Battery SaverYesYes
Windows UpdateYesYes
Windows HelloYesYes
Virtual DesktopsYesYes
Snap AssistYesYes
ContinuumYesYes
Microsoft EdgeYesYes
Device EncryptionYesYes
Microsoft PassportYesYes

How Long Will You be Able to Use Windows without Activating it?

Have you ever wondered how long Windows 10 can be used without a product key or activation? The easy answer is that you can use it indefinitely, but some of the functionality would be disabled in the long run. Gone are the days when Microsoft required customers to purchase a license and rebooted their computers every two hours if the grace period for activation expired.

Unlike previous versions of Windows, Windows 10 does not require you to enter a product key during the installation process. You’ll see a button that says “Skip for now.” After installation, you should be able to use Windows 10 without restrictions for the next 30 days.

Here’s a rundown of the restrictions you’ll face in this situation:

  • The Activate Windows watermark will stay in the lower right-hand corner.
  • You can get alerts from Windows telling you to activate it. I’m not sure how often it will occur, but it will be noticeable every day.
  • In Settings, you’ll see a message that says, “Windows isn’t activated, activate Windows now.”
  • You won’t be able to customize the wallpaper, accent colors, themes, lock screen, or other aspects of the phone. Personalization-related options will be greyed out or unavailable.
  • Any applications and functionality will become unusable.
  • While you can still get Updates, for the time being, Microsoft is expected to change its strategy in the future.
How to Activate Windows 10 Pro?

Now, with this activation method, you can activate all Windows 10 versions. 2021 - Free Activators let’s start the procedures.

Step 1. Clickhere and copy the Windows 10 text activation code.
Step 2. Open Notepad and paste the text. Go to File and click the Save option.

Save

Step 3. Write the File name such as activatewindows10.cmd and click save. Save it to the desktop.
Step 4. Run the batch file as administrator and if you are prompted, click Yes.
How To Activate Windows 10 Pro for free ( No Software Needed) in 2021

Run as administrator

Step 5. Wait for a while. Activating your Windows.

Activating your Windows

Step 6. Finally, your Windows 10 is successfully activated.
How To Activate Windows 10 Pro for free ( No Software Needed) in 2021

Product Activated Successfully

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Neonatal thyroxine activation modifies epigenetic programming of the liver

Abstract

The type 2 deiodinase (D2) in the neonatal liver accelerates local thyroid hormone triiodothyronine (T3) production and expression of T3-responsive genes. Here we show that this surge in T3 permanently modifies hepatic gene expression. Liver-specific Dio2 inactivation (Alb-D2KO) transiently increases H3K9me3 levels during post-natal days 1–5 (P1–P5), and results in methylation of 1,508 DNA sites (H-sites) in the adult mouse liver. These sites are associated with 1,551 areas of reduced chromatin accessibility (RCA) within core promoters and 2,426 within intergenic regions, with reduction in the expression of 1,363 genes. There is strong spatial correlation between density of H-sites and RCA sites. Chromosome conformation capture (Hi-C) data reveals a set of 81 repressed genes with a promoter RCA in contact with an intergenic RCA ~300 Kbp apart, within the same topologically associating domain (χ2 = 777; p < 0.00001). These data explain how the systemic hormone T3 acts locally during development to define future expression of hepatic genes.

Introduction

Thyroid hormone (TH) regulation of gene expression involves binding to nuclear receptors (TR) that are attached or may be directed to TH responsive elements (TREs). This is followed by recruitment of transcriptional coregulators that modify histones and chromatin accessibility to transcriptional enzymes1; noncanonical pathways that do not require binding to TREs might also be involved2. The genomic actions of TH signal promote localized transition of the chromatin from a tightly folded and less transcriptionally active structure known as heterochromatin to a more loosely folded and active structure known as euchromatin3,4,5,6. As these processes involve histone modifications, regulation of gene expression by TH is largely fluid, with the rate of transcription of TH-regulated genes fluctuating rapidly according to the levels of the biologically active T3 in the cell nucleus.

In the absence of T3, most unoccupied TRs (uTR) remain attached to TREs, where they form complexes with transcriptional co-repressors to pack the DNA. Examples of uTR-recruited co-repressors include nuclear receptor corepressor 1 (NCoR1) and the silencing mediator of retinoid and thyroid hormone receptors (SMRT; NCoR2), which recruit deacetylases (e.g., HDAC3), methyl transferases (e.g., HMT), and kinases (e.g.,protein kinase B [PKB; aka Akt]) to activate facultative heterochromatin formation and inhibit gene transcription7,8. Methylation of H3K9, reduction of H3R17 methylation and of phosphorylation/acetylation of H3S10/K14 are all examples of specific histone modifications triggered by uTRs that inhibit transcription9.

uTRs are known to remain bound to TREs and have repressive effects on gene transcription. Nonetheless, exposure of cells to T3 directs additional TR units to TREs, and shifts TRs association 2021 - Free Activators co-repressors to co-activators; these include steroid receptor coactivator (SRC) family, CBP/p300 or CARM1/SNF5, promoting transcriptional activity. In general, the chromatin modifications induced by T3-TR are the opposite of those caused by uTR, e.g., demethylation of H3K9, methylation of H3R17 and phosphorylation/acetylation of H3S10/K149,10. As a result, the T3-TR not only de-represses but also trans-activates transcription of target genes1. T3-TR can also activate gene transcription via long-distance enhancer hyperacetylation, a mechanism that depends on the chromatin context11.

Less is known about TH regulation of gene expression via DNA methylation, a process that can also result from histone methylation12,13, and can affect the expression of gene clusters as opposed to a single target gene14. In general, the effects of DNA methylation on gene expression last longer when compared to histone modifications, and are involved in developmental transitions such as amphibian metamorphosis and mammalian organogenesis15, both processes typically sensitive to TH16,17.

To regulate the timing and intensity of TH signaling on an organ/tissue-specific fashion, developing cells express TH deiodinases, that can both activate (D2) or inactivate (D3) TH. In the embryo, circulating T3 is kept at relatively low levels and tissues predominantly express D3. However, D3 activity diminishes towards birth at the same time that, in some tissues, D2 activity is selectively boosted. A unique blend of D3 and D2 activities seen during this transition independently controls the levels of nuclear T3 in each tissue, hence the timing and intensity of the TH signaling. In the mouse, this process may extend well into the post-natal period given that circulating T3 levels remain low (P1≪P10) through post-natal day 10 (P10)18,19. Indeed, peaks of D2-T3 that enhance TH signaling are seen through this period on a tissue-specific basis3, e.g., embryonic day 17 (E17)-P1 in brown adipose tissue (BAT)20, or P15 in the cochlea21.

In the developing liver there is a D2-T3 peak (P1–P2) that briefly doubles T3 content22 that coincides with the time of C/EBPa-induced maturation of the bi-potential hepatoblasts into hepatocytes23; Dio2 expression in liver is silenced thereafter22. This spike in TH signaling is critical for post-natal liver maturation given that liver-specific Dio2 inactivation (Alb-D2KO) was associated with the formation of 1,508 CpG sites of DNA hypermethylation (H-sites) of the adult Alb-D2KO liver genome22. As a result, the adult Alb-D2KO liver response to high-fat diet (HFD) is affected22; the Alb-D2KO mice exhibit reduced susceptibility to obesity, liver steatosis, hyperlipidemia and alcoholic liver disease22,24.

Hepatocytes normally undergo post-natal epigenetic reprogramming, including changes in DNA methylation, which are the result of terminal differentiation of hepatocyte precursors25,26. For example, between E18.5 until adulthood, ~200,000 CpGs changed DNA methylation by >5%, and ~20,000 CpGs by >30%. These changes in DNA methylation occurred primarily in intergenic enhancer regions and coincided with the terminal differentiation of hepatoblasts into hepatocytes25,26.

Here, we show that during the last steps of the hepatoblast maturation, a transient surge in D2-mediated T3 signaling interferes with the epigenetic remodeling of hepatocytes, permanently modifying the transcriptome in adult mice. In the absence of this T3 surge, there is a transient (neonatal) increase in H3K9me3 and permanent hypermethylation of discrete DNA areas, which are strongly associated with reduced chromatin accessibility and repression of ~1500 genes in the adult mouse liver. Gene repression involves reduction of chromatin accessibility in distant areas that operate as remote enhancers, located within the same topologically associating domain. These studies explain how D2 locally modifies T3 signaling during development to define future hepatic gene expression.

Results

Two mechanisms could explain the formation of the 1508 H-sites found in the adult Alb-D2KO liver: (i) defective neonatal DNA demethylation and/or (ii) de novo neonatal DNA methylation, around P1-P5 but before P10, when circulating T3 reached adult levels. To resolve this, we studied the coordinates of the H-sites (Supplementary Table 1) vs. those of thousands of hepatic DNA sites that are normally demethylated during the P1–P21 time frame25. Only 25 H-sites were among those that are normally demethylated (Supplementary Fig. 1A), indicating that almost all H-sites in the Alb-D2KO liver resulted from de novo DNA methylation.

How were the H-sites formed in the Alb-D2KO liver?

Liver-specific Dio2 inactivation reduces T3 content and T3 signaling in the P1-P5 liver22. A predominance of unoccupied thyroid hormone receptors (uTR) has been shown to foster a histone environment that has been linked to de novo DNA methylation in a number of developmental settings by recruiting co-repressors that triple-methylate H3K99,12,13,16. Thus, we tested if this could explain the formation of H-sites in the liver of Alb-D2KO by performing a liver ChIP-seq of H3K9me3 in P1, P5, and adult Alb-D2KO mice. Indeed, we found at least 86 H-sites in the Alb-D2KO liver transiently imbedded in H3K9me3-enriched areas that were only present in the Alb-D2KO chromatin (Supplementary Table 1); these sites are hereinafter referred to as HH-sites (Fig. 1a). Sixty-six HH-sites were identified in P1 and 51 in P5; in some cases, H-sites remained surrounded by areas enriched with H3K9me3 throughout the P1 and P5 period. In the adult mice, the differences in H3K9me3 enrichment level between control and Alb-D2KO mostly dissipated, remaining only around 16 of the 86 HH-sites. This dynamic is illustrated in the 20 HH-sites identified on the qA1.2 segment of Alb-D2KO chromosome 12 (Fig. 1a). Within this segment, there was an ~80 Kbp island of intense enrichment of H3k9me3 on P1 and P5; the differences in H3K9me3 dissipated in the adult mice; a smaller 14Kbp island with 5 HH-sites that behave similarly was observed 2 Mbp upstream (Supplementary Table 1).

a browser IGV image of the indicated portion of the mouse chromosome 12 containing 15 H-sites; the following tracks contain ChIP signals for: (top to bottom) H-sites (blue), TR ChIP-seq peaks (hypo and T3-treated - pink), H3K9me3 ChIP-seq peaks in Alb-D2KO (red) and control (black) P1, P5 and adult mice; the input track is shown in gray; a close-up picture of a single H-site is shown in Supplementary Fig. 1B; during optimization of the experimental conditions the pull down was repeated 8 times with different samples; hence replication of experiment (repeating the whole experiment) was not performed as the figure shows data from 12 P1 mice and 6 P5 mice; for adult animals, the figure shows data from 6 mice. b heat-maps of H-sites vs. TR ChIP-seq peaks in liver; the x-axis contains the TR peak coordinates at the center +/– 5 Kbp and the y-axis contains the H-site coordinates; the H-site coordinates start at the top and progresses downwards in the following order: Chr 1 through Chr 9, Chr X, Chr 10 through Chr 19; each dot in the heat-map indicates an H-site and its relative distance to a TR peak (center); Hypo indicates TR ChIP peak coordinates obtained from hypothyroid mice, and +T3 indicates TR coordinates obtained from T3-treated mice; c distribution of H-sites as a function of polymerase II (pol-II) ChIP-seq peak locations; the numbers at the bottom indicate the distance in base pairs (bp); H-sites are within the promoter if up to 1 Kbp; the H-sites are grouped in blue circles according to the distance bracket; the numbers of H-sites in each bracket is indicated inside the blue circles, in white; red dots are H-sites imbedded in areas enriched with H3K9me3 during P1-P5; d same as in b, except that Pol-II and H3K4me3 (core promoter makers) ChIP-seq peaks were placed at the center of each respective heat-map; e same as in b, except that H3K27ac and H3K4me1 (enhancer makers) ChIP-seq peaks were placed at the center of each respective heat-map.

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These results support the idea that during the first few days of life, discrete areas of the Alb-D2KO liver chromatin are enriched with H3K9me3, reflecting an environment that favors the methylation of neighboring DNA sites (H-sites). Here, we captured two snap shots, i.e., P1 and P5, of a process that could last until circulating T3 reached adult levels, i.e. around P1018,19. The transient nature of the H3K9me3 pockets and the durability of the H-sites could explain why we only observed their association in 86 cases, given that we only looked at two neonatal time-points.

That liver D2 is only expressed during the first few days of life and the H-sites are only present in the Alb-D2KO livers constitute evidence that formation of H-sites is inherently connected with reduced T3-signaling22. Thus, we next wished to define the relationship between H-sites and TRs in the liver. As we were not able to identify high-quality anti-TR antibodies that could be used to successfully prepare a ChIP-seq library in P1 and P5, we reanalyzed two sets of published liver ChIP-seq data obtained with anti-TR antibodies that are no longer available—one from adult hypothyroid mice, in which uTRs predominate over T3-TRs, and the other from T3-treated adult mice, in which T3-TRs predominate over uTRs,27. We used these datasets to assess the density of uTRs or T3-TRs in the proximity of H-site coordinates. The resulting heat-maps revealed that while only ~10% of the H-sites were flanked by uTRs in the hypothyroid liver (Fig. 1b), >90% of the H-sites were flanked by T3-TR; T3 has been shown to recruit a larger number of TR units to the TH responsive elements (TRE) (Fig. 1b).

Further assessment of the uTRs and T3-TRs revealed that the sample of 86 HH-sites we identified on P1 and P5 was only flanked by 7 uTRs (within 10 Kbp). In contrast, the same sample of HH-sites was flanked by T3-TRs in 69 occasions (Supplementary Table 1). For example, no uTRs were identified on the qA1.2 segment of Alb-D2KO chromosome 12, or the smaller upstream chromatin area. In contrast, both areas combined presented 9 T3-TRs (Supplementary Table 1). It is thus conceivable that uTRs might not play a decisive role in triggering H-site formation in this setting. Instead, it is more likely that the neonatal D2-mediated enrichment of the liver chromatin with T3-TR sustains recruitment of co-activators and preserves an environment unsuitable for the discrete methylation of H-sites, illustrated by the lower levels of H3K9me3 (Fig. 1a).

Location of the H-sites in the Alb-D2KO liver chromatin

To refine the localization of H-sites in liver chromatin, we first annotated the H-sites coordinates and found widespread distribution throughout the genome (Supplementary Data 1). We next reanalyzed published hepatocyte chromatin immunoprecipitation-sequencing (ChIP-seq) data of multiple chromatin markers28 and contrasted with the H-sites coordinates. Proximity analysis revealed that only few H-sites were located within the core promoter marker Pol-II ChIP peaks; most of the H-sites was found between 5–500Kbp of the Pol-II peaks (Fig. 1c). This distant relationship with core promoters is illustrated in heat-maps in which the coordinates for Pol-II ChIP peaks and an additional core promoter marker H3K4me3 were plotted against the H-sites coordinates (Fig. 1d)25,29. The low H-site density in the vicinity of these chromatin markers supports that most are not located in core promoter regions. That most H-sites are likely to be located in remote enhancer regions is suggested by their high density and proximity around the known primed and active enhancer markers, respectively H3K4me1 and H3K27ac (Fig. 1e)25,29.

Reduced chromatin accessibility in the adult Alb-D2KO liver chromatin

Tissue- or cell type-specific DNA hypermethylation is frequently associated with areas of stable heterochromatin, i.e., reduced chromatin accessibility, and has been implicated in the control of gene expression during development30. To test if this was case in the Alb-D2KO liver, we used the transposase-accessible chromatin assay followed by high-throughput sequencing (ATAC-seq) of both adult control and Alb-D2KO mouse liver nuclei (Fig. 2a). To generate the ATAC-seq libraries we used high-quality nuclei extracted from frozen adult liver that were quality checked by light microscopy (Fig. 2a). The ATAC-seq libraries yielded the expected fragment length distribution, with the majority of fragments representing areas of inter-nucleosome open chromatin, with progressively fewer large sized fragments representing mono and oligo-nucleosomes (Fig. 2a).

a the inset contains a representative image of isolated liver nuclei (40x) before adding the transposase enzyme; the graph indicates the lengths of the fragments sequenced within a representative ATAC-seq library; insert size in bp; the first sharp peak (~100 bp) reflects areas of open chromatin, which is followed by 4 peaks of mono (~200 bp) or multinucleosomes of compact chromatin (n = 4/group); the picture in the inset is representative of 14 independent nuclei extractions; the graph is representative of two independent library buildouts; b genomic distribution of peaks obtained in ATAC-Seq data; eight samples were studied with no further replication; c heat-maps prepared as in Fig. 1b, except that the x-axis contains the RCA peak coordinates at the center +/− 10,000 bp and the y-axis contains the coordinates for P300, Pol2 and H3k4me3; d same as c, except that the y-axis contains the coordinates for H3k4me1 and H3k27ac; e classification of RCAs according to the relative intensities of H3K4me1 and H3K4me3 ChIP-seq peaks: promoter-RCAs, weak promoter-RCAs, enhancer-RCAs, weak enhancer-RCAs, and insulator-RCAs; each dot represents one RCA area.

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A total of 22,374 areas of open chromatin were identified in the liver of control animals; after gene annotation, almost half of these open areas were placed in promoter regions up to 200 bp of transcription start site (TSS; Fig. 2b). The Alb-D2KO liver exhibited a smaller number of open-chromatin areas, only 14,343, indicating the existence of 8031 regions with reduced chromatin accessibility (RCAs). The reduction of open-chromatin regions detected in the Alb-D2KO included 51% in exons, 53% in introns, and 50% in intergenic areas. There was also a 13% reduction in promoter regions. Of these RCA areas, 1551 were annotated to core promoters and 2,426 to intergenic regions (Fig. 2b). Plotting the RCA coordinates against Pol-II, P300 and H3K4me3 ChIP-seq peaks, revealed high density with July 12 degrees of superimposition, confirming their proximity to promoter regions (Fig. 2c). At the same time, high density and variable degrees of superimposition features were also observed when RCA areas were plotted against H3k4me1 and H3k27ac ChIP-seq peak coordinates, confirming that they were also present in remote enhancer areas (Fig. 2d).

We next focused on the promoter RCA (p-RCA) areas, and ranked them according to their ATAC-seq signal intensity and signal ratio to two typical chromatin markers H3K4me1 (enhancer) and H3K4me3 (promoter) (Fig. 2e)29,31. This approach revealed that 65% of these areas did function as typical core promoters, while 22% were likely to be insulators and 13% local enhancers (Fig. 2e). Of course, these are all functions that can be affected by chromatin accessibility, which is strongly coupled to binding of transcription factors; in most cases binding only occurs when the chromatin is accessible, unpacked32. Thus, to identify the transcription factors that were affected by the p-RCA areas in the Alb-D2KO chromatin, we performed de novo motif profiling of these areas using the MEME suite. Motifs belonging to major families of transcription factors were identified, including Sp1–3, E2f3, Klf1, Nrf1, Elk1, and Egr2, many of which are known for playing critical roles in liver development and function (Supplementary Fig. 2)33,34,35,36,37,38. In addition, the second and the third most enriched motifs were for ZNF143 and CCCTC-binding factor (CTCF) (Supplementary Fig. 2). Both are transcription factors that cooperate with the multiprotein complex cohesin to promote chromatin folding, allowing remote enhancers to interfere with transcriptional activity39.

Chromatin accessibility and gene expression

To study gene expression in the Alb-D2KO liver and test whether it was affected by p-RCA areas, we next performed an RNA-seq analysis of adult mouse liver (Supplementary Fig. 1c) and identified 1525 genes differentially expressed in Alb-D2KO mouse (>1.2-fold; p < 0.05; Fig. 3aS1D; and Supplementary Data 2). Notably, most of these genes (1363) were downregulated in the Alb-D2KO liver, reflecting the overall reduction in chromatin accessibility. The gene set enrichment analysis (GSEA, Partek Flow) of these differentially expressed genes revealed that the top two gene-sets impoverished in the Alb-D2KO liver were (i) “fatty acid” and (ii) “lipid metabolic process” (ES > 31 and p < 2.9E-14) (Supplementary Data 3). In addition, a pathway enrichment analysis (PEA, Partek Flow) identified metabolic pathways related to drugs and other xenobiotic compounds, as well as five lipid-related pathways among the top 15 pathways impoverished in the Alb-D2KO liver (ES > 5.2 and p < 0.01) (Supplementary Table 2).

a heat-map of liver RNA-seq data showing clustering of genes affected in the ALB-D2KO mouse; green indicates relative down-regulation; red indicates relative upregulation; fold change is shown on the left; most gene names are indicated on the right (nine samples were studied with no further replication); b browser IGV display of transcript areas of selected genes (eight representative genes out of a total of 146 genes) that are downregulated in the Alb-D2KO liver AND exhibit a RCA area within its core promoter region; the distance between the negative RNA-seq peak and the RCA area in all cases is < 5 Kbp; the gene names are indicated on the top of each panel along with the arrow indicating direction of transcription; the red tracks reflects the coverage for the Alb-D2KO Atac-seq and RNA-seq data, and the black tracks reflects the controls; the statistically significant RCA areas are indicated by a blue line.

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In order to identify genes in which there was a high likelihood that a p-RCA was affecting its expression directly, we next analyzed the proximity of the 1551 p-RCAs and the 1363 genes with at least one negative RNA-seq site (n-RNA-seq), selecting those that were within 5 Kbp of each other (p-RCA:n-RNA-seq), a configuration that strongly supports a functional relationship between them. This strict criterion led us to 154 p-RCAs (146 genes; Supplementary Data 4), with key roles in liver development and function, including lipid metabolism, mitochondria, redox control, drug metabolism, TGFB-signaling and fibrosis, and cell signaling. Typical examples of these p-RCA:n-RNA-seq areas and the corresponding gene coverages are shown in Fig. 3b.

An analysis of these 154 p-RCA areas revealed that about three-fourths contained putative footprints of transcription factors, including SP1–3 (n = 63), E2F3 (n = 32), Klf1 (n = 37) and NRF1 (n = 34) (Supplementary data 4). These footprints were rarely alone; most of the time they were present in groups of 3–4 on the same p-RCA. At the same time, about  one-fourth of the p-RCAs was found in insulators. The presence of both cohesin and CTCF (CAC-sites) is typical of insulators that modulate the 3D chromatin structure and gene expression by affecting the connection with remote enhancers. In contrast, insulators that contain cohesin only (CNC-sites) have a local effect, isolating functional promoters and enhancers from spreading neighboring heterochromatin40. Using published mouse liver ChIP-seq data31 for cohesin (Rad21) and CTCF, we looked for overlaps between the 34 RCA/insulator areas and the cohesin/CTCF peaks. There were 30-CAC sites and 4 CNC-sites, highlighting the potential importance of remote regulation in our model (Supplementary Table 3 and Supplementary Fig. 1e).

Functional interplay between H-sites, RCA areas and gene expression

There are multiple pathways through which H-sites could affect gene expression, mainly silencing active promoters or enhancers via creating a p-RCA, or controlling higher-order chromatin structure and the action of long-distance enhancers30. Indeed, the analysis of the density of 1508 H-sites and of all 8,052 RCA areas in individual chromosomes revealed a strong positive correlation (r = 0.85; p < 0.0002). The correlation remained strong when only the densities of H-sites vs. p-RCA areas (r = 0.69; p < 0.0009; Fig. 4a) or intergenic RCA (i-RCA) areas (r = 0.75; p < 0.0002; Fig. 4b) (Supplementary Table 4). These findings support our hypothesis of a close, possibly cause-effect relationship, between H-sites and RCA areas.

a correlation between the density (number of H-sites/size of the chromosome) of H-sites and promoter RCAs sites in each chromosome; the nonparametric Spearman r and the statistical significance are indicated; no adjustments were made for multiple comparisons [p < 0.0009 (two-tailed)]; b same as a, except that i-RCA sites were used [p < 0.0002 (two-tailed)]; c same as a, except that promoter RCAs and i-RCA sites were used [p < 0.0001 (two-tailed)]; d distance between H-sites and i-RCA areas vs. p-RCA areas; the number of H-sites and i-RCA areas at each distance bracket is indicated inside the circles; distances are indicated in Kbp; e same as c except that distances were calculated between intergenic RCA areas (i-RCA) vs. H-sites; there are 572 i-RCA located at a distance >1000 Kbp that are not indicated; f Circa representation of the 121 n-RNA-seq areas and p-RCA areas within 1000 bp of area-1 vs. the closest H-sites and i-RCA to area-2 areas across the Alb-D2KO liver genome; the outer most ring represents chromosome ideograms; on the right, the size of each chromosome is indicated in Mbp; the inner connecting lines indicate the Hi-C interacting points obtained from ref. 43.

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A more granular analysis of the H-sites coordinates revealed that of all H-sites, only 25 were within 5 Kbp of a p-RCA area (Fig. 4d). Notably, we found that 12 of the 154 p-RCA:n-RNA-seq areas did contain at least one H-site within 5 Kbp (10 within 1 Kbp), setting the stage for a possible local negative effect on the promoter of the following genes: 1700047M11Rik, Gstm6, 3110082I17Rik, Mtus1, Dixdc1, Eif5, Dsp, Pde4d, Sco2, Tymp, Odf3b, Cdo1 (Supplementary Data 4). In these locations, the p-RCA areas included mostly core promoters, but also 2 enhancers and 1 insulator (Supplementary data 4).

Most H-sites were much further away from the p-RCA areas. About half of the H-sites was found within 500 Kbp of p-RCAs and two-thirds up to 1 Mbp away (Fig. 4d). In these cases, any effect on gene expression would need to be remote, probably involving intra- 2021 - Free Activators associating domain (TAD) chromatin interaction, which is in keeping with the CAC sites (Supplementary Table 3) and CTCF/ZNF143 footprints detected in p-RCA areas (Supplementary Fig. 2). In the specific case of the remaining 134 p-RCA:n-RNA-seq areas, the nearest H-site was found within 50 Kbp of 18 p-RCA sites, between 50 and 500 Kbp of 62 p-RCA sites, and between 500 Kbp and 1 Mbp of 19 p-RCA sites; the remaining 35 p-RCAs were much further away from an H-site (Fig. 4d).

Whereas it is logical to assume that even distant H-sites per se could affect chromatin structure and folding30, it is also feasible that the disruption of the intergenic enhancers resulted from the combined effects of both H-sites and i-RCAs. Furthermore, distant H-sites could have played a more local role in the formation and maintenance of the i-RCA areas, disrupting proper recruitment of proteins to, and the folding of, chromatin40. Indeed, an analysis of the distance between p-RCAs and H-sites or p-RCAs and i-RCAs shows a remarkably similar profile (Fig. 4d), with relatively minor distances between H-sites and i-RCA areas (Fig. 4e), which was not unexpected, considering the dimension of the intergenic environment and the high-order chromatin structure40. Nonetheless, it is remarkable that the strongest correlation found was between the density of i-RCA vs. p-RCA areas (r = 0.89; p < 0.0001; Fig. 4c).

DNA sequences within a TAD are known to physically interact with each other more frequently than with sequences outside the TAD41. Thus, we tested whether p-RCA and i-RCA areas colocalized within the same TADs. We used published TAD coordinates obtained from mouse liver chromatin31 and used bedops42 to cross them with the coordinates for all p-RCAs and i-RCAs. The analysis of 3,538 TADs revealed that 472 contained p-RCAs and 677 contained i-RCAs, of which 278 contained p-RCAs and i-RCAs within the same TAD, a highly significant association (χ2 = 557; p < 0.00001). We confirmed this association by manually curating the TAD, p-RCA, and i-RCA data for chromosome #1, with similar results (Supplementary data 5).

We next used chromosome conformation data (Hi-C) obtained from primary liver cell cultures43 to identify potential chromatin contacting areas that could explain how disruption of a distant enhancer would have affected the 154 p-RCA:n-RNA-seq sites and their genes. This was done by first building a contact matrix of all statistically significant interacting pairs separated by a minimum distance of 1 Kbp and a maximum distance of 10 Mbp (area-1 x area-2) for each chromosome. This matrix was analyzed by first mining for coordinates that were within 1 Kbp of the 154 p-RCA sites. We found 988 coordinates and 134 p-RCAs that met this strict criterion; these matrix coordinates were arbitrarily named areas-1. The remainder p-RCAs included four genes that contained an H-site near the core promoter, i.e., Sco2, Tymp, Odf3b, Gstm6. Second, we further mined the matrix and verified that these 988 areas-1 were in contact with 1060 distant areas, given that some areas-1 exhibited more than one point of contact; we arbitrarily named these distant points of contact areas-2. The average distance between areas-1 and areas-2 was ~324 Kbp (1 Kbp–2.4Mbp), well within the constraints of a TAD (Fig. 5). Indeed, for these 146 genes (containing 154-pRCAs), 51 TADs contained only p-RCAs and 131 TADs contained only i-RCAs, whereas 81 TADs contained p-RCAs and i-RCAs within the same TAD, a highly significant association (χ2 = 777; p < 0.00001) (Supplementary Data 6).

Only area-1 within 1 Kbp of a p-RCA are shown; the number of area-2 contacting points at each distance bracket is indicated in green and by the relative thickness of the connecting lines; the 120 gene names shown reflect those genes that satisfy the following criteria: a having a n-RNA-seq peak within 5 Kbp of a p-RCA; b having a p-RCA area within 1 Kbp of an area-1; c having an i-RCA area within 50 Kbp of an area-2; in parenthesis after each gene name is the number of interacting areas-2; Asterisk indicates the presence of a H-site within 50 Kbp of area 2. Note that the following genes that were originally included among the 146 are not shown here because they did not meet the strict criterion of having a p-RCA within 1000 bp of a Hi-C area-1:Ncor-1, Rmf167, Cdk5R1, Afmid, Sav1, Zbtb1, Ighm, Gm49413, M09Rik, Sco2, Tymp, Odf3b, Dnmdp, Echdc3, Gstm6, Adgrl2, Lurap1l, Gbp11, Smurf1, J07Rik, O19Rik, Pixbc1, Traip, and Acaa1b.

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To test whether p-RCAs could be directly affected by H-sites via high-order chromatin structure, we circa plotted for each chromosome the 1551 p-RCA vs. the 1508 H-sites, and overlaid the 1060 points of contact provided by the Hi-C analysis (Supplementary Fig. 3a–j). While there was always one or more H-sites nearby an area-2, the smallest distance between them averaged ~1 Mbp (Supplementary Data 7). Subsequently, we applied the same rationale for the i-RCAs and verified that they were in general much closer to the 1060 areas-2, with the smallest distance between them averaging ~0.53 Mbp (Supplementary Data 7). In addition, in many cases an area-2 was in the vicinity of more than one i-RCA. For example, an analysis of a sample of all areas-2 within < 50 Kbp of an i-RCA, identified 273 instances in which an area-2 was surrounded by up to 17 i-RCA areas, at an average distance of ~22 Kbp (Supplementary Data 7); as a comparison, there were only 78 H-sites located at < 50 Kbp of an area-2 (Supplementary Data 7).

This remarkable relative proximity between areas-1 and p-RCAs:n-RNA-seq vs. areas-2 and i-RCAs & H-sites, as revealed by the Hi-C contact matrix, is illustrated by plotting these elements in a single circa-plot with all chromosomes (Fig. 4f). Of the original 146 genes with a p-RCA-n-RNA-seq area, 120 genes were found within 1 Kbp of area-1, of which 82 exhibited an i-RCAs within 50 Kbp of 211 areas-2 (Fig. 5).

Discussion

The investigation of a dramatic phenotype seen in the Alb-D2KO mouse22,24 led to the discovery that neonatal inactivation of liver Dio2 reduced local TH-signaling and set in motion a series of events that reduced chromatin accessibility and future expression of key hepatic genes. The present data suggest that a developmental hepatic peak of D2 locally mitigates the typically low post-natal circulating T3 levels of this period of life, which then prevents creation of a nuclear environment—enrichment of discrete chromatin areas with H3K9me3—that could favor the formation of ~1500 sites of de novo DNA hypermethylation (H-sites). These H-sites were mostly distant from core promoters and distributed similarly to the ~1550 p-RCA and ~2400 i-RCA areas; a TAD analysis revealed a highly significant association between these areas within the same TAD. These elements are likely to have disrupted the function of long-distance enhancers, which then failed to interact and activate the core promoter areas, lowering the expression of ~1300 genes involved in different aspects of liver development and function.

The present findings indicate that localized D2-generated T3 plays a role in the terminal maturation of the hepatocytes. This is reminiscent of the role played by D2 in the post-natal development of brown adipocytes and cochlea20,44. The timing and intensity of T3 signaling in developing cells is regulated via expression of deiodinases. In the embryo, circulating T3 is kept at relatively low levels and tissues predominantly express the inactivating deiodinase, i.e., D3, limiting exposure to T3. However, D3 activity diminishes towards birth at the same time that, in some tissues, D2 activity is selectively boosted. A unique blend of D3 and D2 activities seen during this transition independently controls the levels of nuclear T3 in each tissue, hence the timing and intensity of the thyroid hormone signaling.

In the case of hepatocytes, the short-lived, localized D2-T3 production, enriches discrete areas of the chromatin with T3-TRs, preventing accumulation of H3K9me3 and possibly the formation of the H-sites. Our H3K9me3 ChIP-seq studies in P1 and P5 Alb-D2KO livers caught the moments during which the chromatin environment could favor formation of H-sites, illustrated by the islands of H3K9me3 surrounding H-site coordinates; different timings could have been involved in the formation of the other H-sites, up until P10, when circulating T3 reached adult levels. Insulin signaling has been shown to play a similar role in the post-natal epigenetic programing of the liver, including differential DNA methylation. For example, changes in the DNA demethylation during the neonatal period were found to be essential for the ligand-activated PPARα-dependent gene regulates the hepatic fatty acid β-oxidation45. At the same time, changes in the DNA methylation coincide with the hepatocyte terminal differentiation and occurs after hematopoietic stem cell migration26.

uTRs have been shown to increase H3K9 methylation through recruitment of SUV39H19 and HP1 proteins, a family of heterochromatic adaptor molecules implicated in both gene silencing and supra-nucleosomal chromatin structure46. Indeed, the SUV39H1 was also found to cooperate with DNMTs to establish sites of de novo methylation47, which could explain the formation of the H-sites found in ALB-D2KO liver. Nonetheless, our finding that few uTRs are nearby H-sites suggests that DNA hypermethylation in these areas could be the default hepatocyte differentiation program without the modification normally caused by the D2-mediated surge in T3 and T3-TR. For example, hairless encodes a H3K9 demethylase, and is a highly T3-responsive genes48.

The reduction in gene expression found in the Alb-D2KO liver is dramatic. There are probably multiple mechanisms that explain such changes, but the ones we found evidence for in the present investigation include (i) disruption of few p-RCA function by local H-sites, (ii) disruption of long-distant chromatin interactions, looping enhancers and promoters, (iii) or a combination of both. The relative proximity and similar distribution of H-sites, i-RCAs and p-RCAs within individual chromosomes is remarkable; it is an indication that indeed most of these elements exist inside the same or neighboring TAD unit, and probably exhibit a functional relationship. These concepts were illustrated in the finding of 81 genes that have a p-RCA:n-RNA-seq area along with likely long-distance i-RCA/H-site interacting chromatin areas within the same TAD. It is conceivable that H-sites initiate these processes by creating/maintaining i-RCAs and disrupting the function of the distant enhancers, subsequently depriving core promoters of transcriptional factors that activate gene transcription. Sp1–3, E2F3, Klf1, and Nrf1 were among the potential transcription factors that could be affected in the promoter p-RCAs of the downregulated hepatic genes. It is notable that TR is not one of the transcription factors identified in p-RCAs, confirming that the T3 effects observed on gene transcription are mediated in remote locations.

The analysis of the p-RCAs also revealed negative Nrf1 and Elk1 footprints in the Ncor1 promoter, one of the 146 key downregulated genes with a p-RCA in the adult Alb-D2KO liver. Ncor1 is a TR corepressor7,8, which in the liver plays an essential role down-regulating T3-signaling. It is fascinating that the liver responds to a reduction in neonatal T3-signalig (due to Dio2 inactivation) and preserves T3-signaling homeostasis by inhibiting the adult expression of a TR corepressor.

In conclusion, the present studies revealed that during the hepatoblast-hepatocyte transition in mice, a short-lived surge in D2 expression and T3-signaling substantially modifies the hepatic transcriptome in adult animals. By acting through intergenic TRs, T3-signaling prevents discrete methylation of specific DNA sites, which would otherwise disrupt the function of areas that operate as remote enhancers. In the presence of the normal neonatal D2-T3 peak, these distant areas interact remotely with dozens of gene promoters, increasing chromatin accessibility and expression of genes involved in multiple hepatic functions. This constitutes a mechanism through which TH regulates gene expression, and explains the critical role played by deiodinases in vertebrate development.

Methods

Animals

Experiments were approved by the University of Chicago Institutional Animal Care and Use Committee - protocol # 72577. C57BL/6J mice with hepatocyte-specific Dio2 inactivation (Alb-D2KO) were obtained by crossing floxed C57BL/6J D2 mice (dio2Flx) with mice expressing Cre-recombinase under the albumin promoter (Cre-ALB) [B6.Cg-Tg(Alb-cre)21Mgn/J; The Jackson Laboratory]22. The mice were kept at room temperature (22 °C) under a 12-h dark/light cycle, and maintained on a chow diet (3.1 kcal/g; 2918 Teklad Global Protein rodent diet; Harlan).

Analysis of DNA hypermethylation sites

Liver hypermethylation sites (H-sites) in the Alb-D2KO mice were obtained from a previous methylome analysis that used two methods to identify H-sites: (i) Methylation-Dependent ImmunoPrecipitation followed by sequencing (MeDIP-seq) and (ii) Methylation-sensitive Restriction Enzyme digestion followed by sequencing (MRE-seq)22. Only the H-sites present in both methods were considered. H-sites were annotated to gencode.vM24. using the Partek Genomic suite software 7.0.

ChIP-sequencing (seq) and analysis

Liver ChIP-seq for H3K9me3 was performed in P1, P5 and adult control and Alb-D2KO mice, using the SimpleChIP® Plus Enzymatic Chromatin IP Kit (Magnetic Beads; Cell Signaling). Liver from pups and adult control and Alb-D2KO mice were snap frozen and stored at −80 °C. Four P1 samples (n = 4) were studied. Each sample was made up of a pool of 3 livers, totaling 12 mice: two samples were obtained from 6 Cre control animals and 2 samples were obtained from 6 Alb-D2KO animals. Two P5 sample were studied, each made up of a pool of three livers, totaling six mice. One sample was obtained from three Cre control animals and one sample was obtained from three Alb-D2KO animals; three adult livers were processed and sequenced individually. All samples were sequenced twice in different days; replication (repeating the whole experiment) was not performed because we studied 12 P1 mice and 6 P5 mice and results in both groups were similar. So, we considered that the P5 data replicated the P1 data, in what we called neonatal data. Chromatin lysates were prepared, pre-cleared with Protein G magnetic beads, and immunoprecipitated with antibodies against the H3K9me3 (Part Number 13969S- dilution 1:50- Cell Signaling). Beads were extensively washed before reverse crosslinking. Chip-enriched DNA was submitted to the Genome facility at University of Chicago for library preparation and sequence using Illumina NovaSEQ6000. FASTQ files obtained from sequencing were aligned to the Mouse mm10 genome in Partek-flow platform (Partek Inc. v.10.0.21.0509) using the BWA (v.0.7.17). The peaks were identified using MACS2 (v.2.1.1) tool, broad region and p < 0.05, compared with respective input samples and annotated using the gencode.vM24. This led us to P1: 280,580, P5: 265,920 and adult: 292,552 peaks in control livers vs. P1: 273,767, P5: 268,693 and adult: 286,124 peaks in Alb-D2KO livers. Areas of H3K9me3 enrichment unique to ALB-D2KO livers were also identified by comparing Alb-D2KO vs. controls samples, which led us to P1: 301,105, P5: 301,098, and adult: 287,032 peaks, which were filtered down to P1: 11,303, P5: 10,005 and adult: 16,730 using –log10(p-value)>2.

The following published ChIP-seq datasets from adult mouse liver were reanalyzed and also used in the present studies: histone markers28—GSM722760 (H3K4me1); GSM722761 (H3K4me3); GSM851275 (H3K27ac); GSM722762 (P300); GSM722763 (Pol2); GSM722764 (Input); chromatin-folding markers:31 Rad21 and CTCF (SRP116021) and TR27 (SRP055020). The FASTQ files were aligned to transcriptome with BWA (v.0.7.17) using the Partek flow platform (Partek Inc). The peaks were identified using MACS2 (v.2.1.1) tool (p < 0.05), compared to respective input samples and annotated using the gencode.vM24. In all instances, pre‐ and post-alignment QA/QC was done using Partek Flow (Partek Inc).

ATAC-seq and analysis

Frozen livers were processed for nuclei isolation using a detergent-free kit (Invent; cat # NI-024). Nuclei integrity was verified under light microscopy (Fig. 2a). Fifty-thousand nuclei were used for the transposase reaction as described49. The final libraries were purified using Agencourt AMPure XP beads (Beckman Coulter), and quality checked using a Bioanalyzer High Sensitivity DNA Analysis kit (Agilent); concentration was measured through a qPCR-based method (KAPA Library Quantification Kit for Illumina Sequencing Platforms). Samples were pair-end sequenced with the Illumina HiSeq 4000 platform at the University of Chicago Genomics Facility. The remaining adapter sequences were removed using NGmerge (v.0.3) Sequencing reads were aligned to the Mouse mm10 genome build using BWA (v.0.7.17) and annotated using the gencode.vM24. Sequence quality was assessed using FastQC and tools from the Picard suite including CollectInsertSizeMetrics, which showed an enrichment in short fragments as expected (Fig. 2a). Aligned reads were further filtered to remove chimeric, duplicate, supplementary, and low-quality (MAPQ < 30) alignments. We determined open-chromatin regions (peaks) using Genrich (v.0.6) (q-value threshold = 0.05). Run by individual sample, genrich would find only a handful of peaks, which very obviously were not due to ATAC enrichment. These regions were merged across samples into a blacklist of regions and excluded from consideration. Ultimately genrich was run using all samples grouped together while ignoring the blacklisted regions. Differential peaks were identified by overlap lumion 9 pro kickass - Activators Patch to find open-chromatin regions unique to each condition.

Mouse liver RCAs were classified based on the relative strengths of H3K4me1, H3K4me3, and ATAC signals31. Signals were summarized as transcripts per kilobase millions (TPM) values in each RCA region. Those RCA regions with a TPM > 4 for either H3K4me3 or H3K4me1 were segregated into one of three categories, depending on the value of the ratio of H3K4me3 to H3K4me1. High ratios of > 1.5 were classified as a “promoter”; ratios < 0.67 were classified as “enhancer”, while intermediate values were classified as “weak promoter.” Conversely RCA regions with TPM ≤ 4 in both H3K4me3 and H3K4me1 were segregated into one of two categories depending on the relative values of ATAC-seq to H3K4me1 ratio. If the ATAC-seq signal > H3K4me1 signal, then the RCA was categorized as “insulator”. If the ATAC-seq signal < H3K4me1 signal, then the RCA was categorized as “weak insulator”.

For the motif analysis, the nucleic acid sequence of promoter ATAC-seq peak regions were extracted and masked using RepeatMasker (v.4.0.7, using pre-defined settings for mouse). Motif analysis was carried out using the meme-chip command from MEME Suite (v.5.0.5) using the MOUSE/HOCOMOCOv10, MOUSE/uniprobe, MOUSE/chen2008, EUKARYOTE/jolma2013, and JASPAR/JASPAR_CORE_2016_vertebrates motif libraries. This multiple analysis tool identified known motifs, de novo motifs, characteristic distances and co-occurrences, and collapsed hits by motif similarity.

RNA sequencing and analysis

RNA was isolated from mouse liver using the RNeasy Kit (Qiagen). RNA degradation was monitored using a BioAnalyzer (Agilent). Samples of total RNA with RIN > 7.5 were sent to Genome Technology Access Center at Washington University in St. Louis for library preparation and sequence. Libraries were pair-end sequenced with NovaSeqS4 (Illumina). Base-calls and demultiplexing were performed with Illumina’s bcl2fastq software and a custom python demultiplexing program with a maximum of one mismatch in the indexing read. The FASTQ files were aligned to gencode.vM24 transcriptome with STAR (v.2.6.1d) using the Partek flow platform (Partek Inc.). All pre‐ and post-alignment QA/QC was performed in Partek Flow (Partek Inc.) (Supplementary Fig. 1C). Aligned reads were quantified to annotation model (Partek E/M) and normalized (absolute value). Following the differential analysis (GSA), the biological significance of the changes was interpreted using gene set enrichment analysis (GSEA; Supplementary Data 3) and pathway enrichment analyses (Supplementary Table 2).

Hi-C data analysis

Publicly available liver Hi-C datasets (GSE65126) were analyzed using the HICUP50 pipeline. Briefly, the HICUP (v.0.7.3) pipeline take as input FASTQ data from a Hi-C experiment and produces a filtered set of interaction pairs mapped to the reference genome (mm10). The post-pipeline analysis of the output from HICUP was done using HOMER (v.4.11)51 to create Hi-C interaction and contact matrices. Matrices were then analyzed for long-range interactions involving p-RCAs, i-RCAs as obtained from the analysis of the ATAC-seq, and H-sites.

Bioinformatics tools

R-script using the Bioconductor IRanges package52 (proximity analysis) was used to obtain the intersection of the H-sites and different chromatin markers on the genomic coordinates for the desired distance. The heat-maps used to analyze proximity between different chromosomes coordinates (Figs. 1b, d, e and  2c, d and Supplementary Fig. 1A), were generated using the interactive platform for analysis Easeq. BED files containing the start/end chromosomal coordinates of each peak were used to generate the images. The circos plots (Fig. 4f and Fig. S2A–J) were created with Circa software (v.1.2.1) tool (http://omgenomics.com/circa). The Integrative Genomics Viewer (IGV) 2.7.2 version was use to visualize and integrated all the genomic data analysis (http://www.broadinstitute.org/igv). The analysis of the topologically associated domains (TADs) and RCA regions (intergenic and promoter) were done using bedops (v.2.4.38)42. The results from the bedops FaceGen Artist Pro Crack mined for relevant intersections using an R script.

Data availability

The data that support this study are available from the corresponding author upon reasonable request. The sequencing data generated in the course of this study have been deposited in the GEO under accession number GSE162930. The following publicly available datasets used in the manuscript were downloaded using GEO platform: histone markers—H3K4me1 (GSM722760); H3K4me3 (GSM722761); H3K27ac (GSM851275); P300 (GSM722762); Pol2 (GSM722763); Input (GSM722764); chromatin-folding markers: Rad21 and CTCF (SRP116021) and TR (SRP055020).

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Источник: https://www.nature.com/articles/s41467-021-24748-8

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