May 21, 2021 - Free Activators

Accordingly, public health authorities should prioritize food-handlers in the restaurants for training courses. Abstract · Full text · PDF · References. free. Windows and Office updates may cause Office 365 or Office 2019/21 to become "Disabled" or requiring "Activation". We show you how to fix. The H&R Block Activation Code is used to register your software and unlock your five free federal e-files. If you can't find your H&R Block Tax Software.

May 21, 2021 - Free Activators -

Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19

Abstract

Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe disease show hyperactivation of the immune system, which can affect multiple organs besides the lungs. Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as candidates to treat patients with SARS-CoV-2 infection. The growing understanding of SARS-CoV-2 infection pathogenesis and how it contributes to critical illness and its complications may help to improve risk stratification and develop targeted therapies to reduce the acute and long-term consequences of this disease.

Introduction

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and can present with a range of manifestations, including pneumonia and acute respiratory distress syndrome (ARDS)1. Although many individuals develop asymptomatic or paucisymptomatic SARS-CoV-2 infection, those with severe-to-critical disease show a dysregulated hyperactivation of the immune system that can cause an abnormal cytokine immune response and is likely to be responsible for most of the organ damage occurring in the late phase of the disease2.

It is now apparent that SARS-CoV-2 infection induces a prothrombotic state manifesting especially with microthrombosis3,4, as observed in patients with COVID-19 and in post-mortem samples from individuals who died after SARS-CoV-2 infection5,6,7,8,9. This thrombotic state is reminiscent of a process known as immunothrombosis (Box 1; Fig. 1), in which the immune and coagulation systems cooperate to block pathogens and limit their spread10. In this Perspective, we describe how SARS-CoV-2 might induce a prothrombotic state and discuss how currently available and developing therapies may address COVID-19-associated immunothrombosis.

Following recognition of a pathogen through pattern recognition receptors (PRRs), monocytes and monocyte-derived microvesicles present activated tissue factor (TF) on their surfaces and release it at sites of pathogen localization, thus activating the extrinsic pathway of coagulation (path a). Pathogens also stimulate the NLRP3 inflammasome in monocytes and/or macrophages, leading to the release of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18 (path b). Neutrophils are recruited and contribute to this process through the release of neutrophil extracellular traps (NETs), which directly activate factor XII and, thus, the contact-dependent pathway of coagulation (path c). NETs also bind von Willebrand factor (VWF) and help to recruit platelets (path d). Histones, in particular H3 and H4, trigger activation of platelets. In addition, neutrophil elastase (NE) and myeloperoxidase (MPO) in NETs cleave and inactivate natural anticoagulants (tissue factor pathway inhibitor (TFPA) and thrombomodulin (TM)) (path e). Finally, NETs can externalize and bind TF, promoting activation of the extrinsic pathway of coagulation. Platelets support the immunothrombotic process by activating the contact-dependent pathway of coagulation through the release of polyphosphates and, along with endothelial cells, may promote fibrin generation. Platelets can also be activated by C3a and C5a (path f). Activated platelets release large amounts of pro-inflammatory cytokines in platelet extracellular vesicles (PEVs) (path g). Through this mechanism, pathogens such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) become trapped within the fibrin-based NETs and killed. The immunothrombotic process allows pathogen killing to be restricted to the intravascular compartment, thus limiting injury to organs. Although it is clear that immunothrombosis participates in SARS-CoV-2 pathogenesis, the exact mechanisms are still under investigation. These may include the following: direct injury of endothelial cells by the virus and consequent activation of the coagulation cascade; infiltration of neutrophils that lead to NET formation; induction of hypoxaemia causing upregulation of TF expression by hypoxia-inducible transcription factors and formation of clots; activation of complement that promotes coagulation and recruits and activates platelets, monocytes and neutrophils, thus triggering TF expression; and an abnormal increase in the levels of pro-inflammatory cytokines causing direct cell damage.

Full size image

Box 1 Immunothrombosis: a conserved mechanism of host defence

The term immunothrombosis was originally described by Engelmann and Massberg to refer to an intrinsic effector pathway of innate immunity triggered by pathogens and injured cells to reduce the spread and survival of the invading pathogens10,157. By contrast, the term ‘thromboinflammation’ refers to a process in which inflammation and thrombosis coexist within microvessels in response to harmful stimuli (pathogens, injured cells or other irritants)158. Immunothrombosis is mainly triggered by neutrophils and monocytes and is supported by the formation of microthrombi in small vessels, in which endothelial cells exposed to microorganisms adopt a pro-adhesive phenotype159.

During immunothrombosis, neutrophils and monocytes release tissue factor and extracellular nucleosomes and degrade endogenous anticoagulants, thereby facilitating activation of coagulation induced by inflammation160. Importantly, tissue factor decorates neutrophil extracellular traps (NETs), as found in sepsis161 and, more recently, in coronavirus disease 2019 (COVID-19)-related immunothrombosis86. NETosis by neutrophils also enhances the activity of the coagulation system by increasing fibrin deposition162,163. Histones present in NETs, especially histones H3 and H4, can dose-dependently enhance thrombin generation not only by reducing thrombomodulin-mediated protein C activation164 but also by directly activating platelets141. Finally, NETs can bind plasma proteins needed for platelet adhesion and thrombus development, such as fibronectin and von Willebrand factor (VWF)141. In turn, platelets participate in this process in several ways: they increase the accumulation of immune cells that express tissue factor10,165; they bind directly to neutrophils and NETs162,166,167; they release damage-associated molecular patterns that promote tissue factor expression within thrombi168; and they directly bind to microorganisms for presentation to innate immune cells169,170.

Microorganisms have evolved mechanisms to escape immunothrombosis, such as the expression of streptokinase to dissolve fibrin171 or nucleases to degrade NETs172,173. Some bacteria use immunothrombosis to avoid their killing, such as Staphylococcus aureus, whose staphylocoagulase and VWF-binding protein trigger fibrin generation to form a biofilm and an abscess pseudocapsule174,175.

In sum, immunothrombosis can be considered a beneficial mechanism of intravascular immunity. However, when immunothrombosis is uncontrolled, it causes dysregulated activation of the coagulation cascade, leading to microthrombus formation and inflammation, which in turn enhance each other and may, ultimately, develop into thrombosis (thromboinflammation) and disseminated intravascular coagulation.

Immunothrombosis in COVID-19

COVID-19-associated hyperinflammation

The clinical spectrum of COVID-19 ranges from asymptomatic or paucisymptomatic (in up to 45% of individuals) to severe disease requiring admission of patients to the intensive care unit (ICU)11. Generally, 3–10% of subjects requires hospitalization, with up to 20% of them experiencing severe disease and a high mortality rate12,13. The initial phase of COVID-19 is characterized by damage directly driven by the virus. After approximately 7–10 days of symptoms (including fever, cough, fatigue, anorexia and myalgias), a subgroup of patients progresses to severe disease and develops hypoxaemia (low oxygen levels in the blood) and dyspnoea (shortness of breath), potentially evolving towards ARDS14. This stage of the disease is characterized by high levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6), IL-1β, IL-18 and granulocyte–macrophage colony-stimulating factor (GM–CSF)2,15,16,17. This event has been referred to as a cytokine storm18,19, although recent evidence suggests that cytokine levels in patients with COVID-19 are lower than those reported in patients with non-COVID-19 ARDS, sepsis, influenza virus infection and chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome20,21. SARS-CoV-2 has been shown to trigger the IL-1/IL-6 pathway to a larger extent than other coronaviruses22. Through the analysis of lungs of patients who died from COVID-19-related ARDS, SARS-CoV-2 was found to activate the NLRP3 inflammasome23,24. In vitro studies also showed NLRP3 inflammasome activation by SARS-CoV-2 infection of primary human monocytes. In addition, NLRP3 inflammasome products, such as IL-1β and IL-18, are increased in patients with severe COVID-19 and positively correlated with adverse clinical outcomes24. These findings support a potential relationship between SARS-CoV-2 infection and inflammatory features, such as the dysregulated cytokine response.

Increased levels of ferritin have also been observed among patients with COVID-19, similar to what is observed in macrophage activation syndrome16,19,25. Even though ferritin levels observed in macrophage activation syndrome are markedly higher than those currently observed in COVID-19 (≥10,000–100,000 ng ml–1 versus 500–3,000 ng ml–1), ferritin levels remain predictive of poor outcomes in COVID-19 (refs26,27).

With regard to inflammatory cells, large numbers of CD68+ macrophages were observed in the alveoli of patients who died from COVID-19-associated pneumonia, and SARS-CoV-2 proteins were detected in CD68+ alveolar macrophages28,29. Analysis of the bronchoalveolar fluid of patients with severe or critical COVID-19 showed a higher percentage of macrophages and neutrophils and a lower proportion of myeloid dendritic cells, plasmacytoid dendritic cells and T cells than that of patients with moderate disease30. They also had higher levels of pro-inflammatory cytokines (such as IL-6, IL-8 and IL-1β) and chemokines (such as CCL2, CCL3, CCL4 and CCL7) in the bronchoalveolar fluid30. These data suggest that lung macrophages contribute to inflammatory responses in SARS-CoV-2 infection, favouring excessive inflammation in severe pneumonia. Similar to other respiratory infections, leukocyte recruitment to the lungs is finely tuned by specific molecules31, the uncontrolled activity of which may result in complications observed in patients with COVID-19 in both the lungs and other organs5,32.

COVID-19-associated coagulopathy

An important pathophysiological feature of COVID-19 is the development of a prothrombotic state. The occurrence of a COVID-19-specific coagulopathy is suggested by elevated levels of fibrinogen, von Willebrand factor (VWF) and the fibrin degradation product D-dimer in the blood, whereas patients generally show minor or no changes in prothrombin time (a measure of time to clot), activated partial thromboplastin time (coagulation time), antithrombin levels, activated protein C levels and platelet count33,34,35,36. These features are more consistent with a state of hypercoagulability coupled with a severe inflammatory state rather than with classical disseminated intravascular coagulation (DIC)36. Indeed, DIC has been reported in a few patients, usually in the advanced stages of the disease33,37,38. Recently, low antithrombin levels were linked to poor outcomes in COVID-19, especially among patients with obesity39. Hence, it is possible that antithrombin activity changes as SARS-CoV-2 infection worsens and a putative mechanism might be the cytokine-driven imbalance in endogenous anticoagulant levels40. In macrophage activation syndrome, liver function impairment is a typical feature and may contribute to coagulopathy, yet liver impairment in COVID-19 is usually mild and transient, without overt acute liver injury41,42.

Apart from a state of hypercoagulability in the lungs of patients with ARDS, a hypofibrinolytic state in the alveolar space was observed in COVID-19-related ARDS due to increased levels of fibrinolytic inhibitors43. Accordingly, high levels of plasminogen activator inhibitor 1 (PAI1) were described in patients with SARS-CoV44.

In order to properly identify COVID-19-associated coagulopathy, Iba et al. proposed the occurrence of two or more of the following four criteria in cases of proven COVID-19: a decrease in platelet count (<150 × 109 l–1); an increase in D-dimer levels (more than two times the upper limit of normal); prothrombin time >1 s or international normalized ratio >1.2; and the presence of thrombosis (macrothrombosis and/or microthrombosis)45. The risk of COVID-19-associated coagulopathy is defined by one of the aforementioned four criteria and one of the following ones: increased fibrinogen levels; increased VWF levels (more than two times the upper normal limit); or the presence of lupus anticoagulant and/or high-titre antiphospholipid antibodies45. Importantly, COVID-19-associated coagulopathy and risk of COVID-19-associated coagulopathy may further progress and/or predispose to DIC as COVID-19 severity increases.

COVID-19-associated endothelial dysfunction

Although COVID-19 should be regarded as a systemic disease, it acutely causes a lung-centred injury primarily affecting the vascular endothelium. COVID-19-associated pneumonia is characterized by infiltration of the lungs with macrophages and neutrophils that cause diffuse lung alveolar damage, the histological equivalent of ARDS46,47,48. Similar findings were previously reported in patients with SARS-CoV49. However, the striking finding in COVID-19 compared with SARS-CoV is the more extensive viral infection within the lungs, which results in more diffuse inflammation involving the pulmonary vessels50. This extensive infection reflects the particular tropism of SARS-CoV-2 for angiotensin-converting enzyme 2 (ACE2) — the cellular receptor for SARS-CoV-2 — expressed by type II pneumocytes51, which are anatomically close to the lung vascular network and are typically described to be hyperplasic in samples from patients with COVID-19 (refs52,53,54). This hyperplasia of endothelial cells is likely to be caused by lung tissue ischaemia due to congestion of small vessels by inflammatory cells (that is, immunothrombosis) and thrombosis in large vessels55.

Endothelial dysfunction was suggested to be an important pathophysiological event in infections by other coronaviruses, which can directly infect endothelial cells56,57,58,59. SARS-CoV-2 directly infects vascular endothelial cells and leads to cellular damage and apoptosis, thus decreasing the antithrombotic activity of the normal endothelium7,55. Alveolar damage, vessel wall oedema, hyaline thrombi, microhaemorrhage and diffuse thrombosis of peripheral small vessels have emerged as key features of COVID-19 contributing to respiratory failure6,8,46 (Fig. 2).

A Hyaline membrane formation is a typical finding in patients with alveolar damage irrespective of being ventilated or not (blue arrows in panels a and b). Organizing fibrosis (blue arrowhead) and fibrin thrombi in small blood vessels (black arrows) with oedema, along with extensive haemorrhage (haematoxylin and eosin staining) and hyaline membranes (blue arrows) (panel c). The bronchial respiratory mucosa is almost entirely intact and no squamous metaplasia is evident (panel d), different to that observed in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). B

Prophetic & Activation Conference 2021

Fri May 21 2021 at 07:00 pm to Sat May 22 2021 at 05:00 pm

108 N Main St, Hopewell, VA 23860-2719, United States

Windows 11 ISO File 32/ 64 Bit Download, Leak News, Features, Release date, System requirement, Setup size, how to download and install details are available on this page. Soon after the leak of Windows 11 features and ISO files, Tech-savvy people have gone crazy for all the information about Windows 11 that they can get. If you are one of those crazy ones, do check the complete article for further details.

Windows 11 Download

Right now, no set date for the release of Windows 11 is available. But, An event is scheduled for 24 June 2021 where Microsoft will be talking about the next generation of Windows. This event is scheduled for 11 AM on June 24. So we can expect that they will announce the Windows 11 release date on that day.

In 2015, Windows 10 was launched that Microsoft was adamant that they will not create another version of windows. But, there are revolutionary times for technology and new technology is being introduced every day. So, Microsoft decided to launch Windows 11 for all users.

Windows 11 32/ 64 bit ISO file download

Many of the users have started to search for the Windows 11 32/ 64 bit ISO file even now. Let us tell you that this version of windows is yet to be released. On June 24, some announcements will be made about the release of Windows 11. Once the Win11 is released and available for download, it will be available on the official portal of Microsoft itself.

The Win11 ISO file will be provided free to the users (Early prediction) and users will not have to pay for the new version. We recommend upgrading your OS to Win11 as soon as it is available. Because, after a given time frame, Microsoft can make it paid too.

Windows 11 ISO file will be available for bot 32 and 64 bit operating systems. You will have to download the ISO file of the version as per your OS.

Windows 11 Free or Paid – Price Details

It is being expected that Windows 11 will be available as a free upgrade for those who are already running Windows 10, 7, and Windows 8.1 in their systems. Microsoft had run a similar free upgrade method for Windows 10 in the previous years.

Windows 11

Providing Windows 11 for free will help Microsoft to bring more users to the latest version of Microsoft Windows. It will also help safely removing the old operating systems from the devices of users who are no longer supported by the company.

Windows 11 Leak News

Windows 11 is set for release on June 24, 2021. But it was leaked already on the internet. Some key features of Windows 11 and various others details were leaked. In the leaks, it can be seen that a new start menu is designed for the new version. There are many other interface-level changes that were seen in the Windows 11 Leaked news.

The new start menu will have rounded corners and a new startup sound. This upgrade will be a simplified and faster version of what we are using in Windows 10. This will include various pinned apps, recent files, quick shutdown options, and much more.

Windows 11 Features

  • New Start Menu, Taskbar, and Search Bar
  • New Animations are added while moving and dragging the windows. Even Opening a new window, closing, and minimize tap have different animation than earlier versions of Windows.
  • Featured add to perform multitask with windows like split-screen, creating groups of various task windows, etc.
  • Touch controls are improved significantly. Windows 11 will have various problems fixed which were there in windows 10.
  • New sounds are added in this version. After the release of Windows 10 in 2015, no significant changes were made in the sounds. But in Windows 11, you will see various new sound options.
  • You will have access to dark mode also.
  • Rounded Corners: Pointy corners will not be available in Windows 11. Corners of various bars will be made round.
  • New icons are added which will make it more attractive than the earlier versions.
  • Various new Widgets are added in this version.

There are yet many new features of Windows 11 that we don’t know. These featured will be updated shortly.

Windows 11 System Requirements

Below is the minimum expected system requirement for Win11 installation.

  • 1.2 GHz single-core processor (32-bit)
  • OR 1.4 GHz single-core processor (64-bit)
  • 2 GB RAM or more
  • 1024 x 768 screen resolution
  • Approximately 15 GB of available hard disk space.

Recommended Configuration

  • 2.0 GHz dual-core processor or faster
  • 4 GB RAM or more
  • 1680 x 1050 screen resolution or higher
  • Approximately 18 GB of available hard disk space.

Windows 11 Setup Size

From the leaked version of Windows 11, It can be seen that the Setup file (ISO File) size is 4.54 GB. Considering that the leaked version does not have all the features, We can say that the actual file size will be between 4.5 to 6 GB.

How to Download Windows 11

As we know that the Win11 64 Bit version was leaked online and many people have uploaded it on Google Drive and shared it online. The direct link to download the ISO file is here.

Download Link 1

Download Link 2

Download Link 3

Download Link 4

We do not recommend you download and install the leaked version on your device as it can be full of malware. Hacker may have included some code in this file to steal your information so please do it at your own risk.

How to install Windows 11 on 64 Bit OS

  • Download the ISO file from the download link.
  • Grab a USB drive (With at least 16GB of Space) and make it bootable.
  • You can make this Pendrive bootable using Rufus.
  • Launch Rufus and select Windows 11 ISO file which you just downloaded.
  • Don’t alter any other field and keep them all as default and then click on the Start button at the bottom.
  • After that Windows 11 will be flashed in your USB drive.
  • Plug this USB Drive into the system where you want to install Windows 11.
  • Now restart your laptop/ PC and keep pressing the boot key.
  • Choose USB Drive as primary from the Boot Device Options.
  • After pressing the Enter button, Windows 11 installation process will start.
  • Now Choose your Language, Time, and Keyboard Input Method.
  • Click on Install Now.
  • As you do not have the product key, click the “I don’t have a product key” option.
  • Select the Windows 11 Edition you want to install.
  • Select the partition for Windows 11 Installation.
  • Click next and Your windows will start to install.

This is all we know about Microsoft Windows 11 for now. Be sure to bookmark this page to keep getting the latest updates.

Источник: https://www.mpnrc.org/windows-11-download-iso-file-32-64-bit-links/

Activator KMS Auto ++ for Office 2021

Office 2021 Professional Plus is a world famous solution for organizing office documents. It is owned by Microsoft and provides a multi-application package to users, editors and educational institutions.

The activated Microsoft Office 2021 gained great popularity thanks to three applications: Word, Excel and PowerPoint. These tools will allow you to work with documents, create books and abstracts, keep your own diary, create reports, tables and colorful presentations. Read more about these applications in the office capabilities section.

Almost every modern computer has Office 2021 or other versions installed. The digital age requires a professional and comprehensive approach to working with documents, spreadsheets and presentations, which is what the popular product from Microsoft provides.

Components of Microsoft Office Professional Plus 2021:

  • Microsoft Outlook 2021.
  • Microsoft Word 2021.
  • Microsoft Excel 2021.
  • Microsoft PowerPoint 2021.
  • Microsoft OneNote 2021.
  • Microsoft Publisher 2021.
  • Microsoft Access 2021.
  • Skype for bussines.
  • Project Pro / Standart.
  • Visio Pro / Standart.
  • Microsoft OneDrive 2021.
  • Microsoft Outlook 2021.

What to do if Office 2021 is not activated?

If you use Microsoft Office without activation, opening a blank document, you will see a notification “Your version of Microsoft Office is not activated: most of the functions of Word / Excel / PowerPoint are disabled”, next to which there will be an “Activate” button.

Microsoft Office 2021 is not activated

If you want to use all the features of the program, you need to activate the office, and what to do is described below in this article.

What is KMS Auto ++ Activator for Microsoft Office 2021

At the request of our users, we are posting KMSAuto, this is an activator that allows you to activate operating systems of the Windows family, and in particular the latest version of Windows 11, and of course previous versions. He also knows how to register the Microsoft Office product line from 2010 to 2021.

Like all such tools existing today, licensing is carried out for six months, after the expiration of the specified period, the registration procedure can be repeated again. Its zest, so to speak, can be called the fact that it does not significantly change the files of the system, that is, it does not harm it. Through the program, you can view detailed information about the installed license, as well as the time of its validity. Creation of backups is supported.

Features of Activator

  • Activation of Windows (obtaining a shareware licensed copy).
  • Activation of Microsoft Office 2010 2013 2016 2019 2021 Professional Plus and Standard.
  • Removing traces of other activators (files containing license information).
  • Reactivation tasks.
  • Checking the integrity of system files.
  • Task management in the Task Scheduler.
  • Advanced settings for advanced users.

Pros

  • The program is undemanding to system resources.
  • Possibility of manual and automatic activation.
  • Activation of Microsoft Office 2021 products.
  • Removal of the installed key.
  • Work with x64 and x32 bit systems.
  • Portable version of activator.
  • Work without an internet connection.
  • The program does not require installation.
  • Simple and intuitive interface.

Cons

  • You will definitely have to install Microsoft .NET Framework on your computer.
  • You also need to disable the antivirus, as it instantly removes the activator.

Download Activator

After downloading you may need Instruction of use, look it below.

Download "kms_auto.zip"

Download File

How to activate Office 2021 using KMS Auto?

Attention:

If you do not disable the Antivirus and Windows Defender – they will delete activator’s file and activation won’t happen.

VideoInstruction


 

Frequently Asked Questions (FAQs)

After reading everything about KMS Auto for MS Office 2021, if you still have questions, then you can read this FAQ list. In this list, I have collected some most asked questions around the internet and their answers.

You may also find the answer to the question which you are going to ask. If you are unable to find the answer, then you can also ask me in the comment section. I will try my best to answer your question and love to help you out.

How long does activation take?

Actually for 6 months, but when activation added to the task scheduler – forever (automatic re-activation). If you reinstall Windows – do activation again, it is simple!

What other programs are needed for proper operation?

You only need the .NET Framework 4.5 or older (can be downloaded from the official Microsoft Website). But in Windows 10, 11 have it installed alrdy, so you don’t need nothing to install.

The Office activator downloaded, but it disappeared …

See your Antivirus/ Windows Defender quarantine. During activation and before download/unzip, it is recommended to disable Antivirus and Windows Defender software.

What versions does it support?

Microsoft Office LTSC Professional Plus or Standart Editions 2021 (x32 + x64).

I have an original license for Windows? Will it break my license if I try to activate the Office?

The program is designed in a way that when you try to activate the Windows or Office. This will first check if there are any available licenses or not when you have the original license, it automatically avoids it and doesn’t make changes. So, in this way, you can simply activate Office without breaking your license.

Conclusion

With the help of the KMS activator, it becomes possible to use licensed systems and programs without financial investments. This program has a simple and intuitive interface and does not require any special knowledge and skills on the part of the user. For more advanced users, there is an advanced version with many additional options. Thanks to activation, you can be guaranteed effective use of software packages free of charge.

Microsoft Office 2021 activated using KMS Auto ++

Sharing is Caring: Please Share With Friends And Family

Источник: https://office-activator.com/activate-microsoft-office-2021-using-kms-auto/
Hyaline membrane formation is a typical finding in patients with alveolar damage irrespective of being ventilated or not (blue arrows in panels a and b). Organizing fibrosis (blue arrowhead) and fibrin thrombi in small blood vessels (black arrows) with oedema, along with extensive haemorrhage (haematoxylin and eosin staining) and hyaline membranes (blue arrows) (panel c). The bronchial respiratory mucosa is almost entirely intact and no squamous metaplasia is evident (panel d), different to that observed in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). B

In a Twitter discussion last week on ransomware attacks, KrebsOnSecurity noted that virtually all ransomware strains have a built-in failsafe designed to cover the backsides of the malware purveyors: They simply will not install on a Microsoft Windows computer that already has one of many types of virtual keyboards installed — such as Russian or Ukrainian. So many readers had questions in response to the tweet that I thought it was worth a blog post exploring this one weird cyber defense trick.

The Commonwealth of Independent States (CIS) more or less matches the exclusion list on an awful lot of malware coming out of Eastern Europe.

The Twitter thread came up in a discussion on the ransomware attack against Colonial Pipeline, which earlier this month shut down 5,500 miles of fuel pipe for nearly a week, causing fuel station supply shortages throughout the country and driving up prices. The FBI said the attack was the work of DarkSide, a new-ish ransomware-as-a-service offering that says it targets only large corporations.

DarkSide and other Russian-language affiliate moneymaking programs have long barred their criminal associates from installing malicious software on computers in a host of Eastern European countries, including Ukraine and Russia. This prohibition dates back to the earliest days of organized cybercrime, and it is intended to minimize scrutiny and interference from local authorities.

In Russia, for example, authorities there generally will not initiate a cybercrime investigation against one of their own unless a company or individual within the country’s borders files an official complaint as a victim. Ensuring that no affiliates can produce victims in their own countries is the easiest way for these criminals to stay off the radar of domestic law enforcement agencies.

Possibly feeling the heat from being referenced in President Biden’s Executive Order on cybersecurity this past week, the DarkSide group sought to distance itself from their attack against Colonial Pipeline. In a message posted to its victim shaming blog, DarkSide tried to say it was “apolitical” and that it didn’t wish to participate in geopolitics.

“Our goal is to make money, and not creating problems for society,” the DarkSide criminals wrote last week. “From today we introduce moderation and check each company that our partners want to encrypt to avoid social consequences in the future.”

But here’s the thing: Digital extortion gangs like DarkSide take great care to make their entire platforms geopolitical, because their malware is engineered to work only in certain parts of the world.

DarkSide, like a great many other malware strains, has a hard-coded do-not-install list of countries which are the principal members of the Commonwealth of Independent States (CIS) — former Soviet satellites that mostly have favorable relations with the Kremlin. The full exclusion list in DarkSide (published by Cybereason) is below:

Image: Cybereason.

Simply put, countless malware strains will check for the presence of one of these languages on the system, and if they’re detected the malware will exit and fail to install.

[Side note. Many security experts have pointed to connections between the DarkSide and REvil (a.k.a. “Sodinokibi”) ransomware groups. REvil was previously known as GandCrab, and one of the many things GandCrab had in common with REvil was that both programs barred affiliates from infecting victims in Syria. As we can see from the chart above, Syria is also exempted from infections by DarkSide ransomware. And DarkSide itself proved their connection to REvil this past week when it announced it was closing up shop after its servers and bitcoin funds were seized.]

CAVEAT EMPTOR

Will installing one of these languages keep your Windows computer safe from all malware? Absolutely not. There is plenty of malware that doesn’t care where in the world you wise data recovery with crack - Crack Key For U. And there is no substitute for adopting a defense-in-depth posture, and avoiding risky behaviors online.

But is there really a downside to taking this simple, free, prophylactic approach? None that I can see, other than perhaps a sinking feeling of capitulation. The worst that could happen is that you accidentally toggle the language settings and all your menu options are in Russian.

If this happens (and the first time it does the experience may be a bit jarring) hit the Windows key May 21 the space bar at the same time; if you have more than one language installed you will see the ability to quickly toggle from one to the other. The little box that pops up when one hits that keyboard combo looks like this:

Cybercriminals are notoriously responsive to defenses which cut into their profitability, so why wouldn’t the bad guys just change things up and start ignoring the language check? Well, they certainly can and maybe even will do that (a recent version of DarkSide analyzed by Mandiant did not perform the system language check).

But doing so increases the risk to their personal safety and fortunes by some non-trivial amount, said Allison Nixon, chief research officer at New York City-based cyber investigations firm Unit221B.

Nixon said because of Russia’s unique legal culture, criminal hackers in that country employ these checks to ensure they are only attacking victims outside of the country.

“This is for their legal protection,” Nixon said. “Installing a Cyrillic keyboard, or changing a specific registry entry to say ‘RU’, and so forth, might be enough to convince malware that you are Russian and off limits. This can technically be used as a ‘vaccine’ against Russian malware.”

Nixon said if enough people do this in large numbers, it may in the short term protect some people, but more importantly in the long term it forces Russian hackers to make a choice: Risk losing legal protections, or risk losing income.

“Essentially, Russian hackers will end up facing the same difficulty that defenders in the West must face — the fact that it is very difficult to tell the difference between a domestic machine and a foreign machine masquerading as a domestic one,” she said.

KrebsOnSecurity asked Nixon’s colleague at Unit221B — founder Lance James — what he thought about the efficacy of another anti-malware approach suggested by Twitter followers who chimed in on last week’s discussion: Adding entries to the Windows registry that specify the system is running as a virtual machine (VM). In a bid to stymie analysis by antivirus and security firms, some malware authors have traditionally configured their malware to quit installing if it detects it is running in a virtual environment.

But James said this prohibition is no longer quite so common, particularly since so many organizations have transitioned to virtual environments for everyday use.

“Being a virtual machine doesn’t stop malware like it used to,” James said. “In fact, a lot of the ransomware we’re seeing now is running on VMs.”

But James says he loves the idea of everyone adding a language from the CIS country list so much he’s produced his own clickable two-line Windows batch script that adds a Russian language reference in the specific Windows registry keys that are checked by malware. The script effectively allows one’s Windows PC to look like it has a Russian keyboard installed without actually downloading the added script libraries from Microsoft.

To install a different keyboard language on a Windows 10 computer the old fashioned way, hit the Windows key and X at the same time, then select Settings, and then select “Time and Language.” Select Language, and then scroll down and you should see an option to install another character set. Pick one, and the language should be installed the next time you reboot. Again, if for some reason you need to toggle between languages, Windows+Spacebar is your friend.

This entry was posted on Monday 17th of May 2021 10:14 AM

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Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19

Abstract

Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe disease show hyperactivation of the immune system, which can affect multiple organs besides the lungs. Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as how to install windows 10 on usb drive - Activators Patch to treat patients with SARS-CoV-2 infection. The growing understanding of SARS-CoV-2 infection pathogenesis and how it contributes to critical illness and its complications may help to improve risk stratification and develop targeted therapies to reduce the acute and long-term consequences of this disease.

Introduction

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and can present with a range of manifestations, including pneumonia and acute respiratory distress syndrome (ARDS)1. Although many individuals develop asymptomatic or paucisymptomatic SARS-CoV-2 infection, those with severe-to-critical disease show a dysregulated hyperactivation of the immune system that can cause an abnormal cytokine immune response and is likely to be responsible for most of the organ damage occurring in the late phase of the disease2.

It is now apparent that SARS-CoV-2 infection induces a prothrombotic state manifesting especially with microthrombosis3,4, as observed in patients with COVID-19 and in post-mortem samples from individuals who died after SARS-CoV-2 infection5,6,7,8,9. This thrombotic state is reminiscent of a process known as immunothrombosis (Box 1; Fig. 1), in which the immune and coagulation systems cooperate to block pathogens and limit their spread10. In this Perspective, we describe how SARS-CoV-2 might induce a prothrombotic state and discuss how currently available and developing therapies may address COVID-19-associated immunothrombosis.

Following recognition of a pathogen through pattern recognition receptors (PRRs), monocytes and monocyte-derived microvesicles present activated tissue factor (TF) on their surfaces and release it at sites of pathogen localization, thus activating the extrinsic pathway of coagulation (path a). Pathogens also stimulate the NLRP3 inflammasome in monocytes and/or macrophages, leading to the release of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18 (path b). Neutrophils are recruited and contribute to this process through the release of neutrophil extracellular traps (NETs), which directly activate factor XII and, thus, the contact-dependent pathway of coagulation (path c). NETs also bind von Willebrand factor (VWF) and help to recruit platelets (path d). Histones, in particular H3 and H4, trigger activation of platelets. In addition, neutrophil elastase (NE) and myeloperoxidase (MPO) in NETs cleave and inactivate natural anticoagulants (tissue factor pathway inhibitor (TFPA) and thrombomodulin (TM)) (path e). Finally, NETs can externalize and bind TF, promoting activation of the extrinsic pathway of coagulation. Platelets support the immunothrombotic process by activating the contact-dependent pathway of coagulation through the release of polyphosphates and, along with endothelial cells, may promote fibrin generation. Platelets can also be activated by C3a and C5a (path f). Activated platelets release large amounts of pro-inflammatory cytokines in platelet extracellular vesicles (PEVs) (path g). Through this mechanism, pathogens such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) become trapped within the fibrin-based NETs and killed. The immunothrombotic process allows pathogen killing to be restricted to the intravascular compartment, thus limiting injury to organs. Although it is clear that immunothrombosis participates in SARS-CoV-2 pathogenesis, the exact mechanisms are still under investigation. These may include the following: direct injury of endothelial cells by the virus and consequent activation of the coagulation cascade; infiltration of neutrophils that lead to NET formation; induction of hypoxaemia causing upregulation of TF expression by hypoxia-inducible transcription factors and formation of file viewer plus 4 crack download activation of complement that promotes coagulation and recruits and activates platelets, monocytes and neutrophils, thus triggering TF expression; and an abnormal increase in the levels of pro-inflammatory cytokines causing direct cell damage.

Full size image

Box 1 Immunothrombosis: a conserved mechanism of host defence

The term immunothrombosis was originally described by Engelmann and Massberg to refer to an intrinsic effector pathway of innate immunity triggered by pathogens and injured cells to reduce the spread and survival of the invading pathogens10,157. By contrast, the term ‘thromboinflammation’ refers to a process in which inflammation and thrombosis coexist within microvessels in response to harmful stimuli (pathogens, injured cells or other irritants)158. Immunothrombosis is mainly triggered by neutrophils and monocytes and is supported by the formation of microthrombi in small vessels, in which endothelial cells exposed to microorganisms adopt a pro-adhesive phenotype159.

During immunothrombosis, neutrophils and monocytes release tissue factor and extracellular nucleosomes and degrade endogenous anticoagulants, thereby facilitating activation of coagulation induced by inflammation160. Importantly, tissue factor decorates neutrophil extracellular traps (NETs), as found in sepsis161 and, more recently, in coronavirus disease 2019 (COVID-19)-related immunothrombosis86. NETosis by neutrophils also enhances the activity of the coagulation system by increasing fibrin deposition162,163. Histones present in NETs, especially histones H3 and H4, can dose-dependently enhance thrombin generation not only by reducing thrombomodulin-mediated protein C activation164 but also by directly activating platelets141. Finally, NETs can bind plasma proteins needed for platelet adhesion and thrombus development, such as fibronectin and von Willebrand factor (VWF)141. In turn, platelets participate in this process in several ways: they increase the accumulation of immune cells that express tissue factor10,165; they bind directly to neutrophils and NETs162,166,167; they release damage-associated molecular patterns that promote tissue factor expression 2021 - Free Activators thrombi168; and they directly bind to microorganisms for presentation to innate immune cells169,170.

Microorganisms have evolved mechanisms to escape immunothrombosis, such as the expression of streptokinase to dissolve fibrin171 or nucleases to degrade NETs172,173. Some bacteria use immunothrombosis to avoid their killing, such as Staphylococcus aureus, whose staphylocoagulase and VWF-binding protein trigger fibrin generation to form a biofilm and an abscess pseudocapsule174,175.

In sum, immunothrombosis can be considered a beneficial mechanism of intravascular immunity. However, when immunothrombosis is uncontrolled, it causes dysregulated activation of the coagulation cascade, leading to microthrombus formation and inflammation, which in turn enhance each other and may, ultimately, develop into thrombosis (thromboinflammation) and disseminated intravascular coagulation.

Immunothrombosis in COVID-19

COVID-19-associated hyperinflammation

The clinical spectrum of COVID-19 ranges from asymptomatic or paucisymptomatic (in up to 45% of individuals) to severe disease requiring admission of patients to the intensive care unit (ICU)11. Generally, 3–10% of subjects requires hospitalization, with up to 20% of them experiencing severe disease and a high mortality rate12,13. The initial phase of COVID-19 is characterized by damage directly driven by the virus. After approximately 7–10 days of symptoms (including fever, cough, fatigue, anorexia and myalgias), a subgroup of patients progresses to severe disease and develops hypoxaemia (low oxygen levels in the blood) and dyspnoea (shortness of breath), potentially evolving towards ARDS14. This stage of the disease is characterized by high levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6), IL-1β, IL-18 and granulocyte–macrophage colony-stimulating factor (GM–CSF)2,15,16,17. This event has been referred to as a cytokine storm18,19, although recent evidence suggests that cytokine levels in patients with COVID-19 are lower than those reported in patients with non-COVID-19 ARDS, sepsis, influenza virus infection and chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome20,21. SARS-CoV-2 has been shown to trigger the IL-1/IL-6 pathway to a larger extent than other coronaviruses22. Through the analysis of lungs of patients who died from COVID-19-related ARDS, SARS-CoV-2 was found to activate the NLRP3 inflammasome23,24. In vitro studies also showed NLRP3 inflammasome activation by SARS-CoV-2 infection of primary human monocytes. In addition, NLRP3 inflammasome products, such as IL-1β and IL-18, are increased in patients with severe COVID-19 and positively correlated with adverse clinical outcomes24. These findings support a potential relationship between SARS-CoV-2 infection and inflammatory features, such as the dysregulated cytokine response.

Increased levels of ferritin have also been observed among patients with COVID-19, similar to what is observed in macrophage activation syndrome16,19,25. Even though ferritin levels observed in macrophage activation syndrome are markedly higher than those currently observed in COVID-19 (≥10,000–100,000 ng ml–1 versus 500–3,000 ng ml–1), ferritin levels remain predictive of poor outcomes in COVID-19 (refs26,27).

With regard to inflammatory cells, large numbers of CD68+ macrophages were observed in the alveoli of patients who died from COVID-19-associated pneumonia, and SARS-CoV-2 proteins were detected in CD68+ alveolar macrophages28,29. Analysis of the bronchoalveolar fluid of patients with severe or critical COVID-19 showed a higher percentage of macrophages and neutrophils and a lower proportion of myeloid dendritic cells, plasmacytoid dendritic cells and T cells than that of patients with moderate disease30. They also had higher levels of pro-inflammatory cytokines (such as IL-6, IL-8 and IL-1β) and chemokines (such as CCL2, CCL3, CCL4 and CCL7) in the bronchoalveolar fluid30. These data suggest that lung macrophages contribute to inflammatory responses in SARS-CoV-2 infection, favouring excessive inflammation in severe pneumonia. Similar to other respiratory infections, leukocyte recruitment to the lungs is finely tuned by specific molecules31, the uncontrolled activity of which may result in complications observed in patients with COVID-19 in both the lungs and other organs5,32.

COVID-19-associated coagulopathy

An important pathophysiological feature of COVID-19 is the development of a prothrombotic state. The occurrence of a COVID-19-specific coagulopathy is suggested by elevated levels of fibrinogen, von Willebrand factor (VWF) and the fibrin degradation product D-dimer in the blood, whereas patients generally show minor or no changes in prothrombin time (a measure of time to clot), activated partial thromboplastin time (coagulation time), antithrombin levels, activated protein C levels and platelet count33,34,35,36. These features are more consistent with a state of hypercoagulability coupled with a severe inflammatory state rather than with classical disseminated intravascular coagulation (DIC)36. Indeed, DIC has been reported in a few patients, usually in the advanced stages of the disease33,37,38. Recently, low antithrombin levels were linked to poor outcomes in COVID-19, especially among patients with obesity39. Hence, it is possible that antithrombin activity changes as SARS-CoV-2 infection worsens and a putative mechanism might be the cytokine-driven imbalance in endogenous anticoagulant levels40. In macrophage activation syndrome, liver function impairment is a typical feature and may contribute to coagulopathy, yet liver impairment in COVID-19 is usually mild and transient, without overt acute liver injury41,42.

Apart from a state of hypercoagulability in MobaXterm 21 Crack + Serial Key Free Download 2021 lungs of patients with ARDS, a hypofibrinolytic state in the alveolar space was observed in COVID-19-related ARDS due to increased levels of fibrinolytic inhibitors43. Accordingly, high levels of plasminogen activator inhibitor 1 (PAI1) were described in patients with SARS-CoV44.

In order to properly identify COVID-19-associated coagulopathy, Iba et al. proposed the occurrence of two or more of the following four criteria in cases of proven COVID-19: a decrease in platelet count (<150 × 109 l–1); an increase in D-dimer levels (more than two times the upper limit of normal); prothrombin time >1 s or international normalized ratio >1.2; and the presence of thrombosis (macrothrombosis and/or microthrombosis)45. The risk of COVID-19-associated coagulopathy is defined by one of the aforementioned four criteria and one of the following ones: increased fibrinogen levels; increased VWF levels (more than two times the upper normal limit); or the presence of lupus anticoagulant and/or high-titre antiphospholipid antibodies45. Importantly, COVID-19-associated coagulopathy and risk of COVID-19-associated coagulopathy may further progress and/or predispose to DIC as COVID-19 severity increases.

COVID-19-associated endothelial dysfunction

Although COVID-19 should be regarded as a systemic disease, it acutely causes a lung-centred injury primarily affecting the vascular endothelium. COVID-19-associated pneumonia is characterized by infiltration of the lungs with macrophages and neutrophils that cause diffuse lung alveolar damage, the histological equivalent of ARDS46,47,48. Similar findings were previously reported in patients with SARS-CoV49. However, the striking finding in COVID-19 compared with SARS-CoV is the more extensive viral infection within the lungs, which results in more diffuse inflammation involving the pulmonary vessels50. This extensive infection reflects the particular tropism of SARS-CoV-2 for angiotensin-converting enzyme 2 (ACE2) — the cellular receptor for SARS-CoV-2 — expressed by type II pneumocytes51, which are anatomically close to the lung vascular network and are typically described to be hyperplasic in samples from patients with COVID-19 (refs52,53,54). This hyperplasia of endothelial cells is likely to be caused by lung tissue ischaemia due to congestion of small vessels by inflammatory cells (that is, immunothrombosis) and thrombosis in large vessels55.

Endothelial dysfunction was suggested to be an important pathophysiological event in infections by other coronaviruses, which can directly infect endothelial cells56,57,58,59. SARS-CoV-2 directly infects vascular endothelial cells and leads to cellular damage and apoptosis, thus decreasing the antithrombotic activity of the normal endothelium7,55. Alveolar damage, vessel wall oedema, hyaline thrombi, microhaemorrhage and diffuse thrombosis of peripheral small vessels have emerged as key features of COVID-19 contributing to respiratory failure6,8,46 (Fig. 2).

A

Windows 10

Personal computer operating system by Microsoft released in 2015

This article is about the operating system for personal computers. For the related (now discontinued) operating system for mobile devices, see Windows 10 Mobile.

Not to be confused with Windows 1.0.

Windows 10 Logo.svg
Windows 10 Home Version 21H1 Desktop.png

Screenshot of Windows 10 version 21H1, showing the Start Menu and Action Center in light theme

DeveloperMicrosoft
Written in
OS familyMicrosoft Windows
Source model
Released to
manufacturing
July 15, 2015; 6 years ago (2015-07-15)
General
availability
July 29, 2015; 6 years ago (2015-07-29)
Latest release10.0.19044.1348 (November 16, 2021; 1 day ago (2021-11-16)[5]) [±]
Latest preview10.0.19044.1379 (November 16, 2021; 1 day ago (2021-11-16)[6]) [±]
Marketing targetPersonal computing
Available in110 languages[7][8] (Specific language packs included on the device depend on the mobile operator (for cellular connected devices) or device manufacturer. Additional language packs are available for download on the Microsoft Store, pursuant to manufacturer and carrier support.)

List of languages

Update method
PlatformsIA-32, x86-64, ARMv7,[9][10]ARM64[11][12][13]
Kernel typeHybrid (Windows NT kernel)
UserlandNative API
Windows API
.NET Framework
Universal Windows Platform
Windows Subsystem for Linux
NTVDM (IA-32 only)
Default
user interface
Windows shell (graphical)
LicenseTrialware,[14]Microsoft Software Assurance, MSDN subscription, Microsoft Imagine
Preceded byWindows 8.1 (2013)
Succeeded byWindows 11 (2021)
Official websitewww.microsoft.com/en-us/software-download/windows10
All editions except "Enterprise LTSB/LTSC" are supported until October 14, 2025 as long as they install the latest feature upgrades.[15][16] The Enterprise LTSB/LTSC editions are supported for 10 years after their release date. See § Support lifecycle for details.

Windows 10 is a major release of the Windows NToperating system developed by Microsoft. It is the successor to Windows 8.1, which was released nearly two years earlier, and itself was released to manufacturing on July 15, 2015, and broadly released for the general public on July 29, 2015.[17] Windows 10 was made available for download via MSDN and TechNet, as a free upgrade for retail copies of Windows 8 and Windows 8.1 users via the Windows Store, and to Windows 7 users via Windows Update. Windows 10 receives new builds on an ongoing basis, which are available at no additional cost to users, in addition to additional test builds of Windows 10, which are available to Windows Insiders. Devices in enterprise environments can receive these updates at a slower pace, or use long-term support milestones that only receive critical updates, such as security patches, over their ten-year lifespan of extended support.[18][19]

Windows 10 received generally positive reviews upon its original release. Critics praised Microsoft's decision to provide the desktop-oriented interface in line with previous versions of Windows, contrasting the tablet-oriented approach of Windows 8, although Windows 10's touch-oriented user interface mode was criticized for containing regressions upon the touch-oriented interface of its predecessor. Critics also praised the improvements to Windows 10's bundled software over Windows 8.1, Xbox Live integration, as well as the functionality and capabilities of the Cortana personal assistant and the replacement of Internet Explorer with Microsoft Edge. However, media outlets have been critical of the changes to operating system behaviors, including mandatory update installation, privacy concerns over data collection performed by the OS for Microsoft and its partners, and adware-like tactics used to promote the operating system on its release.[20]

Microsoft initially aimed to have Windows 10 installed on over one billion devices within three years of its release;[18] that goal was ultimately reached almost five years after release on March 16, 2020.[21] By January 2018, Windows 10 surpassed Windows 7 as the most popular version of Windows worldwide.[22] As of June 2021[update], it is estimated that 79% of Windows PCs,[22] 58% of all PCs (the rest being older Windows versions and other operating systems such as macOS and Linux), and 24% of all devices (including mobile, tablet and console)[23] are running Windows 10. On June 24, 2021, Microsoft announced Windows 10's successor, Windows 11, which was released on October 5, 2021.[24]

Windows 10 is the final version of Windows which supports IA-32 and ARMv7-based processors (also known as 32-bit processors). Its successor, Windows 11, requires a 64-bit processor in any supported architecture (x86-64/AMD64 for x86 and ARMv8 for ARM).

Development[edit]

At the Microsoft Worldwide Partner Conference in 2011, Andrew Lees, the chief of Microsoft's mobile technologies, said that the company intended to have a single software ecosystem for PCs, phones, tablets, and other devices: "We won't have an ecosystem for PCs, and one for phones, and one for tablets‍—‌they'll all come together."[25][26]

In December 2013, technology writer Mary Jo Foley reported that Microsoft was working on an update to Windows 8 codenamed "Threshold", after a planet in its Halo franchise.[27] Similarly to "Blue" (which became Windows 8.1),[28] Foley described Threshold, not as a single operating system, but as a "wave of operating systems" across multiple Microsoft platforms and services, quoting Microsoft sources, scheduled for the second quarter of 2015. She also stated that one of the goals for Threshold was to create a unified application platform and development toolkit for Windows, Windows Phone and Xbox One (which all use a similar kernel based on Windows NT).[27][29]

At the Build Conference in April 2014, Microsoft's Terry Myerson unveiled an updated version of Windows 8.1 (build 9697) that added the ability to run Windows Store apps inside desktop windows and a more traditional Start menu in place of the Start screen seen in Windows 8. The new Start menu takes after Windows 7's design by using only a portion of the screen and including a Windows 7-style application listing in the first column. The second column displays Windows 8-style app tiles. Myerson said that these changes would occur in a future update, but did not elaborate.[30][31] Microsoft also unveiled the concept of a "universal Windows app", allowing Windows Store apps created for Windows 8.1 to be ported to Windows Phone 8.1 and Xbox One while sharing a common codebase, with an interface designed for different device form factors, and allowing user data and licenses for an app to be shared between multiple platforms. Windows Phone 8.1 would share nearly 90% of the common Windows Runtime APIs with Windows 8.1 on PCs.[30][32][33][34]

Screenshots of a Windows build purported to be Threshold were leaked in July 2014, showing the previously presented Start menu and windowed Windows Store apps,[35] followed May 21 a further screenshot of a build identifying itself as "Windows Technical Preview", numbered 9834, in September 2014, showing a new virtual desktop system, a notification center, and a new File Explorer icon.[36]

Announcement[edit]

"Windows 9" redirects here. For the Windows versions produced from 1995 to 2000, see Windows 9x.

On September 30, 2014, Microsoft officially announced that Threshold would be unveiled during a media event as Windows 10. Myerson said that Windows 10 would be Microsoft's "most comprehensive platform ever", providing a single, unified platform for desktop and laptop computers, tablets, smartphones, and all-in-one devices.[37][38][39] He emphasized that Windows 10 would take steps towards restoring user interface mechanics from Windows 7 to improve the experience for users on non-touch devices, noting criticism of Windows 8's touch-oriented interface by keyboard and mouse users.[40][41] Despite these concessions, Myerson noted that the touch-optimized interface would evolve as well on 10.[42]

In regards to Microsoft naming the new operating system Windows 10 instead of Windows 9, Terry Myerson said that "based on the product that's coming, and just how different our approach will be overall, it wouldn't be right to call it Windows 9."[43] He also joked that they could not call it "Windows One" (alluding to several recent Microsoft products with a similar brand, such as OneDrive, OneNote, and the Xbox One) because Windows 1.0 already existed.[44] At a San Francisco conference in October 2014, Tony Prophet, Microsoft's Vice President of Windows Marketing, said that Windows 9 "came and went", and that Windows 10 would not be "an incremental step from Windows 8.1," but "a material step. We're trying to create one platform, one eco-system that unites as many of the devices from the small embedded Internet of Things, through tablets, through phones, through PCs and, ultimately, into the Xbox."

Further details surrounding Windows 10's consumer-oriented features were presented during another media event held on January 21, 2015, entitled "Windows 10: The Next Chapter". The keynote featured the unveiling of Cortana integration within the operating system, new Xbox-oriented features, Windows 10 Mobile, an updated Office Mobile suite, Surface Hub‍—‌a large-screened Windows 10 device for enterprise collaboration based upon Perceptive Pixel technology,[46] along with HoloLens‑augmented reality eyewear and an associated platform for building May 21 that can render holograms through HoloLens.[47]

Additional developer-oriented details surrounding the "Universal Windows Platform" concept were revealed and discussed during Microsoft's Build developers' conference. Among them were the unveiling of "Islandwood", which provides a middlewaretoolchain for compiling Objective-C-based software (particularly iOS) to run as universal apps on Windows 10 and Windows 10 Mobile. A port of Candy Crush Saga made using the toolkit, which shared much of its code with the iOS version, was demonstrated, alongside the announcement that the King-developed game would be bundled with Windows 10 at launch.[48][49][50][51]

At the 2015 Ignite conference, Microsoft employee Jerry Nixon stated that Windows 10 would be the "last version of Windows", a statement that Microsoft confirmed was "reflective" of its Acme CAD Converter Free Download of the operating system being a "service" with new versions and updates to be released over time.[52][53][54] In 2021, however, Microsoft announced that Windows 10 would be succeeded on compatible hardware by Windows 11–and that Windows 10 support will end on October 14, 2025.[55][56]

Release and marketing[edit]

On June 1, 2015, Microsoft announced that Windows 10 would be released on July 29.[17] On July 20, 2015 Microsoft began "Upgrade Your World", an advertising campaign centering on Windows 10, with the premiere of television commercials in Australia, Canada, France, Germany, Japan, the United Kingdom, and the United States. The commercials focused on the tagline "A more human way to do", emphasizing new features and technologies supported by Windows 10 that sought to provide a more "personal" experience to users.[57][58] The campaign culminated with launch events in thirteen cities on July 29, 2015, which celebrated "the unprecedented role our biggest fans played in the development of Windows 10".[59]

Features[edit]

Main article: Features new to Windows 10

See also: List of features removed in Windows 10

Windows 10 makes its user experience and functionality more consistent between different classes of device and addresses most of the shortcomings in the user interface that were introduced in Windows 8.[40][41][60]Windows 10 Mobile, the successor to Windows Phone 8.1, shared some user interface elements and apps with its PC counterpart.[61]

Windows 10 supports universal apps, an expansion of the Metro-style first introduced in Windows 8. Universal apps can be designed to run across multiple Microsoft product families with nearly identical code‍—‌including PCs, tablets, smartphones, embedded systems, Xbox One, Surface Hub and Mixed Reality. The Windows user interface was revised to handle transitions between a mouse-oriented interface and a touchscreen-optimized interface based on available input devices‍—‌particularly on 2-in-1 PCs, both interfaces include an updated Start menu which incorporates elements of Windows 7's traditional Start menu with the tiles of Windows 8. Windows 10 also introduced the Microsoft Edgeweb browser, a virtual desktop system, a window and desktop management feature called Task View, support for fingerprint and face recognition login, new security features for enterprise environments, and DirectX 12.

The Windows Runtime app ecosystem was revised into the Universal Windows Platform (UWP).[32][62][63] These universal apps are made to run across multiple platforms and device classes, including smartphones, tablets, Xbox One consoles, and other devices compatible with Windows 10. Windows apps share code across platforms, have responsive designs that adapt to the needs of the device and available inputs, can synchronize data between Windows 10 devices (including notifications, credentials, and allowing cross-platform multiplayer for games), and are distributed through the Microsoft Store (rebranded from Windows Store since September 2017).[64] Developers can allow "cross-buys", where purchased licenses for an app apply to all of the user's compatible devices, rather than only the one they purchased on (e.g., a user purchasing an app on PC is also entitled to use the smartphone version at no extra cost).[33][65][66]

The ARM version of Windows 10 allows running applications for x86 processors through 32-bit software emulation.[67]

On Windows 10, Microsoft Store serves as a unified storefront for apps, video content, and eBooks.[68] Windows 10 also allows web apps and desktop software (using either Win32 or .NET Framework) to be packaged for distribution on Microsoft Store. Desktop software distributed through Windows Store is packaged using the App-V system to allow sandboxing.[69][70]

User interface and desktop[edit]

The "Task View" display is a new feature to Windows 10, allowing the use of multiple workspaces.

A new iteration of the Start menu is used on the Windows 10 desktop, with a list of places and other options on the left side, and tiles representing applications on the right. The menu can be resized, and expanded into a full-screen display, which is the default option in Tablet mode.[40][60][71] A new virtual desktop system was added by a feature known as Task View, which displays all open windows and allows users to switch between them, or switch between multiple workspaces.[40][60] Universal apps, which previously could be used only in full screen mode, can now be used in self-contained windows similarly to other programs.[40][60] Program windows can now be snapped to quadrants of the screen by dragging them to the corner. When a window is snapped to one side of the screen, Task View appears and the user is prompted to choose a second window to fill the unused side of the screen (called "Snap Assist").[60] The Windows system icons were also changed.[71]

Charms have been removed; their functionality in universal apps is accessed from an App commands menu on their title bar.[40][60] In its place is Action Center, which displays notifications and settings toggles. It is accessed by clicking an icon in the notification area, or dragging from the right of the screen. Notifications can be synced between multiple devices.[61][71] The Settings app (formerly PC Settings) was refreshed and now includes more options that were previously exclusive to the desktop Control Panel.

Windows 10 is designed to adapt its user interface based on the type of device being used and available input methods. It offers two separate user interface modes: a user interface optimized for mouse and keyboard, and a "Tablet mode" designed for touchscreens. Users can toggle between these two modes at any time, and Windows can prompt or automatically switch when certain events occur, such as disabling Tablet mode on a tablet if a keyboard or mouse is plugged in, or when a 2-in-1 PC is switched to its laptop state. In Tablet mode, programs default to a maximized view, and the taskbar contains a back button and hides buttons for opened or pinned programs by default; Task View is used instead to switch between programs. The full screen Start menu is used in this mode, similarly to Windows 8, but scrolls vertically instead of horizontally.[41][74][75][76]

System security[edit]

Windows 10 incorporates multi-factor authentication technology based upon standards developed by the FIDO Alliance.[77] The operating system includes improved support for biometric authentication through the Windows Hello platform. Devices with supported cameras (requiring infrared illumination, such as Intel RealSense) allow users to log in with iris or face recognition, similarly to Kinect. Devices with supported readers allow users to log in through fingerprint recognition. Support was also added for palm-vein scanning through a partnership with Fujitsu in February 2018.[78] Credentials are stored locally and protected using asymmetric encryption.[79]

In 2017, researchers demonstrated that Windows Hello could be bypassed on fully-updated Windows 10 1703 with a color printout of a person's picture taken with an IR camera.[80] In 2021, researchers were again able to bypass the Windows Hello functionalities by using custom hardware disguised as a camera, which presented an IR photo of the owner's face.[81]

In addition to biometric authentication, Windows Hello supports authentication with a PIN. By default, Windows requires a PIN to consist of four digits, but can be configured to permit more complex PINs. However, a PIN is not a simpler password. While passwords are transmitted to domain controllers, PINs are not. They are tied to one device, and if compromised, only one device is affected. May 21 by a Trusted Platform Module (TPM) chip, Windows uses PINs to create strong asymmetric key pairs. As such, the authentication token transmitted to the server is harder to crack. In addition, whereas weak passwords may be broken via rainbow tables, TPM causes the much-simpler Windows PINs to be resilient to brute-force attacks.[82]

When Windows 10 was first introduced, multi-factor authentication was provided by two components: Windows Hello and Passport (not to be confused with the Passport platform of 1998). Later, Passport was merged into Windows Hello.[83][79]

The enterprise edition of Windows 10 offers additional security features; administrators can set up policies for the automatic encryption of sensitive data, selectively block applications from accessing encrypted data, and enable Device Guard‍—‌a system which allows administrators to enforce a high-security environment by blocking the execution of software that is not digitally signed by a trusted vendor or Microsoft. Device Guard is designed to protect against zero-day exploits, and runs inside a hypervisor so that its operation remains separated from the operating system itself.[77][84]

Command line[edit]

The console windows based on Windows Console (for any console app, not just PowerShell and Windows Command Prompt) can now be resized without any restrictions, can be made to cover the full screen by pressing +, and can use standard keyboard shortcuts, such as those for cut, copy, and paste. Other features such as word wrap and transparency were also added. These functions can be disabled to revert to the legacy console if needed.[85]

The Anniversary Update added Windows Subsystem for Linux (WSL), which allows the installation of a user space environment from a supported Linuxdistribution that runs natively on Windows. The subsystem translates Linux system calls to those of the Windows NT kernel (only claims full system call compatibility as of WSL 2, included in a later Windows update). The environment can execute the Bash shell and 64-bit command-line programs (WSL 2 also supports 32-bit Linux programs and graphics, assuming supporting software installed,[86] and GPUs support for other uses[87]). Windows applications cannot be executed from the Linux environment, and vice versa. Linux distributions for Windows Subsystem for Linux are obtained through Microsoft Store. The feature initially supported an Ubuntu-based environment; Microsoft announced in May 2017 that it would add Fedora and OpenSUSE environment options as well.[88][89][90][91][92][93][94]

Storage requirements[edit]

To reduce the storage footprint of the operating system, Windows 10 automatically compresses system files. The system can reduce the storage footprint of Windows by approximately 1.5 GB for 32-bit systems and 2.6 GB for 64-bit systems. The level of compression used is dependent on a performance assessment performed during installations or by OEMs, which tests how much compression can be used without harming operating system performance. Furthermore, the Refresh and Reset functions use runtime system files instead, making a separate recovery partition redundant, allowing patches and updates to remain installed following the operation, and further reducing the amount of space required for Windows 10 by up to 12 GB. These functions replace the WIMBoot mode introduced on Windows 8.1 Update, which allowed OEMs to configure low-capacity devices with flash-based storage to use Windows system files out of the compressed WIM image typically used for installation and recovery.[95][96][97] Windows 10 also includes a function in its Settings app that allows users to view a breakdown of how their device's storage capacity is being used by different types of files, and determine whether certain types of files are saved to internal storage or an SD card by default.[98]

Online services and functionality[edit]

Windows 10 introduces Microsoft Edge, a new default web browser. It initially featured a new standards-compliant rendering engine derived from Trident, and also includes annotation tools and integration with other Microsoft platforms present within Windows 10.[99][100][101] Internet Explorer 11 is maintained on Windows 10 for compatibility purposes, but is deprecated in favor of Edge and will no longer be actively developed.[102][103] In January 2020, the initial version of Edge was succeeded by a new iteration derived from the Chromium project and the Blink layout engine and the old Edge based on EdgeHTML is now called 'Microsoft Edge Legacy'.[104] The legacy version of Edge is currently being replaced by the new Chromium-based Edge via Windows Update, though this version can also be downloaded manually. Every Windows 10 version from 20H2, which was released on October 20, 2020, will come with the new version of the browser preinstalled.[105] The Windows 10 October 2020 update added a price comparison tool to the Edge browser.[106]

Windows 10 incorporates a universal search box located alongside the Start and Task View buttons, which can be hidden or condensed into a single button.[107][108] Previous versions featured Microsoft's intelligent personal assistant Cortana, which was first introduced with Windows Phone 8.1 in 2014, and supports both text and voice input. Many of its features are a direct carryover from Windows Phone, including integration with Bing, setting reminders, a Notebook feature for managing personal information, as well as searching for files, playing music, launching applications and setting reminders or sending emails.[109][110][71] Since the November 2019 update, Microsoft has begun to downplay Cortana as part of a repositioning of the product towards enterprise use, with the May 2020 update removing its Windows shell integration and consumer-oriented features.[111][112][107][113]

Microsoft Family Safety is replaced by Microsoft Family, a parental controls system that applies across Windows platforms and Microsoft online services. Users can create a designated family, and monitor and restrict the actions of users designated as children, such as access to websites, enforcing age ratings on Microsoft Store purchases, and other restrictions. The service can also send weekly e-mail reports to parents detailing a child's computer usage. Unlike previous versions of Windows, child accounts in a family must be associated with a Microsoft account‍—‌which allows these settings to apply across all Windows 10 devices that a particular child is using.[114][115]

Windows 10 also offers the Wi-Fi Sense feature originating from Windows Phone 8.1; users can optionally have their device automatically connect to suggested open hotspots, and share their home network's password with contacts (either via Skype, People, or Facebook) so they may automatically connect to the network on a Windows 10 device without needing to manually enter its password. Credentials are stored in an encrypted form on Microsoft servers and sent to the devices of the selected contacts. Passwords are not viewable by the guest user, and the guest user is not allowed to access other computers or devices on the network. Wi-Fi Sense is not usable on 802.1X-encrypted networks. Adding "_optout" at the end of the SSID will also block the corresponding network from being used for this feature.[116]

Universal calling and messaging apps for Windows 10 are built in as of the November 2015 update: Messaging, Skype Video, and Phone. These offer built-in alternatives to the Skype download and sync with Windows 10 Mobile.[117][118]

Multimedia and gaming[edit]

See also: List of Xbox Live Games on Windows 10

Windows 10 provides greater integration with the Xbox ecosystem. Xbox SmartGlass is succeeded by the Xbox Console Companion (formerly the Xbox app), which allows users to browse their game library (including both PC and Xbox console games), and Game DVR is also available using a keyboard shortcut, allowing users to save the last 30 seconds of gameplay as a video that can be shared to Xbox Live, OneDrive, or elsewhere.[119][120] Windows 10 also allows users to control and play games from an Xbox One console over a local network.[121] The Xbox Live SDK allows application developers to incorporate Xbox Live functionality into their apps, and future wireless Xbox One accessories, such as controllers, are supported on Windows with an adapter.[122] Microsoft also intends to allow cross-purchases and save synchronization between Xbox One and Windows 10 versions of games; Microsoft Studios games such as ReCore and Quantum Break are intended as being exclusive to Windows 10 and Xbox One.[123]

Candy Crush Saga and Microsoft Solitaire Collection are also automatically installed upon installation of Windows 10.[124][125]

Windows 10 adds native game recording and screenshot capture ability using the newly introduced Game Bar. Users can also have the OS continuously record gameplay in the background, which then allows the user to save the last few moments of gameplay to the storage device.[126]

Windows 10 adds FLAC and HEVC codecs and support for the Matroska media container, allowing these formats to be opened in Windows Media Player and other applications.[127][128][129]

DirectX 12[edit]

Windows 10 includes DirectX 12, alongside WDDM 2.0.[130][131] Unveiled March 2014 at GDC, DirectX 12 aims to provide "console-level efficiency" with "closer to the metal" access to hardware resources, and reduced CPU and graphics driver overhead.[132][133] Most of the performance improvements are achieved through low-level programming, which allow developers to use resources more efficiently and reduce single-threaded CPU bottlenecking caused by abstraction through higher level APIs.[134][135] DirectX 12 will also feature support for vendor agnostic multi-GPU setups.[136] WDDM 2.0 introduces a new virtual memory management and allocation system to reduce workload on the kernel-mode driver.[130][137]

Fonts[edit]

Main article: List of typefaces included with Microsoft Windows

Windows 10 adds three new default typefaces compared to Windows 8, but removes dozens of others. The removed typefaces are available in supplemental packs and may be added manually over a non-metered internet connection.

Editions and pricing[edit]

Main article: Windows 10 editions

Windows 10 is available in five main editions for personal computing devices; the Home and Pro editions of which are sold at retail in most countries, and as pre-loaded software on new computers. Home is aimed at home users, while Pro is aimed at power users and small businesses. Each edition of Windows 10 includes all of the capabilities and features of the edition below it, and add additional features oriented towards their market segments; for example, Pro adds additional networking and security features such as BitLocker, Device Guard, Windows Update for Business, and the ability to join a domain. Enterprise and Education, the other editions, contain additional features aimed towards business environments, and are only available through volume licensing.[138][139]

As part of Microsoft's unification strategies, Windows products that are based on Windows 10's common platform but meant for specialized platforms are marketed as editions of the operating system, rather than as separate product lines. An updated version of Microsoft's Windows Phone operating system for smartphones, and also tablets, was branded as Windows 10 Mobile.[140] Editions of Enterprise and Mobile will also be produced for embedded systems, along with Windows 10 IoT Core, which is designed specifically for use in small footprint, low-cost devices and Internet of Things (IoT) scenarios and is similar to Windows Embedded.[138][139]

On May 2, 2017, Microsoft unveiled Windows 10 S (referred to in leaks as Windows 10 Cloud), a feature-limited edition of Windows 10 which was designed primarily for devices in the education market (competing, in particular, with Chrome OS netbooks), such as the Surface Laptop that Microsoft also unveiled at this time. The OS restricts software installation to applications obtained from Microsoft Store; the device may be upgraded to Windows 10 Pro for a fee to enable unrestricted software installation. As a time-limited promotion, Microsoft stated that this upgrade would be free on the Surface Laptop until March 31, 2018.[141] Windows 10 S also contains a faster initial setup and login process, and allows devices to be provisioned using a USB drive with the Windows Intune office home and business 2019 - Crack Key For U Education platform.[142][143][144][145][146] In March 2018, Microsoft announced that Windows 10 S would be deprecated because of market confusion and would be replaced by "S Mode", an OEM option wherein Windows defaults to only allowing applications to be installed from Microsoft Store, but does not require payment in order to disable these restrictions.[147][148]

Preview releases[edit]

See also: Windows Insider

A public beta program for Windows 10 known as the Windows Insider Program began with the first publicly available preview release on October 1, 2014. Insider preview builds are aimed towards enthusiasts and enterprise users for the testing and evaluation of updates and new features.[149] Users of the Windows Insider program receive occasional updates to newer preview builds of the operating system and will continue to be able to evaluate preview releases after general availability (GA) in July 2015‍—‌this is in contrast to previous Windows beta programs, where public preview builds were released less frequently and only during the months preceding GA.[40][42][150][151][152] Windows Insider builds continued being released after the release to manufacturing (RTM) of Windows 10.[153]

Public release[edit]

On July 29, 2015, Microsoft officially announced that Windows 10 would be released for retail purchase as a free IES VisualAnalysis License key from earlier versions of Windows. In comparison to previous Windows releases, which had a longer turnover between the release to manufacturing (RTM) and general release to allow for testing by vendors (and in some cases, the development of "upgrade kits" to prepare systems for installation of the new version), an HP executive explained that because it knew Microsoft targeted the operating system for a 2015 release, the company was able to optimize its then-current and upcoming products amibroker login - Activators Patch Windows 10 in advance of its release, negating the need for such a milestone.[155][better source needed]

The general availability build of Windows 10, numbered 10240, was first released to Windows Insider channels for pre-launch testing on July 15, 2015, prior to its formal release.[156] Although a Microsoft official said there would be no specific RTM build of Windows 10, 10240 was described as an RTM build by media outlets because it was released to all Windows Insider members at once (rather than to users on the "Fast ring" first), it no longer carried pre-release branding and desktop watermark text, and its build number had mathematical connections to the number 10 in reference to the operating system's naming.[158][159][160][161][162][163] The Enterprise edition was released to volume licensing on August 1, 2015.[164]

Windows 10 is distributed digitally through the "Media Creation Tool", which is functionally identical to the Windows 8 online installer, and can also be used to generate an ISO image or USB install media.[165] In-place upgrades are supported from most editions of Windows 7 with Service Pack 1 and Windows 8.1 with Update 1, while users with Windows 8 must first upgrade to Windows 8.1. Changing between architectures (e.g., upgrading from 32-bit edition to a 64-bit editions) via in-place upgrades is not supported; a clean install is required.[166][167] In-place upgrades may be rolled back to the device's previous version of Windows, provided that 30 days have not passed since installation, and backup files were not removed using Disk Cleanup.

Windows 10 was available in 190 countries and 111 languages upon its launch, and as part of efforts to "re-engage" with users in China, Microsoft also announced that it would partner with Qihoo and Tencent to help idm crack 6.35 with 32bit+64bit patch latest - Activators Patch and distribute Windows 10 in China, and that Chinese PC maker Lenovo would provide assistance at its service centers and retail outlets for helping users upgrade to Windows 10.[168][169][170] At retail, Windows 10 is priced similarly to editions of Windows 8.1, with U.S. prices set at $119 and $199 for Windows 10 Home and Pro respectively. A Windows 10 Pro Pack license allows upgrades from Windows 10 Home to Windows 10 Pro.[171][172] Retail copies only ship on USB flash drive media; however, system builder copies still ship as DVD-ROM media.[173] New devices shipping with Windows 10 were also released during the operating system's launch window.[174]

Windows RT devices cannot be upgraded to Windows 10.[167][175]

Free upgrade offer[edit]

Main article: Windows 10 editions § Free upgrade

During its first year of availability,[176] upgrade licenses for Windows 10 could be obtained at no charge for devices with a genuine license for an eligible edition of Windows 7 or 8.1.[172][177][178]

This offer did not apply to Enterprise editions, as customers under an active Software Assurance (SA) contract with upgrade rights are entitled to obtain Windows 10 Enterprise under their existing terms. All users running non-genuine copies of Windows, and those without an existing Windows 7 or 8 license, were ineligible for this promotion; although upgrades from a non-genuine version were possible, they result in a non-genuine copy of 10.[153][168][178][179][180]

On the general availability build of Windows 10 (version 1507), to activate and generate the "digital entitlement" for Windows 10, the operating system must have first been installed as an in-place upgrade. During the free upgrade, a file is created in the background and the system's motherboard details are registered with a Microsoft Product Activation server. Once installed, the operating system can be reinstalled on that particular system via normal means without a product key, and the system's license will automatically be detected via online activation - in essence, the Microsoft Product Activation Server will remember the system's motherboard and give it the green light for product re-activation.[166][181][182] Because of installation issues with Upgrade Only installs, the November Update (version 1511) included additional activation mechanisms. This build treated Windows 7 and Windows 8/8.1 product keys as Windows 10 product keys, meaning they could be entered during installation to activate the free license, without the need to upgrade first to "activate" the hardware with Microsoft's activation servers.[183] For major Original Equipment Manufacturers (OEMs), Windows 8/8.1 and Windows 10 OEM product keys are embedded in the firmware of the motherboard and if the correct edition of Windows 10 is present on the installation media, they are automatically inputted during installation. Since the release of the Fall Creators Update (version 1709), Microsoft decided to release multi-edition installation media, to alleviate installation and product activation issues users experienced because of accidentally installing the wrong edition of Windows 10.

The Windows Insider Preview version of Windows 10 automatically updated itself to the generally released version as part of the version progression and continues to be updated to new beta builds, as it had throughout the testing process. Microsoft explicitly stated that Windows Insider was not a valid upgrade path for those running a version of Windows that is ineligible for the upgrade offer; although, if it was not installed with a license carried over from an in-place upgrade to 10 Insider Preview from Windows 7 or 8, the Insider Preview does remain activated as long as the user does not exit the Windows Insider program.[153]

The offer was promoted and delivered via the "Get Windows 10" application (also known as GWX), which was automatically installed via Windows Update ahead of Windows 10's release, and activated on systems deemed eligible for the upgrade offer. Via a notification area icon, users could access an application that advertised Windows 10 and the free upgrade offer, check device compatibility, and "reserve" an automatic download of the operating system upon its release.[184][185] On July 28, a pre-download process began in which Windows 10 installation files were downloaded to some computers that had reserved it. Microsoft said that those who reserved Windows 10 would be able to install it through GWX in a phased rollout process. The operating system could alternatively be downloaded at any time using a separate "Media Creation Tool" setup program, that allows for the creation of DVD or USB installation media.[165][174][186][187]

In May 2016, Microsoft announced that the free upgrade offer would be extended to users of assistive technologies; however, Microsoft did not implement any means of certifying eligibility for this offer, which some outlets thereby promoted as being a loophole to fraudulently obtain a free Windows 10 upgrade. Microsoft said that the loophole is not intended to be used in this manner.[188][189][190] In November 2017, Microsoft announced that this program would end on December 31, 2017.[191]

However, another loophole was found that allowed Windows 7 and 8.1 users upgrade to Windows 10 using existing licenses, even though the free upgrade offers officially ended in 2017. No word from Microsoft was given whether it will be closed[192] and some outlets have continued to promote it as a free method of upgrading from the now-unsupported Windows 7.[193]

Licensing[edit]

During upgrades, Windows 10 licenses are not tied directly to a product key. Instead, the license status of the system's current installation of Windows is migrated, and a "Digital license" ( known as "Digital entitlement" in version 1511 or earlier) is generated during the activation process, which is bound to the hardware information collected during the process. If Windows 10 is reinstalled cleanly and there have not been any significant hardware changes since installation (such as a motherboard change), the online activation process will automatically recognize the system's digital entitlement if no product key is entered during installations. However, unique product keys are still distributed within retail copies of Windows 10. As with previous non-volume-licensed variants of Windows, significant hardware changes will invalidate the digital entitlement, and require Windows to be re-activated.[166][181]

Updates 2021 - Free Activators support[edit]

Main article: Windows 10 version history

Unlike previous versions of Windows, Windows Update does not allow the selective installation of updates, and all updates (including patches, feature updates, and driver software) are downloaded and installed automatically. Users can only choose whether their system will reboot automatically to install updates when the system is inactive, or be notified to schedule a reboot.[194][195] If a wireless network is designated as "Metered"—a function which automatically reduces the operating system's background network activity to conserve limits on Internet usage—most updates are not downloaded until the device is connected to a non-metered network. Version 1703 allows wired (Ethernet) networks to be designated as metered, but Windows may still download certain updates while connected to a metered network.[196][197]

In version 2004, by installing the August 2020 security update and later versions, driver and non-security updates pushed via Windows Update that are considered optional are no longer automatically downloaded and installed in their devices. Users can access them on Settings > Update & Security > Windows Update > View optional update.[198]

Updates can cause compatibility or other problems; a Microsoft troubleshooter program allows bad updates to be uninstalled.[199][200]

Under the Windows end-user license agreement, users consent to the automatic installation of all updates, features and drivers provided by the service, and implicitly consent "without any additional notice" to the possibility of features being modified or removed.[201][202][203] The agreement also states, specifically for users of Windows 10 in Canada, that they may pause updates by disconnecting their device from the Internet.[204]

Windows Update can also use a peer to peer system for distributing updates; by default, users' bandwidth is used to distribute previously downloaded updates to other users, in combination with Microsoft servers. Users can instead choose to only use peer-to-peer updates within their local area network.[205]

Support lifecycle[edit]

Mainstream supportVaries by version[206][207]
Extended supportOctober 14, 2025 (2025-10-14)[206][207]
Home, Pro, Pro for Workstations, S, Education, Pro Education, Enterprise, IoT Enterprise, IoT Core, Team, Enterprise 2015 LTSB, and IoT Enterprise 2015 LTSB.[208]
Windows 10 Mobile, Mobile Enterprise, and IoT MobileUnsupported as of January 14, 2020[209]
Windows 10 Enterprise and IoT Enterprise 2016 LTSBMainstream support ended on October 12, 2021[207]
Extended support until October 13, 2026[207]
Windows 10 Enterprise, IoT Enterprise, and IoT Core 2019 LTSCMainstream support until January 9, 2024[207]
Extended support until January 9, 2029[207]
Windows 10 Enterprise 2021 LTSCMainstream support until January 12, 2027[207]
Windows 10 IoT Enterprise and IoT Core 2021 LTSCMainstream support until January 12, 2027[207]
Extended support until January 13, 2032[207]

The original release of Windows 10 receives mainstream support for five years after its original release, followed by five years of extended support, but this is subject to conditions. Microsoft's support lifecycle policy for the operating system notes that "Updates are cumulative, with each update built upon all of the updates that preceded it", that "a device needs to install the latest update to remain supported", and that a device's ability to receive future updates will depend on hardware compatibility, driver availability, and whether the device is within the OEM's "support period"‍—‌a new aspect not accounted for in lifecycle policies for previous versions.[210][178][211][212] This policy was first invoked in 2017 to block Intel Clover Trail devices from receiving the Creators Update, as Microsoft asserts that future updates "require additional hardware support to provide the best possible experience", and that Intel no longer provided support or drivers for the platform. Microsoft stated that these devices would no longer receive feature updates, but would still receive security updates through January 2023.[213] Microsoft will continue to support at least one standard Windows 10 semi-annual channel release until October 14, 2025.[15][16]

The following table collects current status of the aforementioned updating and support of different branches of Windows 10:

Update branchMicrosoft internal channels
(more detail here)
Alpha software
Windows Insider Preview Branch
(WIPB)
Beta software
Semi-Annual Channel
(formerly CB)
"End user"
Long-term Servicing channel
(formerly LTSB)
"Mission critical"
EditionHome  
Pro  
Education  
Enterprise Enterprise LTSC
Critical updates
Security patches and stability updates
Continuous Continuous as made available
(choice of Beta, Dev, or Release Preview channel)
Automatic User can defer updates indefinitely
Feature upgrades
Non-critical functionality and feature updates
Automatic or defer[218]Only through LTSC in-place upgrades
Feature upgrades cadence Continuous Continuous as released Continuous, deferrable for 12 months at a time; once a deferral period is past, no further deferrals possible until latest updates are installed LTSC releases are stable 'snapshots' of SAC
Upgrade support Continuous updating, features come and go silently with new builds Continuous updating or in-place upgrade to supported LTSC builds In-place upgrade support for the three most recent LTSC builds
Update support Only the latest build is supported 10 years (or until future builds require hardware support the old device doesn't have or ~4 months after a missed cumulative update made into SAC.)[210]10 years (or ~6 months from deferring build upgrade or until future builds require hardware support the old device doesn't have.) 5 years (for 21H2 and newer, non IoT) or 5 years mainstream + 5 years extended (for 2019 and older, all IoT versions)
Update methods Windows UpdateWindows Update
Windows Update for Business
Windows Server Update Services

Feature updates[edit]

Windows 10 is often described by Microsoft as being a "service", as it receives regular "feature updates" that contain new features and other updates and fixes.[178][219][220][221] In April 2017, Microsoft stated that these updates would be released twice a year every March and September in the future.[222] Mainstream builds of Windows 10, until and including 2004, were labeled "YYMM", with "YY" representing the two-digit year and "MM" representing the month of release. For example, version 1809 was released in September (the ninth month) of 2018. This was changed with the 20H2 release where "MM" represents the half of the year in which the update was released, for example H1 for the first half and H2 for the second half.[223]

The pace at which feature updates are received by devices is dependent on which release channel is used. The default branch for all users of Windows 10 Home and Pro is "Semi-Annual Channel (Targeted)" (formerly "Current Branch", or "CB"),[221] which receives stable builds after they are publicly released by Microsoft. Each build of Windows 10 is supported for 18 months after its original release.[221] In enterprise environments, Microsoft officially intends that this branch is used for "targeted" deployments of newly-released stable versions so that they can be evaluated and tested on a limited number of devices before a wider deployment. Once a stable build is certified by Microsoft and its partners as being suitable for broad deployment, the build is then released on the "Semi-Annual Channel" (formerly "Current Branch for Business", or "CBB"), which is supported by the Pro and Enterprise editions of Windows 10.[221][195][224] Semi-Annual Channel receives stable builds on a four-month delay from their release on the Targeted channel,[221] Administrators can also use the "Windows Update for Business" system, as well as existing tools such as WSUS and System Center Configuration Manager, to organize structured deployments of feature updates across their networks.[221][195]

The Windows Insider branches receive unstable builds as they are released; it is divided into two channels, "Dev" (which receives new builds immediately after their release), and "Beta" (whose releases are slightly delayed from their "Dev" release).[221]

Enterprise licensees may use the Windows 10 Enterprise LTSC (formerly LTSB) edition, where "LTSC" stands for "long-term servicing channel", which only receive quality of life updates (i.e. security patches), and has a full, 5 or 10-year support lifecycle for each build.[221][224][217] This edition is designed for "special-purpose devices" that perform a fixed function (such as automated teller machines and medical equipment). For this reason, it excludes Cortana, Microsoft Store, and all bundled Universal Windows Platform apps (including but not limited to Microsoft Edge, hence these builds ship only with Internet Explorer as browser).[225][226][221][178][227][228] Microsoft director Stella Chernyak explained that "we have businesses [that] may have mission-critical environments where we respect the fact they want to test and stabilize the environment for a long time."[229] Three LTSC builds have been released, correlating with the 1507, 1607, and 1809 versions of Windows 10, respectively.[230][231]

In July 2017, Microsoft announced changes in the terminology for Windows branches as part of its effort to unify the update cadence with that of Office 365 ProPlus and Windows Server 2016.[232][221] The branch system now defines two paces of upgrade deployment in enterprise environments, "targeted" initial deployment of a new version on selected systems immediately after its stable release for final testing, and "broad" deployment afterwards. Hence, "Current Branch" is now known as "Semi-Annual Channel (Targeted)", and "Current Branch for Business" for broad deployment is now referred to as "Semi-Annual Channel".[233][221]

In February 2019, Microsoft announced changes again in delivering updates in beginning of release of version 1903: a single SAC will be released and SAC-T will be retired, and users are 2021 - Free Activators longer able to switch to different channels. Instead, these updates can be deferred from 30 to 90 days, or depending how the device was configured to deferred the updates.[234] In April 2019, it was announced that, in addition, feature updates will no longer be automatically pushed to users.[235] However after the release of version 2004, the update only pushed for those running a feature update version that is nearing end of service or it can be paused for up to 35 days.[236][237]

Feature updates prior to version 1909 are distributed solely as an in-place upgrade installation, requiring the download of a complete operating system package (approximately 3.5 GB in size for 64-bit systems). Unlike previous builds, version 1909 is designed primarily as an update rollup version of 1903, focusing primarily on minor feature additions and enhancements. For upgrades to 1909 from 1903, a new delivery method is used where its changes were delivered as part of the monthly cumulative update, but are left in a dormant state until the 1909 update "enablement" patch is installed. The full upgrade process is still used for those using builds prior to 1903.[238][239]

Features in development[edit]

In May 2017, Microsoft unveiled Fluent Design System (previously codenamed "Project Neon"), a revamp of Microsoft Design Language 2 that will include guidelines for the designs and interactions used within software designed for all Windows 10 devices and platforms. The new design language will include the more prominent use of motion, depth, and translucency effects. Microsoft stated that the implementation of this design language would be performed over time, and it had already started to implement elements of it in Creators Update and Fall Creators Update.[240]

On December 7, 2016, Microsoft announced that, as part of a partnership with Qualcomm, it planned to introduce support for running Win32 software on ARM architecture with a 32-bit x86 processor emulator, in 2017. Terry Myerson stated that this move would enable the production of Qualcomm Snapdragon-based Windows devices with cellular connectivity and improved power efficiency over Intel-compatible devices, and still capable of running the majority of existing Windows software (unlike the previous Windows RT, which was restricted to Windows Store apps). Microsoft is initially targeting this project towards laptops.[67] Microsoft launched the branding Always Connected PCs in December 2017 to market Windows 10 devices with cellular connectivity, which included two ARM-based 2-in-1 laptops from Asus and HP featuring the Snapdragon 835 system-on-chip, and the announcement of a partnership between AMD and Qualcomm to integrate its Snapdragon X16 gigabit LTE modem with AMD's Ryzen Mobile platform.[241][242]

In August 2019, Microsoft began testing changes to its handling of the user interface on convertible devices—downplaying the existing "Tablet Mode" option in favor of presenting the normal desktop with optimizations for touch when a keyboard is not present, such as increasing the space between taskbar buttons and displaying the virtual keyboard when text fields are selected.[243]

In April 2021, the ability to run Linux applications using a graphical user interface, such as Audacity, directly in Windows, was introduced as a preview.[244] This feature would later be included as part of the updated Windows Subsystem for Linux 2 for Windows 11 only.

System requirements[edit]

The basic hardware requirements to install Windows 10 were initially the same as those for Windows 8.1 and Windows 8, and only slightly higher than for Windows 7 and Windows Vista. As of the May 2019 update, the minimum disk space requirement has been increased to 32 GB. In addition, on new installations, Windows permanently reserves up to 7 GB of disk space in order to ensure proper installation of future feature updates.[246][247]

The 64-bit variants require a CPU that supports certain instructions.[248] Devices with low storage capacity must provide a USB flash drive or SD card with sufficient storage for temporary files during upgrades.[249]

Some pre-built devices may be described as "certified" by Microsoft. Certified tablets must include, and keys; and keys are no longer required.[250]

As with Windows 8, all certified devices must ship with UEFI Secure Boot enabled by default. Unlike Windows 8, OEMs are no longer required to make Secure Boot settings user-configurable, meaning that devices may optionally be locked to run only Microsoft-signed operating systems.[251] A supported infrared-illuminated camera is required for Windows Hello face authentication, and a supported fingerprint reader is required for Windows Hello fingerprint authentication.[177] Device Guard requires a UEFI system with no third-party certificates loaded, and CPU virtualization extensions (including SLAT and IOMMU) enabled in firmware.

Beginning with Intel Kaby Lake and AMD Bristol Ridge, Windows 10 is the only version of Windows that Microsoft will officially support on newer CPU microarchitectures.[252][253] Terry Myerson stated that Microsoft did not want to make further investments in optimizing older versions of Windows and associated software for newer generations of processors.[254][255] These policies were criticized by the media, who especially noted that Microsoft was refusing to support newer hardware (particularly Intel's Skylake CPUs, which was also originally targeted by the new policy with a premature end of support that was ultimately retracted)[256][257] on Windows 8.1, a version of Windows that was still in mainstream support until January 2018.[258][259] In addition, an enthusiast-created modification was released that disabled the check and allowed Windows 8.1 and earlier to continue to work on the platform.[260]

Windows 10 version 1703 and later do not support Intel Clover Trail system-on-chips, per Microsoft's stated policy of only providing updates for devices during their OEM support period.[213][261]

Starting with Windows 10 version 2004, Microsoft will require new OEM devices to use 64-bit processors, and will therefore cease the distribution of x86 (32-bit) variants of Windows 10 via OEM channels. The 32-bit variants of Windows 10 will remain available via non-OEM channels, and Microsoft will continue to "[provide] feature and security updates on these devices".[262] This would later be followed by Windows 11 dropping 32-bit hardware support altogether, and thus making Windows 10 the final version of Windows to have a 32-bit version.[263]

Reception[edit]

Main article: Criticism of Windows 10

Critics characterized the initial release of Windows 10 as being rushed, citing the incomplete state of some of the operating system's bundled software, such as the Edge web browser, as well as the stability of the operating system itself on launch.[264][265][266] However, TechRadar felt that it could be "the new Windows 7", citing the operating system's more familiar user interface, improvements to bundled apps, performance improvements, a "rock solid" search system, and the Settings app being more full-featured than its equivalents on 8 and 8.1. The Edge browser was praised for its performance, although it was not in a feature-complete state at launch. While considering them a "great idea in principle", concerns were shown for Microsoft's focus on the universal app ecosystem:

It's by no means certain that developers are going to flock to Windows 10 from iOS and Android simply because they can convert their apps easily. It may well become a no-brainer for them, but at the moment a conscious decision is still required.[265]

Engadget was similarly positive, noting that the upgrade process was painless and that Windows 10's user interface had balanced aspects of Windows 8 with those of previous versions with a more mature aesthetic. Cortana's always-on voice detection was considered to be its "true strength", also citing its query capabilities and personalization features, but noting that it was not as pre-emptive as Google Now. Windows 10's stock applications were praised for being improved over their Windows 8 counterparts, and for supporting windowed modes. The Xbox app was also praised for its Xbox One streaming functionality, although recommending its use over a wired network because of inconsistent quality over Wi-Fi. In conclusion, it was argued that "Windows 10 delivers the most refined desktop experience ever from Microsoft, and yet it's so much more than that. It's also a decent tablet OS, and it's ready for a world filled with hybrid devices. And, barring another baffling screwup, it looks like a significant step forward for mobile. Heck, it makes the Xbox One a more useful machine."[267]

Ars Technica panned the new Tablet mode interface for removing the charms and app switching, making the Start button harder to use by requiring users to reach for the button on the bottom-left rather than at the center of the screen when swiping with a thumb, and for making application switching less instantaneous through the use of Task View. Microsoft Edge was praised for being "tremendously promising", and "a much better browser than Internet Explorer ever was", but criticized it for its lack of functionality on-launch. In conclusion, contrasting Windows 8 as being a "reliable" platform albeit consisting of unfinished concepts, Windows 10 was considered "the best Windows yet", and was praised for having a better overall concept in its ability to be "comfortable and effective" across a wide array of form factors, but that it was buggier than previous versions of Windows were on-launch.[264]ExtremeTech felt that Windows 10 restricted the choices of users, citing its more opaque setting menus, forcing users to give up bandwidth for the peer-to-peer distribution of updates, and for taking away user control of specific functions, such as updates, explaining that "it feels, once again, as if Microsoft has taken the seed of a good idea, like providing users with security updates automatically, and shoved the throttle to maximum."[268] Windows 10 has also received criticism because of deleting files without user permission after auto updates.[269]

Critics have noted that Windows 10 heavily emphasizes freemium services, and contains various advertising facilities. Some outlets have considered these to be a hidden "cost" of the free upgrade offer.[270][271][272] Examples of these have included microtransactions in bundled games such as Microsoft Solitaire Collection,[273][270][274][275] default settings that display promotions of "suggested" apps in the Start menu, "tips" on the lock screen that may contain advertising,[271][272] ads displayed in File Explorer for Office 365 subscriptions on Creators' Update,[272] and various advertising notifications displayed by default which promote Microsoft Edge when it is not set as the default web browser (including, in a September 2018 build, nag pop-ups displayed to interrupt the installation process of competitors).[276][277]

Market share and sales[edit]

See also: Usage share of operating systems § Crossover to smartphones having majority share

Windows PC market share (of Windows) statistics
Windows 10

81.43%
Windows 7

13.57%
Windows 8.1

3.17%
Windows 8

1.07%
Windows XP

0.53%
Windows Vista

0.21%
Other

0.02%
"Desktop Windows Version Market Share Worldwide" according to StatCounter for October 2021.[278] Note, StatCounter tracks Windows vs. macOS, Linux etc. separately, and this statistic is only thereof Windows share.

Up to August 2016, Windows 10 usage was increasing, with it then plateauing,[279] while eventually in 2018, it became more popular than Windows 7[280][281] (though Windows 7 was still more used in some countries in Asia and Africa in 2019). As of March 2020[update], the operating system is running on over a billion devices, reaching the goal set by Microsoft two years after the initial deadline.[21]

Twenty-four hours after it was released, Microsoft announced that over 14 million devices were running Windows 10.[282] On August 26, Microsoft said over 75 million devices were running Windows 10, in 192 countries, and on over 90,000 unique PC or tablet models.[283] According to Terry Myerson, there were over 110 million devices running Windows 10 as of October 6, 2015.[284] On January 4, 2016, Microsoft reported that Windows 10 had been activated on over 200 million devices since the operating system's launch in July 2015.[285][286]

According to StatCounter, Windows 10 overtook Windows 8.1 in December 2015.[287][288]Iceland was the first country where Windows 10 was ranked first (not only on the desktop, but across all platforms),[289] with several larger European countries following. For one week in late November 2016, Windows 10 overtook first rank from Windows 7 in the United States, before losing it again.[290] By February 2017, Windows 10 was losing market share to Windows 7.[291]

In mid-January 2018, Windows 10 had a slightly higher global market share than Windows 7,[280] with it noticeably more popular on weekends,[292] while popularity varies widely by region, e.g. Windows 10 was then still behind in Africa[293] and far ahead in some other regions e.g. Oceania.[294]

Update system changes[edit]

Windows 10 Home is permanently set to download all updates automatically, including cumulative updates, security patches, and drivers, and users cannot individually select updates to install or not.[295] Microsoft offers a diagnostic tool that can be used to hide updates and prevent them from being reinstalled, but only after they had been already installed, then uninstalled without rebooting the system.[296][297] Tom Warren of The Verge felt that, given web browsers such as Google Chrome had already adopted such an automatic update system, such a requirement would help to keep all Windows 10 devices secure, and felt that "if you're used to family members calling you for technical support because they've failed to upgrade to the latest Windows service pack or some malware disabled Windows Update then those days will hopefully be over."[298]

Concerns were raised that because of these changes, users would be unable to skip the automatic installation of updates that are faulty or cause issues with certain system configurations—although build upgrades will also be subject to public beta testing via Windows Insider program.[296][298] There were also concerns that the forced installation of driver updates vMix 24.0.0.66 Crack + Registration Key Free Download 2021 Windows Update, where they were previously designated as "optional", could cause conflicts with drivers that were installed independently of Windows Update. An example of such a situation occurred prior to the general release of the operating system, when an Nvidiagraphics card driver that was automatically pushed to Windows 10 users via Windows Update caused issues that prevented the use of certain functions, or prevented their system from booting at all.[296]

Criticism was also directed towards Microsoft's decision to no longer provide specific details on the contents of cumulative updates for Windows 10.[299] On February 9, 2016, Microsoft retracted this decision and began to provide release notes for cumulative updates on the Windows website.[300]

Some users reported that during the installation of the November upgrade, some applications (particularly utility programs such as CPU-Z and Speccy) were automatically uninstalled during the upgrade process, and some default programs were reset to Microsoft-specified defaults (such as Photos app, and Microsoft Edge for PDF viewing), both without warning.[301][302]

Further issues were discovered upon the launch of the Anniversary Update ("Redstone"), including a bug that caused some devices to freeze (but addressed by cumulative update KB3176938, released on August 31, 2016),[303][304] and that fundamental changes to how Windows handles webcams had caused many to stop working.[305]

In June 2017, PC Cleaner Pro 2021 Crack + License Key Free Download Redstone 3 Insider build (RS_EDGE_CASE in PC and rs_IoT on Mobile) was accidentally released to both Insider and non-Insider users on all Windows 10 devices, but the update was retracted, with Microsoft apologizing and releasing a note on their Windows Insider Program blog describing how to prevent the build from being installed on their device.[306] According to Dona Sarkar, this was due to "an inadvertent deployment to the engineering system that controls which builds/which rings to push out to insiders."[307]

A Gartner analyst felt that Windows 10 Pro was becoming increasingly inappropriate for use in enterprise environments because of support policy changes by Microsoft, including consumer-oriented upgrade lifecycle length, and only offering extended support for individual builds to Enterprise and Education editions of Windows 10.[308]

Critics have acknowledged that Microsoft's update and testing practices had been affecting the overall quality of Windows 10. In particular, it was pointed out that Microsoft's internal testing departments had been prominently affected by a major round of layoffs undertaken by the company in 2014. Microsoft relies primarily on user testing and bug reports via the Windows Insider program (which may not always be of sufficient quality to identify a bug), as well as correspondence with OEMs and other stakeholders. In the wake of the known folder redirection data loss bug in the version 1809, it was pointed out that bug reports describing the issue had been present on the Feedback Hub app for several months prior to the public release. Following the incident, Microsoft updated Feedback Hub so that users may specify the severity of a particular bug report. When announcing the resumption of 1809's rollout, Microsoft stated that it planned to be more transparent in its handling of update quality in the future, through a series of blog posts that will detail its testing process and the planned development of a "dashboard" that will indicate the rollout progress of future updates.[309][310][311][312][313]

Distribution practices[edit]

Источник: https://en.wikipedia.org/wiki/Windows_10
Two thrombi, one in a small pulmonary artery (blue arrow) and one in a pulmonary venule (blue arrowhead), in the haematoxylin and eosin staining (panel a) and in the CD61 immunostaining for platelets within thrombi (panel b). Megakaryocytes within small vessels and alveolar capillaries (panel c, blue arrow). CD61 immunostaining of a fibrin- and platelet-rich thrombus in a small vessel (panel d), with a megakaryocyte stained below (blue arrow). Small, perivascular aggregates of lymphocytes (panel e). COVID-19, coronavirus disease 2019. Images reprinted from The Lancet, 8, Fox, S. E. et al., Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans, 681–686, Copyright (2020), with permission from Elsevier (ref.6).

Full size image

Endothelial cells of lung blood vessels can be activated by the high levels of pro-inflammatory cytokines (IL-1, IL-6 and TNF) and ferritin in severe COVID-19 (ref.60). Moreover, increased levels of the endothelial adhesion protein VWF were reported both in patients admitted to the ICU and in non-critically ill patients34,35,61,62, and this increase seems to be associated with a mild reduction in the activity of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), a metalloproteinase that regulates the size of VWF multimers63. Endothelial cell perturbation along with the release of large VWF multimers and relative insufficient VWF cleavage owing to ADAMTS13 consumption may account for increased platelet–vessel wall interactions causing thrombotic microangiopathy. Indeed, a relative deficiency in ADAMTS13 activity was previously described in inflammatory conditions with high levels of IL-6, as found in patients with SARS-CoV-2 infection64. Other markers of endothelial cell injury have been recently investigated. Higher levels of soluble P-selectin (a marker of endothelial and platelet activation) were observed in patients admitted to the ICU than in patients not in the ICU, whereas increased levels of thrombomodulin (a specific marker of endothelial activation generally released during endothelial cell injury) were associated with increased mortality risk35. Higher numbers of circulating endothelial cells were described in patients with COVID-19, especially among those admitted to the ICU, and the presence of circulating endothelial cells positively correlated with platelet and lymphocyte counts and with the classical endothelial marker soluble vascular cell adhesion molecule 1 (sVCAM1)65. This was recently confirmed by another report from Italy, showing that patients with COVID-19 had increased circulating endothelial cells and higher plasma levels of soluble intercellular adhesion molecule 1 (sICAM1) and sVCAM1, further supporting the concept of endothelial dysfunction in COVID-19 (ref.66).

Considering the important role of the endothelium in regulating haemostasis, fibrinolysis and vessel wall permeability, endothelial dysfunction in pulmonary microvessels acts as a trigger for immunothrombosis, resulting in the coagulopathy observed in patients with COVID-19 (refs27,47,67,68). In addition, endothelial dysfunction is recognized as a risk factor of microvascular dysfunction through a shift towards vasoconstriction, by promoting ischaemia, inflammation and a procoagulant state69. In addition, the inflammatory environment triggers the expression of activated tissue factor on endothelial cells, macrophages and neutrophils, which amplifies activation of the coagulation cascade within the lungs60. These events fuel a positive immunothrombotic feedback loop in which hyperinflammation triggers the hypercoagulant state, with thrombosis occurring within pulmonary microvessels. Lastly, platelet activation within the microvasculature is increased in patients with severe COVID-19 and is associated with poor outcomes70,71. Platelet–vessel wall interactions, mediated by surface receptors (integrins and selectins) and adhesive proteins (VWF and fibrinogen), impair vessel wall integrity or increase endothelial injury, ultimately leading to microvascular obstruction72. Moreover, platelets were found to be hyperactivated in patients with COVID-19 and to be a source of procoagulant extracellular vesicles73 and polyphosphates, which can exacerbate the thromboinflammatory cascade via neutrophils74. Of importance, activated platelets are critically involved in neutrophil extracellular trap (NET) formation71, which is an essential element of immunothrombosis. All of these elements support the hypothesis that endothelial dysfunction, or endotheliopathy35,75, and platelet activation are key features of COVID-19-associated coagulopathy and may mediate the damage leading to severe disease.

COVID-19-associated ARDS

COVID-19-related ARDS is considered atypical, with its main characteristic being a dissociation between hypoxaemia severity and relatively good respiratory mechanics76,77. From a clinical standpoint, two phenotypes are described67,78. Patients with ‘type L’ have high lung compliance, lower lung weight as estimated by computed tomography scan and poor response to positive end-expiratory pressure. Patients with ‘type H’ are those with a deteriorating disease or suboptimally treated disease that present with areas of accumulation of inflammatory exudate in the alveoli as observed through computed tomography scan, low lung compliance, greater lung weight and good response to positive end-expiratory pressure. This clinical picture couples with endothelial damage, breaking down pulmonary vasoregulation, stimulating ventilation–perfusion mismatch — which is mainly responsible for hypoxaemia — and supporting immunothrombosis. In this respect, the events leading to atypical ARDS can be summarized by the term ‘microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome’ (MicroCLOTS)79. According to this proposed definition, ARDS is the result of a hyperimmune reaction of the host to SARS-CoV-2 that is both directly mediated by the virus through cellular injury and release of pro-inflammatory signals and indirectly mediated by complement activation (Box 2), leading to leukocyte recruitment and increased release of pro-inflammatory cytokines. This results in a severe tissue injury with vascular endothelial dysfunction and alveolar cell damage, which may explain the progressive worsening of ventilation–perfusion mismatch and pulmonary microthrombosis79.

Box 2 The role of complement in sepsis

The complement system is an important component of the innate immune system and activates following infections. After complement activation (through the classic, alternative or lectin pathways), the common pathway is responsible for the production of C3a and C5a, then stimulating formation of the C5b–9 membrane attack complex, which causes the lysis of pathogen cells176. In a mouse model of intranasal infection with severe acute respiratory syndrome coronavirus (SARS-CoV), early activation of the complement system, especially complement component C3, caused acute respiratory distress syndrome (ARDS)177. However, C3-deficient mice experienced reduced respiratory dysfunction, limited neutrophil and monocyte lung infiltration, and showed lower levels of cytokines both in the lungs and the blood177. Excessive activation of complement in the advanced phases of sepsis may therefore cause tissue injury contributing to organ failure.

The complement and coagulation pathways are closely linked178,179. In particular, complement end products can trigger the release of procoagulant products and reduce the production of natural anticoagulants178. Additionally, the binding of C1q to its receptor on platelets triggers the expression of integrins and P-selectin180, whereas C3 stimulates platelet activation and aggregation. The activation of C5 during the inflammatory response is responsible for the expression of tissue factor on leukocytes and endothelial cells181,182. Complement may indirectly induce procoagulant changes; for example, activated C3 and C5 contribute to cytokine release soon after the innate immune response starts, particularly increasing the concentrations of tumour necrosis factor (TNF) and interleukin-6 (IL-6).

NETs in COVID-19-associated immunothrombosis

NETs are likely to be important players in deregulated immunothrombosis in COVID-19 (ref.80). Indeed, ARDS can be considered as a NETopathy81; higher levels of NETs were described in the plasma and bronchoalveolar fluid of patients with transfusion-associated and pneumonia-related ARDS compared with those without ARDS82,83,84. NETs are markers of disease severity in patients with SARS-CoV-2 infection80,85. Compared with controls, patients with COVID-19 have higher levels of serum85 or plasma80 myeloperoxidase (MPO)–DNA complexes, which are biomarkers of circulating NET fragments, and further increases were found in those patients requiring invasive mechanical ventilation. MPO–DNA complexes and thrombin–antithrombin complexes were positively correlated in patients with COVID-19, and the anticoagulant dabigatran or complement targeting inhibited NETosis86, further suggesting a central role for NETs in the immunothrombotic milieu. MPO–DNA levels return to normal in convalescent plasma, indicating that this is a transient increase80. High-dimensional flow cytometric analysis of circulating neutrophils revealed a highly activated phenotype in patients with most severe COVID-19 (ref.71). Neutrophils can be found embedded in fibrin clots and in close association with platelets within microthrombi in the lungs80, heart and kidneys of patients with COVID-19 (ref.71). In severe disease, neutrophils adopted the so-called low-density phenotype that is more prone to spontaneously form NETs; this greater NETosis was linked to increased intravascular aggregation, leading to microthrombosis and organ 2021 - Free Activators. NETs have also been identified in the lung parenchyma and alveolar space in autopsy case reports9,88. Interestingly, neutrophils from healthy donors showed increased adhesion to activated platelets in plasma from patients with COVID-19 compared with that from control patients, causing enhanced NET generation71. Indeed, both serum and plasma from patients with COVID-19 strongly stimulate the production of NETs from healthy neutrophils71,80,85. In addition, neutrophils isolated from patients with COVID-19 showed elevated NET release at baseline similar to phorbol myristate acetate (PMA)-stimulated neutrophils from healthy donors, indicating that the COVID-19 plasma environment promotes NET formation80. The virus itself is also reported to directly activate neutrophils towards NETosis, promoting epithelial cell death89. NETs may provide a scaffold for the deposition of C3, properdin and factor B, thus directly participating in complement activation90. This mechanism may fuel an amplifying feedback loop promoting further NET formation and platelet and endothelial cell activation91. The observation of antiphospholipid antibodies, which can directly stimulate NETosis92, in patients with COVID-19, as well as in other infections93, suggests that SARS-CoV-2 infection might synergize with antiphospholipid antibodies to promote the immunothrombotic process. Indeed, higher titres of antiphospholipid antibodies were associated with increased activity of neutrophils and platelets and more severe respiratory disease94.

Whether NETs are direct contributors to the dysregulated cytokine response is still unclear. Indeed, NETs participate in acute lung injury by inducing macrophage release of IL-1β, which in turn can increase NET formation95,96. In addition, most inflammatory mediators that are increased in patients with COVID-19 are known to regulate neutrophil activity through the expression of chemotactic products16,97. These data suggest that dysregulated cytokine release might be sustained by crosstalk between neutrophils and macrophages mediated by NETs, resulting in a deranged or exaggerated immunothrombotic status.

COVID-19: a syndrome of deregulated immunothrombosis?

On the basis of the aforementioned evidence, we propose that exaggerated immunothrombosis, occurring for the most part within lung microvessels, drives the clinical manifestations of COVID-19 (ref.3), although systemic viraemia early in the disease course may also be important98 (Fig. 1). The occurrence of severe events, such as acute respiratory failure and ARDS, may be explained by a deregulated process of immunothrombosis involving the pulmonary microcirculation. In support of this, there is increasing evidence that COVID-19 is a disease of the endothelium35 that results in elevated levels of PAI1 and VWF, increased platelet activation and a state of hypercoagulability, with consequent venous, arterial and microvascular thrombosis. The exact factors triggering this endotheliopathy have not yet been recognized, but potentially include the virus itself (causing endothelial cell injury that triggers the coagulation cascade involving fibrin and platelets47,99), immune cell (neutrophil and/or macrophage and platelet73,100,101) infiltration, hypoxaemia (that can induce hypoxia-inducible transcription factors that upregulate tissue factor expression102 and lead to fibrin-based clot formation, thus supporting a thromboinflammatory feedback loop), complement-mediated damage or a surge in pro-inflammatory cytokine (such as IL-1β and IL-6) release with direct cell damage.

Thrombosis management in COVID-19

If we consider COVID-19 as a vascular disease primarily involving the endothelium, an ideal therapeutic approach would be both antithrombotic and anti-inflammatory. Here, we describe some of the main approaches that are being explored to address these features of COVID-19 (Table 1).

Full size table

Antithrombotic therapies

As the coagulation cascade is dysregulated in COVID-19, anticoagulation approaches have been explored for the treatment, particularly of patients with incident venous thromboembolism (VTE) or acute coronary syndrome due to plaque rupture103. Indeed, a study reported that 40% of patients hospitalized with COVID-19 are at high risk of VTE104 and data from a large retrospective cohort of patients in the United States suggested that anticoagulation may reduce mortality, especially among those with severe disease requiring invasive mechanical ventilation105. Pharmacological VTE prophylaxis, including daily low molecular weight heparin or twice-daily subcutaneous unfractionated heparin, may also be of benefit to patients hospitalized with COVID-19 who are bedridden or need intensive care, or patients discharged from hospital but with relevant risk of VTE — that is, individuals with reduced mobility, pro-thrombotic comorbidities (active cancer or obesity), older age, a history of VTE and persistently elevated levels of D-dimer103,106,107.

Studies of heparin treatment of COVID-19 have shown positive results103,106 (Supplementary Table 1), and this is now one of a growing number of agents available to manage COVID-19 either as a prophylactic or therapeutic regimen108 (Table 1). The use of fondaparinux (a selective indirect antithrombin-dependent factor Xa inhibitor) in patients with COVID-19 was reported in two papers, with contrasting results about its safety109,110. The same applies to direct oral anticoagulants, the use of which in patients with COVID-19 has been little studied to date111,112. Several trials of heparin and other anticoagulant agents are in progress: the Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) (NCT02735707); the Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4) trial (NCT04505774); and the Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC) trial (NCT04372589). These trials are testing whether the use of full-dose versus low-dose unfractionated heparin or low molecular weight heparin benefits patients with COVID-19 requiring ICU admission. However, enrolment of critically ill patients has been temporarily stopped owing to futility and safety concerns for this subgroup of patients. Response to this anticoagulant therapy may depend on the time of administration; if given too late, thrombi in the microcirculation and large vessels may already be too extensive.

An alternative approach to pharmacologically disrupt the coagulation cascade involves blockade of factor XII (FXII), which is responsible for activation of the contact pathway (Table 1). FXII blockade has been shown to protect from occlusive thrombosis in animal models without impairing haemostasis113,114. Thus, a FXII-blocking antibody (garadacimab) is currently being explored in a multicentre, double-blind, placebo-controlled phase II trial in patients with respiratory distress and COVID-19 (NCT04409509). Similarly, a serine protease inhibitor of thrombin, plasmin and trypsin known as nafamostat mesylate (used in Japan for the treatment of pancreatitis and DIC and the prevention of clots during dialysis115) is being investigated in clinical trials for COVID-19 (NCT04352400, NCT04418128). This drug showed potential to block Middle East respiratory syndrome coronavirus infection in vitro116 (Table 1).

The hypofibrinolytic state observed in ARDS has been targeted by the use of tissue-type plasminogen activator, which is responsible for the conversion of plasminogen into plasmin, leading to the breakdown of cross-linked fibrin117,118. Indeed, tissue-type plasminogen activator infusion showed benefit in three patients with severe COVID-19 (ref.119), and a phase IIa trial in patients with COVID-19-related ARDS is currently ongoing (NCT04357730).

The antiplatelet agent dipyridamole may have therapeutic potential120 (Table 1). This agent, apart from its antiplatelet function, was shown to provide broad-spectrum antiviral activity (especially against positive-stranded RNA viruses), suppress inflammation and favour mucosal healing, and prevent acute injury and fibrosis in the lungs, heart and kidney121,122,123. Dipyridamole treatment in patients with COVID-19 may also have the added benefit of preventing NETosis by promoting 3′,5′-cyclic adenosine monophosphate (cAMP) generation in neutrophils, as was shown in the context of antiphospholipid syndrome124. Liu et al. demonstrated that dipyridamole can suppress SARS-CoV-2 replication in vitro and improve lung pathology in an animal model of viral pneumonia through a type I interferon response125. This drug was tested in 14 patients and led to an improvement in clinical status compared with controls125. A trial of dipyridamole is currently ongoing (NCT04391179). Another antiplatelet agent, ticagrelor, showed the ability to attenuate NET formation126. Accordingly, two trials of ticagrelor are ongoing or recently completed (NCT02735707, NCT04518735).

Anti-inflammatory therapies

Immunomodulatory therapies, such as inhibitors of IL-6, IL-1, GM-CSF and Janus kinases (JAKs), aim to blunt the cytokine dysregulation associated with severe COVID-19 (refs15,127,128) (Table 1), but little is known about their impact on the thrombotic complications of the disease.

Given that NETs have a direct role in the immunothrombotic process in COVID-19, blocking NETs may help to improve prognosis (Table 1). Some drugs targeting NETs already exist or are under development, such as inhibitors of neutrophil elastase (NE), PAD4 and gasdermin D129. For example, NE inhibitors can block NET formation, limit the toxic activities of NE itself on lung connective tissue and reduce spike protein proteolytic activation that camera control pro 2 product keygen 2022 responsible for SARS-CoV-2 binding to host cells130. Sivelestat, an NE inhibitor, has been approved to treat ARDS in Japan and South Korea, but findings are inconsistent as the severity of lung injury is likely to represent the most important predictor for patient outcome131,132,133. However, no evidence is currently available in favour of using NE inhibitors for COVID-19-induced ARDS.

NETs can be degraded by recombinant DNase I (dornase alpha), which is currently given by inhalation to patients with cystic fibrosis to target NETs in the airways134. Dornase alpha may help to dissolve respiratory secretions in patients with COVID-19 (ref.135), reducing the risk for secondary infections and improving ventilation, and may also reduce the risk of progression towards ARDS, as shown in animal models136,137. Two case studies have shown that administration of dornase alpha is well tolerated in patients with COVID-19-associated ARDS138,139, and several trials are underway to determine the efficacy of this approach (NCT04402944, NCT04355364, NCT04432987, NCT04359654, NCT04445285, NCT04402970). Nebulizer administration of DNase provides direct access to NETs within the alveolar space, but there may be a barrier to reaching systemic efficacy owing to the high reported levels of platelet factor 4 (PF4) in severe COVID-19 (ref.80). PF4 binding to NETs leads to their compaction and decreased susceptibility to DNase degradation140. Therefore, DNase administration is unlikely to ameliorate NET-mediated thrombosis, although the combination with heparin (which also digests NETs141) may be able to overcome this DNase resistance.

Other promising approaches to prevent NET formation rather than target already released NETs include JAK1/2 inhibition with ruxolitinib142, dipyridamole124, ticagrelor126 and neonatal NET-inhibitory factor, an endogenous peptide produced in newborns that restricts the ability of neutrophils to produce NETs143. Neonatal NET-inhibitory factor was shown to prevent COVID-19 plasma-induced NET formation by healthy donor neutrophils in vitro, but the mechanism of action remains to be elucidated80.

Finally, evidence is accumulating on the role of complement activation in the pathogenesis and severity of SARS-CoV-2 (ref.144) as well as on complement-mediated thrombotic microangiopathy in patients with COVID-19 (ref.145). Thus, therapies for thrombotic microangiopathy — complement inhibitors — may be used in this setting. C3 blockade can inhibit the production of both C3a and C5a, but also of intrapulmonary C3a and the release of IL-6 from alveolar macrophages146. Currently, two FDA-approved complement inhibitors are available, eculizumab and ravulizumab, both of which bind to C5 and sterically block the cleavage of C5 to C5a, and thus membrane attack complex formation. Four patients with COVID-19 receiving eculizumab intravenously showed a prompt reduction in C-reactive protein levels and an improvement of the lesions observed through chest computed tomography scan147. Among 35 patients admitted to the ICU with COVID-19, eculizumab treatment improved 15-day survival and hypoxia compared with patients treated with standard care alone148. Trials with eculizumab (NCT04288713) and ravulizumab (NCT04369469, NCT04390464) are currently ongoing. In a report from Italy, a patient with severe COVID-19-related ARDS was safely and successfully treated with the compstatin-based complement C3 inhibitor AMY-101 (ref.149). A recent study comparing two different strategies targeting C3 and C5 has shown a general beneficial impact in patients with COVID-19, although C3 inhibition led to a broader therapeutic effect blocking cytokine dysregulation and NET generation, thereby having a positive impact on immunothrombosis-driven disease pathways150. The C3 inhibitor AMY-101 is currently being evaluated in three phase II clinical trials in patients with COVID-19-associated ARDS (EudraCT number 2020-001550-22, EudraCT number 2020-004408-32, NCT04395456). Another C3 inhibitor, the pegylated compound APL-9, is being tested in a phase I/II randomized controlled trial for severe COVID-19 (NCT04402060). The C1 esterase inhibitor ruconest (NCT04414631, NCT04530136) and the C5a inhibitor IFX-1 (NCT04333420) are being tested as well.

Conclusions

Progressive advancements in our understanding of the pathophysiology of COVID-19 have been crucial for better management of COVID-19. Severe COVID-19 is not limited to the respiratory tract but is a multisystem syndrome in which the vascular endothelium is the most damaged organ, characterized by a state of immunothrombosis within microvessels (MicroCLOTS) and a predisposition to macrothrombosis. McGonagle et al. recently pointed out the potential role of thrombosis in pulmonary veins distal to the alveolar capillary bed, which should act as a clot filter, suggesting this could be a SARS-CoV-2-related vasculitis responsible for ischaemic manifestations in different organs151. Based on all of these features, anticoagulant therapy and immunomodulatory agents are likely necessary to blunt the hyperinflammatory and prothrombotic conditions. Evidence from clinical trials is still limited and consensus-based guidelines recommend anticoagulation therapy based on an individual risk profile. With regard to immunomodulatory therapies, evidence is accumulating about a beneficial role in COVID-19. Timing of administration, however, is a challenging point that needs to be carefully considered, and data about a consistent effect on immunothrombosis are still lacking.

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Источник: https://www.nature.com/articles/s41577-021-00536-9
Hopewell

Prophetic & Activation Conference 2021

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Blessings to you all who’s ready for the Prophetic & Activation Conference May ,21-22,2021 you don’t want to miss this powerful encounter
There is no registration it is free to the public more information is on the flyer, we will be following the CDC guidelines with social distance, face mask is required

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Event Venue & Nearby Stays

108 N Main St, Hopewell, VA 23860-2719, United States

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Источник: https://stayhappening.com/e/prophetic-andamp-activation-conference-2021-E2ISTH18W6I

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5 Replies to “May 21, 2021 - Free Activators”

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