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The Application was Unable to Start Correctly (0xc000007b) [FIXED]

You may get an error message that says “The application was unable to start correctly” accompanied by an error code (0xc000007b). This error message appears when you are trying to open an application on Windows. Usually this happens after you upgrade from an earlier version of Windows and something goes wrong with certain files or programs.

You can try the methods below and see if they can help you get rid of this error.

1) Reboot your computer

2) Run your application as administrator

3) Reinstall your application

4) Reinstall Microsoft .NET framework (for Windows 7 or below)

5) Reinstall Microsoft Visual C++ Redistributable Packages

6) Update your Windows

7) Run check disk

8) Switch to ChromeOS


Fix 1: Reboot your computer

There can be something tiny that goes wrong in your system when you see a “The application was unable to start correctly” error. A simple reboot of your computer can fix your 0xc000007b error.


Fix 2: Run your application as administrator

When you come across a 0xc000007b error, you can try running your application as administrator and see if this is helpful.

a) Right click on the application you want to open. Then select Properties.

b) Go to Compatibility tab. Check Run this program as an administrator. Then hit OK.

c) Try running your application and see if this method fixes the error.


Fix 3: Reinstall your application

Sometimes the application you want to run may contain something that has corrupted. In this case, you should uninstall your application completely and then reinstall it. After that run the program and see if your problem resolves.


Fix 4: Reinstall Microsoft .NET framework

In fact, in many cases the “The application was unable to start correctly” error results from issues on Microsoft .NET framework. (.NET framework is a framework developed by Microsoft which supports applications using .Net technologies.) You may need to reinstall it to fix the issue.

* Microsoft .NET framework has been integral part of Windows 8 and 10. You cannot remove or reinstall it manually. Therefore the steps below may only apply to Windows 7 or earlier versions. For Windows 10/8 users, you can try updating your Windows to install the latest .NET framework (if any).

a) Press Win + R keys. Type “control” and hit OK.

b) In Control Panel, scroll down to find and open Programs and Features.

c) Single click on every item starts with “Microsoft .NET“. Click on Uninstall/Change and follow the instruction to uninstall these items. 

d) Go to Microsoft .NET Framework download website to download and install the framework.


Fix 5: Reinstall Microsoft Visual C++ Redistributable Packages

Microsoft Visual C++ Redistributable Package is a runtime component necessary for running of multiple applications. The files in Microsoft Visual C++ Redistributable Package usually corrupt due to many reasons. And this can cause the 0xc000007b error. In this case you need to reinstall this components.

a) Open Programs and Features (as steps a and b in the method above shows)

b) Uninstall all items with the name of “Microsoft Visual C++ 2*** Redistributable“.

c) Go to Microsoft to download and install Visual C++ Redistributable Packages.


Fix 6: Update your Windows

Updating your operating system can fix the bugs that cause troubles. In addition, some features and programs built in Windows, such as DirectX and .NET Framework, can also be updated during the process. It is recommended that you update your operating system and see if this can help you fix your 0xc000007b error.


Fix 7: Run check disk

The error can also result from hardware issues, especially from your hard drive. You should run check disk using Command Prompt and see if there is any problem on your disk.

a) Click on Start menu and type “cmd“. Right click Command Prompt in the result and select Run as administrator.

b) Enter “chkdsk c: /f /r“. (This means you are going to check and repair C drive. If you want to check another drive, replace “c” with the corresponding letter of that drive.) Follow the instruction to complete the process.

c) After that check and see if the problem is solved.

Fix 8: Switch to ChromeOS

Windows is a very old technology. Sure, Windows 10 is relatively new, but it’s still just the latest iteration of a decades-old operating system, designed for a bygone era (pre-internet).

Now that we have the internet, fast connection speeds, free cloud storage, and endless web apps (like Gmail, Google Docs, Slack, Facebook, Dropbox and Spotify), the entire Windows way of doing things – with locally installed programs and local file storage – is totally outdated.

Why is that a problem? Because when you’re constantly installing uncontrolled third-party programs, you’re constantly opening the door to viruses and other malware. (And Windows’ insecure permission system compounds this problem.)

Plus the way Windows manages installed software and hardware has always been a problem. If your computer shuts down unexpectedly, or a program installs, uninstalls or updates incorrectly, you can get ‘registry’ corruptions. That’s why Windows PCs always slow down and become unstable over time.

Also because everything’s installed and saved locally, it doesn’t take long before you run out of disk space, and your disk gets fragmented, which makes everything even slower and more unstable.

For most people, the simplest way to solve Windows problems is to ditch Windows altogether, and switch to a faster, more reliable, more secure, easier to use and cheaper operating system…

Google ChromeOS.

ChromeOS feels much like Windows, but instead of installing heaps of programs to email, chat, browse the internet, write documents, do school presentations, create spreadsheets, and whatever else you normally do on a computer, you use web apps. You don’t need to install anything at all.

That means you don’t have virus and malware problems, and your computer doesn’t slow down over time, or become unstable.

And that’s just the start of the benefits…

To learn more about the benefits of ChromeOS, and to see comparison videos and demos, visit GoChromeOS.com.

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Data input device

Not to be confused with keyboard computer.

A computer keyboard is a peripheralinput device modeled after the typewriter keyboard[1] which uses an arrangement of buttons or keys to act as mechanical levers or electronic switches. Replacing early punched cards and paper tape technology, interaction via teleprinter-style keyboards have been the main input method for computers since the 1970s, supplemented by the computer mouse since the 1980s.

Keyboard keys (buttons) typically have a set of characters engraved or printed on them, and each press of a key typically corresponds to a single written symbol. However, producing some symbols may require pressing and holding several keys simultaneously or in sequence.[2] While most keyboard keys produce letters, numbers or symbols (characters), other keys or simultaneous key presses can prompt the computer to execute Sony Catalyst Production Suite 2020.1 Crack + Keygen {Full Version} Free commands, such as such as the Control-Alt-Delete combination used with Microsoft Windows.[3][4] In a modern computer, the interpretation of key presses is generally left to the software: the information sent to the computer, the scan code, tells it only which key (or keys) on which row and column, was pressed or released.[5]

In normal usage, the keyboard is used as a text entry interface for typing text, numbers, and symbols into application software such as a word processor, web browser or social media app.

History

While typewriters are the definitive ancestor of all key-based text entry devices, the computer keyboard as a device for electromechanical data entry and communication derives largely from the utility of two devices: teleprinters (or teletypes) and keypunches. It was through such devices that modern computer keyboards inherited their layouts.

As early as the 1870s, teleprinter-like devices were used to simultaneously type and transmit stock market text data from the keyboard across telegraph lines to stock ticker machines to be immediately copied and displayed onto ticker tape.[6] The teleprinter, in its more contemporary form, was developed from 1907 to 1910 by American mechanical engineer Charles Krum and his son Howard, with early contributions by electrical engineer Frank Pearne. Earlier models were developed separately by individuals such as Royal Earl House and Frederick G. Creed.

Earlier, Herman Hollerith developed the first keypunch devices, which soon evolved to include keys for text and number entry akin to normal typewriters by the 1930s.[7]

The keyboard on the teleprinter played a strong role in point-to-point and point-to-multipoint communication for most of the 20th century, while the keyboard on the keypunch device played a strong role in data entry and storage for just as long. The development of the earliest computers incorporated electric typewriter keyboards: the development of the ENIAC computer incorporated a keypunch device as both the input and paper-based output device, while the BINAC computer also made use of an electromechanically controlled typewriter for both data entry onto magnetic tape (instead of paper) and data output.[8]

The keyboard remained the primary, most integrated computer peripheral well into the era of personal computing until the introduction of the mouse as a consumer device in 1984. By this time, text-only user interfaces with sparse graphics gave way to comparatively graphics-rich icons on screen.[9] However, keyboards remain central to human-computer interaction to the present, even as mobile personal computing devices such as smartphones and tablets adapt the keyboard as an optional virtual, touchscreen-based means of data entry.

Types and standards

Further information: Keyboard layout

A wired computer keyboard for desktop use manufactured by Lenovo

Different types of keyboards are available and each is designed with a focus on specific features that suit particular needs.[10] Today, most full-size keyboards use one of three different mechanical layouts, usually referred to as simply ISO (ISO/IEC 9995-2), ANSI (ANSI-INCITS 154-1988), and JIS (JIS X 6002-1980), referring roughly to the organizations issuing the relevant worldwide, United States, and Japanese standards, respectively. (In fact, the mechanical layouts referred such as "ISO" and "ANSI" comply to the primary recommendations in the named standards, while each of these standards in fact also allows the other way.) ANSI standard alphanumeric keyboards have keys that are on three-quarter inch centers (0.75 inches (19 mm)), and have a key travel of at least 0.15 inches (3.8 mm).[citation needed]

Modern keyboard models contain a set number of total keys according to their given standard, described as 101, 104, 105, etc. and sold as "Full-size" keyboards.[11] Modern keyboards matching US conventions typically have 104 keys while the 105 key layout is the norm in the rest of the world. This number is not always followed, and individual keys or whole sections are commonly skipped for the sake of compactness or user preference. The most common choice is to not include the numpad, which can usually be fully replaced by the alphanumeric section. Laptops and wireless peripherals often lack duplicate keys and ones seldom used. Function- and arrow keys are nearly always present.

Another factor determining the size of a keyboard is the size and spacing of the keys. The reduction is limited by the practical consideration that the keys must be large enough to be easily pressed by fingers. Alternatively, a tool is used for pressing small keys.

Desktop or full-size

Desktop computer keyboards include alphabetic characters and numerals, typographical symbols and punctuation marks, one or more currency symbols and other special characters, diacritics and a variety of function keys. The repertoire of glyphs engraved on the keys of a keyboard accords with national conventions and language needs. Computer keyboards are similar to electric-typewriter keyboards but contain additional keys, such as the command key or Windows keys.

Laptop-size

Keyboards on laptops usually have a shorter travel distance and a reduced set of keys.

Keyboards on laptops and notebook computers usually have a shorter travel distance for the keystroke, shorter over travel distance, and a reduced set of keys. They may not have a numeric keypad, and the function keys may be placed in locations that differ from their placement on a standard, full-sized keyboard. The switch mechanism for a laptop keyboard is more likely to be a scissor switch than a rubber dome; this is opposite the trend for full-size keyboards.

Flexible keyboards

Flexible driverpack solution 18 - Crack Key For U are a junction between normal type and laptop type keyboards: normal from the full arrangement Comodo antivirus 2021 Crack + License Key Latest Free Download keys, and laptop from the short key distance. Additionally, the flexibility allows the user to fold/roll the keyboard for better storage and transfer. However, for typing the keyboard must be resting on a hard surface. The vast majority[12] of flexible keyboards in the market are made from silicone; this material makes them water- and dust-proof. This is useful in hospitals,[13] where keyboards are subjected to frequent washing, and other dirty or must-be-clean environments.

Handheld

An AlphaGrip handheld keyboard

Handheld ergonomic keyboards[14][15] are designed to be held like a game controller, and can be used as such, instead of laid out flat on top of a table surface.

Typically handheld keyboards hold all the alphanumeric keys and symbols that a standard keyboard would have, yet only be accessed by pressing two sets of keys at once; one acting as a function key similar to a 'Shift' key that would allow for capital letters on a standard keyboard.[16] Handheld keyboards allow the user the ability to move around a room or to lean back on a chair while also being able to type in front or away from the computer.[17] Some variations of handheld ergonomic keyboards also include a trackball mouse that Antivirus - Free Activators mouse movement and typing included in one handheld device.[18]

Thumb-sized

Smaller external keyboards have been introduced for devices without a built-in keyboard, such as PDAs, and smartphones. Small keyboards are also useful where there is a limited workspace.[19]

A thumb keyboard (thumb board) is used in some personal digital assistants such as the Palm Treo and BlackBerry and some Ultra-Mobile PCs such as the OQO.

Numeric keyboards contain only numbers, mathematical symbols for addition, subtraction, multiplication, and division, a decimal point, and several function keys. They are often used to facilitate data entry with smaller keyboards that do not have a numeric keypad, commonly those of laptop computers.[20] These keys are collectively known as a numeric pad, numeric keys, or a numeric keypad, and it can consist of the following types of keys: Arithmetic operators, numbers, arrow keys, Navigation keys, Num Lock and Enter key.

Multifunctional

Multifunction keyboard with LCD function keys

Multifunctional keyboards provide additional function beyond the standard keyboard. Many are programmable, configurable computer keyboards and some control multiple PCs, workstations and other information sources, usually in multi-screen work environments. Users have additional key functions as well as the standard functions and can typically use a single keyboard and mouse to access multiple sources.

WEY Smart Touch
Multifunction keyboard with touch

Multifunctional keyboards may feature customised keypads, fully programmable function or soft keys for macros/pre-sets, biometric or smart card readers, trackballs, etc. New generation multifunctional keyboards feature a touchscreen display to stream video, control audio visual media and alarms, execute application inputs, configure individual desktop environments, etc. Multifunctional keyboards may also permit users to share access to PCs and other information sources. Multiple interfaces (serial, USB, audio, Ethernet, etc.) are used to integrate external devices. Some multifunctional keyboards are also used to directly and intuitively control video walls.

Common environments for multifunctional keyboards are complex, high-performance workplaces for financial traders and control room operators (emergency services, security, air traffic management; industry, utilities management, etc.).

Non-standard layout and special-use types

Chorded

Main article: Chorded keyboard

While other keyboards generally associate one action with each key, chorded keyboards associate actions with combinations of key presses. Since there are many combinations available, chorded keyboards can effectively produce more actions on a board with fewer keys. Court reporters' stenotype machines use chorded keyboards to enable them to enter text much faster by typing a syllable with each stroke instead of one letter at a time. The fastest typists (as of 2007) use a stenograph, a kind of chorded keyboard used by most court reporters and closed-caption reporters. Some chorded keyboards are also made for use in situations where fewer keys are preferable, such as on devices that can be used with only one hand, and on small mobile devices that don't have room for larger keyboards. Chorded keyboards are less desirable in many cases because artlantis 2019 crack only - Free Activators usually takes practice and memorization of the combinations to become proficient.

Software

Software keyboards or on-screen keyboards often take the form of computer programs that display an image of a keyboard on the screen. Another input device such as a mouse or a touchscreen can be used to operate each virtual key to enter text. Software keyboards have become very popular in touchscreen enabled cell phones, due to the additional cost and space requirements of other types of hardware keyboards. Microsoft Windows, Mac OS X, and some varieties of Linux include on-screen keyboards that can be controlled with the mouse. In software keyboards, the mouse has to be maneuvered onto the on-screen letters given by the software. On the click of a letter, the software writes the respective letter on the respective spot.

Projection

Projection keyboards project an image of keys, usually with a laser, onto a flat surface. The device then uses a camera or infrared sensor to "watch" where the user's fingers move, and will count a key as being pressed when it "sees" the user's finger touch the projected image. Projection keyboards can simulate a full size keyboard from a very small projector. Because the "keys" are simply projected images, they cannot be felt when pressed. Users of projected keyboards often experience increased discomfort in their fingertips because of the lack of "give" when typing. A flat, non-reflective surface is also required for the keys to be projected. Most projection keyboards are made for use with PDAs and smartphones due to their small form factor.

Optical keyboard technology

Further information: Keyboard technology

Also known as photo-optical keyboard, light responsive keyboard, photo-electric keyboard and optical key actuation detection technology.

An optical keyboard technology[21] utilizes LEDs and photo sensors to optically detect actuated keys. Most commonly the emitters and sensors are located in the perimeter, mounted on a small PCB. The light is directed from side to side of the keyboard interior and it can only be blocked by the actuated keys. Most optical keyboards[22] require at least 2 beams (most commonly vertical beam and horizontal beam) to determine the actuated key. Some optical keyboards use a special key structure that blocks the light in a certain pattern, allowing only one beam per row of keys (most commonly horizontal beam).

Key types

Alphanumeric

Alphabetical, numeric, and punctuation keys are used in the same fashion as a typewriter keyboard to Sony Catalyst Production Suite 2020.1 Crack + Keygen {Full Version} Free their respective symbol into a word processing program, text editor, data spreadsheet, or other program. Many of these keys will produce different symbols when modifier keys or shift keys are pressed. The alphabetic characters become uppercase when the shift driverpack solution 18 - Crack Key For U or Caps Lock key is depressed. The numeric characters become symbols or punctuation marks when the shift key is depressed. The alphabetical, numeric, and punctuation keys can also have other functions when they are pressed at the same time as some modifier keys. The Space bar is a horizontal bar in the lowermost row, which is significantly wider than other keys. Like the alphanumeric characters, it is also descended from the mechanical typewriter. Its main purpose is to enter the space between words during typing. It is large enough so that a thumb from either hand can use it easily. Depending on the operating system, when the space bar is used with a modifier key such as the control key, it may have functions such as resizing or closing the current window, half-spacing, or backspacing. In computer games and other applications the key has myriad uses in addition to its normal purpose in typing, such as jumping and adding marks to check boxes. In certain programs for playback of digital video, the space bar is used for pausing and resuming the playback.

Modifier keys

Modifier keys are special keys that modify the normal action of another key, when the two are pressed in combination. For example, + in Microsoft Windows will close the program in an active window. In contrast, pressing just will probably do nothing, unless assigned a specific function in a particular program. By themselves, modifier keys usually do nothing. The most widely used modifier keys include the Control key, Shift key and the Alt key. The AltGr key is used to access additional symbols for keys that have three symbols printed on them. On the Macintosh and Apple keyboards, the modifier keys are the Option key and Command key, respectively. On Sun Microsystems and Lisp machine keyboards, the Meta key is used as a modifier and for Windows keyboards, there is a Windows key. Compact keyboard layouts often use a Fn key. "Dead keys" allow placement of a diacritic mark, such as an accent, on the following letter (e.g., the Compose key). The Enter/Return key typically causes a command line, window form or dialog box to operate its default function, which is typically to finish an "entry" and begin the desired process. In word processing applications, pressing the enter key ends a paragraph and starts a new one.

Cursor keys

Navigation keys or cursor keys include a variety of keys which move the cursor to different positions on the screen.[23]Arrow keys are programmed to move the cursor in a specified direction; page scroll keys, such as the Page Up and Page Down keys, scroll the page up and down. The Home key is used to return the cursor to the beginning of the line where the cursor is located; the End key puts the cursor at the end of the line. The Tab key advances the cursor to the next tab stop. The Insert key is mainly used to switch between overtype mode, in which the cursor overwrites any text that is present on and after its current location, and insert mode, where the cursor inserts a character at its current position, forcing all characters past it one position further. The Delete key discards the character ahead of the cursor's position, moving all following characters one position "back" towards the freed place. On many notebook computer keyboards the key labeled Delete (sometimes Delete and Backspace are printed on the same key) serves the same purpose as a Backspace key. The Backspace key deletes the preceding character. Lock keys lock part of a keyboard, depending on the settings selected. The lock keys are scattered around the keyboard. Most styles of keyboards have three LEDs indicating which locks are enabled, in the upper right corner above the numeric pad. The lock keys include Scroll lock, Num lock (which allows the use of the numeric keypad), and Caps lock.[24]

System commands

4800-52 mainframe / dumb terminal keyboard, circa mid 1980s. Note the obscure configuration of modifier and arrow keys, line feed key, break key, blank keys, and repeat key.

The SysRq and Print screen commands often share the same key. SysRq was used in earlier computers as a "panic" button to recover from crashes (and it is still used in this sense to some extent by the Linux kernel; see Magic SysRq key). The Print screen command used to capture the entire screen and send it to the printer, but in the present it usually puts a screenshot in the clipboard.

Break key

The Break key/Pause key no longer has a well-defined purpose. Its origins go back to teleprinter users, who wanted a key that would temporarily interrupt the communications line. The Break key can be used by software in several different driverpack solution 18 - Crack Key For U, such as to switch between multiple login sessions, to terminate a program, or to interrupt a modem connection. In programming, especially old DOS-style BASIC, Pascal and C, Break is used (in conjunction with Ctrl) to stop program execution. In addition to this, Linux and variants, as well as many DOS programs, treat this combination the same as Ctrl+C. On modern keyboards, the break key is usually labeled Pause/Break. In most Windows environments, the key combination Windows key+Pause brings up the system properties.

Escape key

Main article: Esc key

The escape key (often abbreviated Esc) "nearly all of the time"[25] signals Stop -[26]QUIT -[27] let me "get out of a dialog"[25] (or pop-up window):[28] LET ME ESCAPE.

Another common application today of the Esc key is to trigger the Stop button in many web browsers.[29]

ESC origins

ESC was part of the standard keyboard of the Teletype Model 33 (introduced in 1964 and used with many early minicomputers).[30] The DECVT50, introduced July 1974, also had an Esc key. The TECO text editor (ca 1963) and its descendant Emacs (ca 1985) use the Esc key extensively.

Historically it also served as a type of shift key, such that one or more following characters were interpreted differently, hence the term escape sequence, which refers to PDF Annotator 8.0.0.827 Crack + Serial Key Free Download 2021 series of characters, usually preceded by the escape character.[31][32]

On machines running Microsoft Windows, prior to the implementation of the Windows key on keyboards, the typical practice for invoking the "start" button was to hold down the control key and press escape. This process still works in Windows 95, 98, Me, NT 4, 2000, XP, Vista, 7, 8, and 10.[33]

Enter key

The Enter key is located: One in the alphanumeric keys and the other one is in the numeric keys. When one worked something on their computer and wanted to do something with their work, pressing the enter key would do the command they ordered. Another function is to create a space for next paragraph. When one typed and finished typing a paragraph and they wanted to have a second paragraph, they could press enter and it would do spacing.

Shift key

Shift key: when one presses shift and a letter, it will capitalize the letter pressed with the shift key. Another use is to type more symbols than appear to be available, for instance the apostrophe key is accompanied with a quotation mark on the top. If one wants to type the quotation mark but pressed that key alone, the symbol that would appear would be the apostrophe. The quotation mark will only appear if both the required key and the Shift key are pressed.

The Menu key or Application key is a key found on Windows-oriented computer keyboards. It is used to launch a context menu with the keyboard rather than with the usual right mouse button. The key's symbol is usually a small icon depicting a cursor hovering above a menu. On some Samsung keyboards the cursor in the icon is not present, showing the menu only. This key was created at the same time as the Windows key. This key is normally used when the right mouse button is not present on the mouse. Some Windows public terminals do not have a Menu key on their keyboard to prevent users from right-clicking (however, in many Windows applications, a similar functionality can be invoked with the Shift+F10 keyboard shortcut).

Number pad

Many, but not all, computer keyboards have a numeric keypad to the right of the alphabetic keyboard, often separated from the other groups of keys such as the function keys and system command keys, which contains numbers, basic mathematical symbols (e.g., addition, subtraction, etc.), and a few function keys. In addition to the row of number keys above the top alphabetic row, most desktop keyboards have a number pad or accounting pad, on the right hand side of the keyboard. While num lock is set, the numbers on these keys duplicate the number row; if not, they have alternative functions as engraved. In addition to numbers, this pad has command symbols concerned with calculations such as addition, subtraction, multiplication and division symbols. The enter key in this keys indicate the equal sign.

Miscellaneous

Multimedia buttons on some keyboards give quick access to the Internet or control the volume of the speakers.

On Japanese/Korean keyboards, there may be Language input keys for changing the language to use. Some keyboards have power management keys (e.g., power key, sleep key and wake key); Internet keys to access a web browser or E-mail; and/or multimedia keys, such as volume controls; or keys that can be programmed by the user to launch a specified application or a command like minimizing all windows.

Multiple layouts

It is possible to install multiple keyboard layouts within an operating system and switch between them, either through features implemented within the OS, or through an external application. Microsoft Windows,[34] Linux,[35] and Mac[36] provide support to add keyboard layouts and choose from them.

Illumination

Keyboards and keypads may be illuminated from inside, especially on equipment for mobile use. Both keyboards built into computers and external ones may support backlighting; external backlit keyboards may have a wired USB connection, or be connected wirelessly and powered by batteries. Illumination facilitates the use of the keyboard or keypad in dark environments.

For general productivity, only the keys may be uniformly backlit, without distracting light around the keys.

Keys with integrated LED indicator lights

Many gaming keyboards are designed to have an aesthetic as well as functional appeal, with multiple colours, and colour-coded keys to make it easier for gamers to find command keys while playing in a dark room.[37] Many keyboards not otherwise illuminated may have small LED indicator lights in a few important function keys, or elsewhere on the housing, if their function is activated (see photo).

See also: ThinkLight

Technology

Main article: Keyboard technology

Key switches

In the first electronic keyboards in the early 1970s, the key switches were individual switches inserted into holes in metal frames. These keyboards cost from 80 to 120 USD and were used in mainframe data terminals. The most popular switch types were reed switches (contacts enclosed in a vacuum in a glass capsule, affected by a magnet mounted on the switch plunger).[citation needed]

In the mid-1970s, lower-cost direct-contact key switches were introduced, but their life in switch cycles was much shorter (rated ten million cycles) because they were open to the environment. This became more acceptable, however, for use in computer terminals at the time, which began to see increasingly shorter model lifespans as they advanced.[38]

In 1978, Key Tronic Corporation introduced keyboards with capacitive-based switches, one of the first keyboard technologies not to use self-contained switches.[39] There was simply a sponge pad with a conductive-coated Mylar plastic sheet on the switch plunger, and two half-moon trace patterns on the printed circuit board below. As the key was depressed, the capacitance between the plunger pad and the patterns on the PCB below changed, which was detected by integrated circuits (IC). These keyboards were claimed to have the same reliability as the other "solid-state switch" keyboards such as inductive and Hall-effect, but competitive with direct-contact keyboards. Prices of $60 for keyboards were achieved, and Key Tronic rapidly became the largest independent keyboard manufacturer.

Meanwhile, IBM made their own keyboards, using their own patented technology: Keys on older IBM keyboards[40] were made with a "buckling spring" mechanism, in which a coil spring under the key buckles under pressure from the user's finger, triggering a hammer that presses two plastic sheets (membranes) with conductive traces together, completing a circuit. This produces a clicking sound and gives physical feedback for the typist, indicating that the key has been depressed.[41]

The first electronic keyboards had a typewriter key travel distance of 0.187 inches (4.75 mm), keytops were a half-inch (12.7 mm) high, and keyboards were about two inches (5 cm) thick. Over time, less key travel was accepted in the market, finally landing on 0.110 inches (2.79 mm). Coincident with this, Key Tronic was the first company to introduce a keyboard that was only about one inch thick. And now keyboards measure only about a half-inch thick.

Keyboard with some keytops removed to show the Cherry MX "Black"switches it is based on. MX switches are a common choice for mechanical keyboards.
The tactile, non-clicky "brown" version of the Cherry MX switch shown in disassembled form (four parts, left and centre), with the top off (top right) and reassembled (bottom right).

Keytops are an important element of keyboards. In the beginning, keyboard keytops had a "dish shape" on top, like typewriters before them. Keyboard key legends must be extremely durable over tens of millions of depressions, since they are subjected to extreme mechanical wear from fingers and fingernails, and subject to hand oils and creams, so engraving and filling key legends with paint, as was done previously for individual switches, was never acceptable. So, for the first electronic keyboards, the key legends were produced by two-shot (or double-shot, or two-color) molding, where either the key shell or the inside of the key with the key legend was molded first, and then the other color molded second. But, to save cost, other methods were explored, such as sublimation printing and laser engraving, both methods which could be used to print a whole keyboard at the same time.

Initially, sublimation printing, where a special ink is printed onto the keycap surface and the application of heat causes the ink molecules to penetrate and commingle with the plastic modules, had a problem because finger oils caused the molecules to disperse, but then a necessarily very hard clear coating was applied to prevent this. Coincident with sublimation printing, which was first used in high volume by IBM on their keyboards, was the introduction by IBM of single-curved-dish keycaps to facilitate quality printing of key legends by having a consistently curved surface instead of a dish. But one problem with sublimation or laser printing was that the processes took too long and only dark legends could be printed on light-colored keys. On another note, IBM was unique in using separate shells, or "keycaps", on keytop bases. This might have made their manufacturing of different keyboard layouts more flexible, but the reason for doing this was that the plastic material that needed to be used for sublimation printing was different from standard ABS keytop plastic material.

Three final mechanical technologies brought keyboards to where they are today, driving the cost well under $10:

  1. "Monoblock" keyboard designs were developed where individual switch housings were eliminated and a one-piece "monoblock" housing used instead. This was possible because of molding techniques that could provide very tight tolerances for the switch-plunger holes and guides across the width of the keyboard so that the key plunger-to-housing clearances were not too tight or too loose, either of which could cause the keys to bind.
  2. The use of contact-switch membrane sheets under the monoblock. This technology came from flat-panel switch membranes, where the switch contacts are printed inside of a top and bottom layer, with a spacer layer in between, so that when pressure is applied to the area above, a direct electrical contact is made. The membrane layers can be printed by very-high volume, low-cost "reel-to-reel" printing machines, with each keyboard membrane Malwarebytes 4.1.2.179 and punched out afterwards.

Plastic materials played a very important part in the development and progress of electronic keyboards. Until "monoblocks" came along, GE's "self-lubricating" Delrin was the only plastic material for keyboard switch plungers that could withstand the beating over tens of millions of cycles of lifetime use. Greasing or oiling switch plungers was undesirable because it would attract dirt over time which would eventually affect the feel and even bind the key switches (although keyboard manufacturers would sometimes sneak this into their keyboards, especially if they could not control the tolerances of the key plungers and housings well enough to have a smooth key depression feel or prevent binding). But Delrin was only available in black and white, and was not suitable for keytops (too soft), so keytops use ABS plastic. However, as plastic molding advanced in maintaining tight tolerances, and as key travel length reduced from 0.187-inch to 0.110-inch (4.75 mm video downloader - Crack Key For U 2.79 mm), single-part keytop/plungers could be made of ABS, with the keyboard monoblocks also made of ABS.

In common use, the term "mechanical keyboard" refers to a keyboard with individual mechanical key switches, each of which contains a fully encased plunger with a spring below it and metallic electrical contacts on a side. The plunger sits on the spring and the key will often close the contacts when the plunger is pressed half-way. Other switches require the plunger to be fully pressed down. The depth at which the plunger must be pressed for the contacts to close is known as the activation distance. Analog keyboards with key switches whose activation distance can be reconfigured through software, optical switches that work by blocking laser beams, and Hall Effect keyboards that use key switches that use a magnet to activate a hall sensor, are also available.

Control processor

Computer keyboards include control circuitry to convert key presses into key codes[42] (usually scancodes) that the computer's electronics can understand. The key switches are connected via the printed circuit board in an electrical X-Y matrix where a voltage is provided sequentially to the Y lines and, when a key is depressed, detected sequentially by scanning the X lines.

The first computer keyboards were for mainframe computer data terminals and used discrete electronic parts. The first keyboard microprocessor was introduced in 1972 by General Instruments, but keyboards have been using the single-chip 8048microcontroller variant since it became available in 1978.[43] The keyboard switch matrix is wired to its inputs, it converts the keystrokes to key codes, and, for a detached keyboard, sends the codes down a serial cable (the keyboard cord) to the main processor on the computer motherboard. This serial keyboard cable communication is only bi-directional to the extent that the computer's electronics controls the illumination of the caps lock, num lock and scroll lock lights.

One test for whether the computer has crashed is pressing the caps lock key. The keyboard sends the key code to the keyboard driver running in the main computer; if the main computer is operating, it commands the light to turn on. All the other indicator lights work in a similar way. The keyboard driver also tracks the Shift, alt and control state of the keyboard.

Some lower-quality keyboards have multiple or false key entries due to inadequate electrical designs. These are caused by inadequate keyswitch "debouncing" or inadequate keyswitch matrix layout that don't allow multiple keys to be depressed at the same time, both circumstances which are explained below:

When pressing a keyboard key, the key contacts may "bounce" against each adobe acrobat reader dc crack - Crack Key For U for several milliseconds before they settle into firm contact. When released, they bounce some more until they revert to the uncontacted state. If the computer were watching for each pulse, it would see many keystrokes for what the user thought was just one. To resolve this problem, the processor in a keyboard (or computer) "debounces" the keystrokes, by aggregating them across time to produce one "confirmed" keystroke.

Some low-quality keyboards also suffer problems with rollover (that is, when multiple keys pressed at the same time, or when keys are pressed so fast that multiple keys are down within the same milliseconds). Early "solid-state" keyswitch keyboards did not have this problem because the keyswitches are electrically isolated from each other, and early "direct-contact" keyswitch keyboards avoided this problem by having isolation diodes for every keyswitch. These early keyboards had "n-key" rollover, which means any number of keys can be depressed and the keyboard will still recognize the next key depressed. But when three keys are pressed (electrically closed) at the same time in a "direct contact" keyswitch matrix that doesn't have isolation diodes, the keyboard electronics can see a fourth "phantom" key which is the intersection of the X and Y lines of the three keys. Some types of keyboard circuitry will register a maximum number of keys at one time. "Three-key" rollover, also called "phantom key blocking" or "phantom key lockout", will only register three keys and ignore all others until one of the three keys is lifted. This is undesirable, especially for fast typing (hitting new keys before the fingers can release previous keys), and games (designed for multiple key presses).

As direct-contact membrane keyboards became popular, the available rollover of keys was optimized by analyzing the most common key sequences and placing these keys so that they do not potentially produce phantom keys in the electrical key matrix (for example, simply placing three or four keys that might be depressed simultaneously on the same X or same Y line, so that a phantom key intersection/short cannot happen), so that blocking a third key usually isn't a problem. But lower-quality keyboard designs and unknowledgeable engineers may not know these tricks, and it can still be a problem in games due to wildly different or configurable layouts in different games.

Connection types

There are several ways of connecting a keyboard to a system unit (more precisely, to its keyboard controller) using cables, including the standard AT connector commonly found on motherboards, which was eventually replaced by the PS/2 and the USB connection. Prior to the iMac line of systems, Apple used the proprietary Apple Desktop Bus for its keyboard connector.

Wireless keyboards have become popular. A wireless keyboard must have a transmitter built in, and a receiver connected to the computer's keyboard port; it communicates either by radio frequency (RF) or infrared (IR) signals. A wireless keyboard may use industry standard Bluetooth radio communication, in which case the receiver may be built into the computer. Wireless keyboards need batteries for power, and may be at risk of data eavesdropping. Wireless solar keyboards charge their batteries from small solar panels using natural or artificial light. The 1984 Apricot Portable is an early example of an IR keyboard.

Alternative text-entering methods

On-screen keyboard controlled with the mouse can be used by users with limited mobility

Optical character recognition (OCR) is preferable to rekeying for converting existing text that is already written down but not in machine-readable format (for example, a Linotype-composed book from the 1940s). In other words, to convert the text from an image to editable text (that is, a string of character codes), a person could re-type it, or a computer could look at the image and deduce what each character is. OCR technology has already reached an impressive state (for example, Google Book Search) and promises more for the future.

Speech recognition converts speech into machine-readable text (that is, a string of character codes). This technology has also reached an advanced state and is implemented in various software products. For certain uses (e.g., transcription of medical or legal dictation; journalism; writing essays or novels) speech recognition is starting to replace the keyboard. However, the lack of privacy when issuing voice commands and dictation makes this kind of input unsuitable for many environments.

Pointing devices can be used to enter text or characters in contexts where using a physical keyboard would be inappropriate or impossible. These accessories typically present characters on a display, in a layout that provides fast access to the more frequently used characters or character combinations. Popular examples of this kind of input are Graffiti, Dasher and on-screen virtual keyboards.

Other issues

Keystroke logging

Unencrypted wireless Bluetooth keyboards are known to be vulnerable to signal theft by placing a covert listening device in the same room as the keyboard to sniff and record Bluetooth packets for the purpose of logging keys typed by the user. Microsoft wireless keyboards 2011 and earlier are documented to have this vulnerability.[44]

Keystroke logging (often called keylogging) is a method of capturing and recording user keystrokes. While it is used legally to measure employee productivity on certain clerical tasks, or by law enforcement agencies to find out about illegal activities, it is also used by hackers for various illegal or malicious acts. Hackers use keyloggers as a means to obtain passwords or encryption keys and thus bypass other security measures.

Keystroke logging can be achieved by both hardware and software means. Hardware key loggers are attached to the keyboard cable or installed inside standard keyboards. Software keyloggers work on the target computer's operating system and gain unauthorized access to the hardware, hook into the keyboard with functions provided by the OS, or use remote access software to transmit recorded data out of the target computer to a remote location. Some hackers also use wireless keylogger sniffers to collect packets of data being transferred from a wireless keyboard and its receiver, and then they crack the encryption key being used to secure wireless communications between the two devices.

Anti-spyware applications are able to detect many keyloggers and cleanse them. Responsible vendors of monitoring software support detection by anti-spyware programs, thus preventing abuse of the software. Enabling a firewall does not stop keyloggers per se, but can possibly prevent transmission of the logged material over Internet Download Manager Activation Code - Crack Key For U net if properly configured. Network monitors (also known as reverse-firewalls) can be used to alert the user whenever an application attempts to make a network connection. This gives the user the chance to prevent the keylogger from "phoning home" with his or her typed information. Automatic form-filling programs can prevent keylogging entirely by not using the keyboard at all. Most keyloggers can be fooled by alternating between typing the login credentials and typing characters somewhere else in the focus window.[45]

Keyboards are also known to emit electromagnetic signatures that can be detected using special spying equipment to reconstruct the keys pressed on the keyboard. Neal O'Farrell, executive director of the Identity Theft Council, revealed to InformationWeek that "More than 25 years ago, a couple of former spooks showed me how they could capture a user's ATM PIN, from a van parked across the street, simply by capturing and decoding the electromagnetic signals generated by every keystroke," O'Farrell said. "They could even capture keystrokes from computers in nearby offices, but the technology wasn't sophisticated enough to focus in on any specific computer."[46]

Physical injury

Proper ergonomic design of computer keyboard desks is necessary to prevent repetitive strain injuries, which can develop over time and can lead to long-term disability.[47]Research suggests that the upright position formerly advocated can lead to degenerative disc disease, and that a 45 degree reclined position is healthier.[48]

The use of any keyboard may cause serious injury (that is, carpal tunnel syndrome or other repetitive strain injury) to hands, wrists, arms, neck or back.[49] The risks of injuries can be reduced by taking frequent short breaks to get up and walk around a couple of times every hour. As well, users should vary tasks throughout the day, to avoid overuse of the hands and wrists. When inputting at the keyboard, a person should keep the shoulders relaxed with the elbows at the side, with the keyboard and mouse positioned so that reaching is not necessary. The chair height and keyboard tray should be adjusted so that the wrists are straight, and the wrists should not be rested on sharp table edges.[50] Wrist or palm rests should not be used while typing.[51]

Some adaptive driverpack solution 18 - Crack Key For U ranging from special keyboards, mouse replacements and pen tablet interfaces to speech recognition software can reduce the risk of injury. Pause software reminds the user to pause frequently. Switching to a much more ergonomic mouse, such as a vertical mouse or joystick mouse may provide relief.

By using a touchpad or a stylus pen with a graphic tablet, in place of a mouse, one driverpack solution 18 - Crack Key For U lessen the repetitive strain on the arms and hands.[52]

See also

References

  1. ^"computer keyboard". TheFreeDictionary.com. Retrieved 26 June 2018.
  2. ^Khalid Saeed (2016). New Directions in Behavioral Biometrics. ISBN .
  3. ^"Bill Gates Says He's Sorry About Control-Alt-Delete". SlashDot.org.
  4. ^"Control-Alt-Delete in the World of VDI".
  5. ^Microsoft Keyboard Scan Code Specification (Appendix C, "USB Keyboard/Keypad Page (0x07)"), Microsoft. Revision 1.3a, 2000-03-16, accessed 2018-10-13.
  6. ^"Essay on Technology Advancements in Computer Interfaces".
  7. ^Smith, Andy (15 June 2011). "Gallery: IBM: 100 Years of THINKing Big". ZDNet. Archived from the original on 10 December 2015. Retrieved 20 October 2015.
  8. ^"Past is prototype: The evolution of the computer keyboard". ComputerWorld.com. 2 November 2012.
  9. ^D Kocielinski (2013). "Linear interface for graphical interface of touch-screen".
  10. ^"Master your keyboard - The ULTIMATE guide". 27 May 2019.
  11. ^Judd, William. "Full-size, TKL, 60% and more: a guide to mechanical keyboard sizes". The Keyboard Company. Retrieved 18 October 2019.
  12. ^"What is a Flexible Keyboard?". Nelson-Miller.com. 31 August 2017.
  13. ^"Specifications Wireless Multimedia Flexible Keyboard"(PDF).
  14. ^"One of the first products we caught wind of at the Consumer Electronics Show was the TrewGrip keyboard, a handheld model" "TrewGrip handheld keyboard almost a solution for thumb-typing". 11 January 2014.
  15. ^"Jul 28, 2009 – If you do a lot of typing, or if you have employees who do a lot of typing – ergonomic keyboards make a great deal of sense." "10 ergonomic keyboards that actually do their job". TechRepublic.com. 28 July 2009.
  16. ^Alpha Grip Programming and Productivity Improvement White PaperArchived 25 February 2015 at the Wayback Machine. Alphagrips.com. Retrieved on 9 December 2013.
  17. ^The Alphagrip – The World's most Comfortable Ergonomic Keyboard for Typing and ProgrammingArchived 25 February 2015 at the Wayback Machine. Alphagrips.com. Retrieved on 9 December 2011.
  18. ^"It combines the body of a game controller with the functions of both a trackball and a keyboard." "AlphaGrip Review (iGrip)". 9 February 2018.
  19. ^MB Trudeau (2013). "Tablet Keyboard Configuration Affects Performance, Discomfort". PLOS ONE. 8 (6): e67525. doi:10.1371/journal.pone.0067525. PMC 3694062. PMID 23840730.
  20. ^Ian Morris (23 May 2014). "Hate Your Android Keyboard? Try One Of These Four Alternatives". Forbes.
  21. ^"What is an Optical Keyboard?".
  22. ^"Best Optical Keyboards".
  23. ^"Dedicated Cursor Control and Navigation Keys".
  24. ^JoshuaBsfc (14 November 2014). "Keyboard, num lock and caps lock key LED's not working". Windows 10 Insider August 4, 2021 - Free Activators General. TechNet Forums. Retrieved 21 October 2021.
  25. ^ ab"The Qodem Homepage". SourceForge. 18 June 2017.
  26. ^Pagan Kennedy (5 October 2012). "Who Made That Escape Key?". NYTimes.com.
  27. ^"Kermit Manual".
  28. ^"Escape key".
  29. ^"The Qodem Homepage". SourceForge. 18 June 2017.
  30. ^Gesswein, David (n.d.). "ASR 33 Information".
    https://www.pdp8.net/asr33/pics/kbd_top.shtml?large
  31. ^"ASCII Table – ANSI Escape sequences".
  32. ^"Accessing Alternate Graphic Character Sets".
  33. ^"Keyboard shortcuts in Windows". microsoft.com.
  34. ^"Use a keyboard layout for a specific language". Archived from the original on 24 September 2010. Retrieved 7 October 2010.
  35. ^"Changing The Language & Keyboard Layout On Various Distributions". Archived from the original on 1 July 2010. Retrieved 7 October 2010.
  36. ^"Change the default keyboard layout". Archived from the original on 12 September 2010. Retrieved 7 October 2010.
  37. ^Kenneth Kimari (2 September 2018). "10 best backlit keyboards to buy". Windows Report. Retrieved 19 March 2019.
  38. ^"Keyboard Switches – How Computer Keyboards Work".
  39. ^Complete Computer Hardware Only. p. 159.
  40. ^"Why I Use the IBM Model M Keyboard That's Older Than I Am". SlashDot.org. 7 July 2018.
  41. ^A Passion for the Keys: Particular About What You Type On? Relax – You're Not Alone.Archived 10 August 2017 at the Wayback Machine Loose Wire, by Jeremy Wagstaff, Wall Street Journal, 23 November 2007.
  42. ^"Electrical commutation matrixer keyboards for computers". IOPscience.org.
  43. ^Complete Computer Hardware Only. p. 161.
  44. ^"This Fake Phone Charger Is Actually Recording Every Key You Type". TechCrunch. AOL. 14 January 2015. Archived from the MuTools MuLab Crack on 10 August 2017.
  45. ^Herley, Cormac and Florencio, Dinei (2006). "How To Login From an Internet Cafe Without Worrying About Keyloggers"(PDF). Microsoft Research, Redmond. Archived from the original(PDF) on 8 August 2017. Retrieved 10 September 2008.CS1 maint: multiple names: authors list (link)
  46. ^"6 Tips To Secure Webcams, Stop Keyloggers". Dark Reading. Archived from the original on 30 December 2013.
  47. ^Berkeley Lab. Integrated Safety Management: ErgonomicsArchived 11 October 2008 at the Wayback Machine. Website. NordVPN Offline Installer 9 July 2008.
  48. ^Radiology Society of North America The Way You Sit Will Never Be the Same! Alterations of Lumbosacral Curvature and Intervertebral Disc Morphology in Normal Subjects in Variable Sitting Positions Using Whole-body Positional MRIArchived 13 October 2014 at the Wayback Machine.
  49. ^"How To Prevent Carpal Tunnel Syndrome: 9 Hand & Wrist Exercises".
  50. ^"Sharp Edges on Mac Book Pro".
  51. ^"Wrist Rests : OSH Answers".
  52. ^Complete Computer Hardware. p. 165.

External links

Источник: https://en.wikipedia.org/wiki/Computer_keyboard

Dramatic activation of an antibody by a single amino acid change in framework

Abstract

Antibody function is typically entirely dictated by the Complementarity Determining Regions (CDRs) that directly bind to the antigen, while the framework region acts as a scaffold for the CDRs and maintains overall structure of the variable domain. We recently reported that the rabbit monoclonal antibody 4A11 (rbt4A11) disrupts signaling through both TGFβ2 and TGFβ3 (Sun et al. in Sci Transl Med, 2021. https://doi.org/10.1126/scitranslmed.abe0407). Here, we report a dramatic, unexpected discovery during the humanization of rbt4A11 where, two variants of humanized 4A11 (h4A11), v2 and v7 had identical CDRs, maintained high affinity binding to TGFβ2/3, yet exhibited distinct differences in activity. While h4A11.v7 completely inhibited TGFβ2/3 signaling like rbt4A11, h4A11.v2 did not. We solved crystal structures of TGFβ2 complexed with Fab fragments of h4A11.v2 or h4A11.v7 and identified a novel interaction between the two heavy chain molecules in the 2:2 TGFb2:h4A11.v2-Fab complex. Further characterization pdf architect 7 free download - Free Activators that framework residue variations at either position 19, 79 or 81 (Kabat numbering) of the heavy chain strikingly converts h4A11.v2 into an inhibitory antibody. Our work suggests that in addition to CDRs, framework residues and interactions between Fabs in an antibody could be engineered to further modulate activity of antibodies.

Introduction

Transforming Growth Factor-beta (TGFβ) is a key driver of fibrogenesis. There are three TGFβ isoforms with highly homologous receptor-binding domains with high sequence similarity, and have similar effects on target cells in vitro. Unlike TGFβ1, both TGFβ2 and TGFβ3 are expressed at elevated levels in human lung and liver fibrotic tissues and can be activated via distinct mechanisms1. Further, inhibiting both TGFβ2 and TGFβ3 while sparing TGFβ1 could alleviate lung fibrosis while avoiding toxicity concerns associated with pan-TGFβ blockade. We recently identified an isoform-selective rabbit monoclonal antibody (rbt4A11) that binds mature forms of both TGFβ2 and TGFβ3 with picomolar (pM) affinity, but shows no binding to the mature form of TGFβ1. It also has potent inhibitory activity against both TGFβ2 and TGFβ3 with the potential to be developed as a therapeutic for lung fibrosis. Humanization of rbt4A11 was performed to enable development of a potential clinical candidate for non-human primate pharmacokinetics and safety studies. Unlike previously described pan-TGFβ blocking antibodies such as Fresolimumab (Sanofi), the structure of a humanized rbt4A11 Fab (h4A11.v7) complexed with TGFβ2 shows that the epitope for h4A11.v7 is not near the TGFβR1/R2 binding site, and it does not sterically compete for receptor binding. Instead h4A11.v7 Fabs induce a conformational change in TGFβ2, causing the two monomers to “pinch” together by several degrees, demonstrating an allosteric mechanism of inhibition1.

For humanization of rbt4A11, we adopted well-accepted approaches in humanization of rodent (mouse and rat) monoclonal antibodies (mAbs) by grafting complementarity-determining regions (CDRs) and framework residues at the Vernier zone of rabbit antibody onto the human immunoglobulin germline gene segments which shared the highest sequence identity2,3. Combining this approach with the framework shuffling strategy, an efficient and effective way to manipulate and improve antibody properties in humanization of murine mAbs allowed us to rapidly select the most favorable combinations of human germline frameworks to maintain the affinity and activity of the parental antibody4,5.

In the course of rbt4A11 humanization, the entire panel of humanized 4A11 (h4A11) variants exhibited pM binding affinities very similar to the parental clone, but surprisingly varied in inhibition properties for TGFβ2 and TGFβ3 in a cell-based activity assay. To better understand the molecular mechanisms that conferred drastically different functionality of the different humanized variants that still had almost identical CDRs, we solved crystal structures of antigen-binding fragments (Fabs) from a complete blocker (h4A11.v7)(previous work)1 and an incomplete blocker (h4A11.v2)(current work) in complex with human TGFβ2. The structures revealed specific interactions between framework regions in the heavy chains of the two h4A11.v2 Fabs bound to the TGFβ2 dimer. Disruption of this interaction by a single amino acid variation at either position 19, 79 or 81 in the heavy chain framework converts h4A11.v2 to a ‘complete blocker’, similar to h4A11.v7 and rbt4A11.

Results

Humanization of rabbit mAb 4A11 by grafting CDRs to the closest human frameworks

Rabbit monoclonal antibody 4A11 (rbt4A11) was humanized in a two-step strategy. First, the human germline frameworks that are closest to the variable light chain (VL) and variable heavy chain (VH) of rbt4A11 were identified based on the selection criteria of the highest amino acid sequence identity in variable region, frequent usage in antibody repertoire, and functional genes in different germline family. In total, we found four human light chain germline genes (IGKV1D-39*01, IGKV4-1*01, IGKV3-20*01, IGKV2-24*01) and two human heavy chain germline genes (IGHV3-48*01, IGHV4-59*06) as the closest acceptor frameworks, which were 62%, 61%, 54% and 54% identical to the VL, and 57% and 52% identical to the VH of rbt4A11, respectively. Subsequently, the rbt4A11 CDRs, which covered the definition of Kabat and Chothia6, and fifteen rabbit framework residues at the Vernier zone (position 2, 4, 36, 43 and 58 of VL, and position 2, 24, 37, 48, 49, 67, 71, 78, 91 and 105 of VH) were grafted onto each acceptor framework to generate four humanized VL and two humanized VH gene segments for molecular cloning (Fig. 1). To assess the best humanized variants, a panel of eight humanized 4A11 variants (h4A11.v1–h4A11.v8) was generated through mixing and matching the cloned humanized gene segments and expressing each variant as human IgG1 for further characterization (Table 1). The expression and purification profiles of all humanized variants were good (> 99% monomer) with no noticeable differences between germline usage. The variable domains of these eight humanized 4A11 variants comprised an identity of 77–81% in the human immunoglobulin germline sequence, which were further improved by framework Vernier permutation from original rabbit residues to the corresponding human germline residues to meet World Health Organization standards as a humanized antibody (data not shown).

Amino acid sequence alignment of VL and VH of rbt4A11 with the closest human germline acceptor frameworks for humanization. The variable light chain (VL) and heavy chain (VH) domain of rbt4A11 was aligned with its closets human germlines to specify the different (letter) and identical (dot) amino acid residues in framework regions (FWR) and complementarity-determining regions (CDRs) by Kabat numbering scheme6. Six CDRs (box) and fifteen framework residues at Vernier zone (black fill) of rbt4A11 were fused in-frame to individual human germline acceptor framework for shuffling. Three positions (19, 79, 81) at the heavy chain framework guided by structure complex analysis were residues used to modulate antibody function (asterisk). The positions with sequence deletion and undefined heavy chain germline CDR3 were shown in blanks.

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Functional characterization of humanized 4A11 variants

Each humanized 4A11 variant was purified and characterized by measuring its binding affinity and blocking activity against all three mature TGFβ isoforms. To minimize the avidity effect on binding, the affinity of each variant was measured by real-time Biacore SPR using label-free TGFβ in solution with low level of antibody bound to the biosensor surface, as previously described6. Further, the blocking activity of the variant IgGs to inhibit mature TGFβ induced TGFβ receptor dependent signaling was determined using reporter cell lines (HEK-Blue™ TGFβ)1.

After initial characterization, we observed that all eight primary humanized 4A11 variants preserved the same selectivity profiles as parental antibody (rbt4A11) by binding to human mature TGFβ2 and TGFβ3, but not TGFβ1 (Table 1). Although the humanized variants differed slightly in binding affinity compared to rbt4A11, they retained picomolar binding affinity. However, dramatic differences of blocking activity in the cell-based assay for these humanized variants were observed, which was unexpected because the variants contained almost identical CDRs and closely matched germline frameworks. After detailed analysis, we concluded that humanized variants (v3, 4, 7, and 8) using the heavy chain germline (IGHV4-59*06) as an acceptor framework maintained similar potency compared to rbt4A11, whereas the humanized variants (v1, 2, 5 and 6) using the other heavy chain germline (IGHV3-48*01) significantly lost their blocking activity and also turned into incomplete blockers without reaching maximum inhibition at the highest antibody concentration (< 70%). The usage of different light chain germlines had minimal impact on the blocking activity. Among all eight primary humanized variants, v7 had the most desirable affinity (TGFβ2_KD: 6.3 pM; TGFβ3_KD: 9.7 pM) with the best blocking activity (TGFβ2_IC50: 0.9 nM; TGFβ3_IC50: 0.2 nM), and was pursued further as the lead candidate1. This result pointed out that the usage of two different yet closely related human heavy chain germlines in the humanization led to the dramatic difference in their blocking activities.

Crystal structures of TGFβ2 in complex with antigen-binding fragments (Fabs) of h4A11.v2 and h4A11.v7

To further investigate how the heavy chain germline acceptor framework differences in the humanized 4A11 variants resulted in significant functional differences in blocking TGFβ2 and TGFβ3, we selected one of the incomplete blockers (h4A11.v2) and the top complete blocker (h4A11.v7) to obtain crystal structures of Fab fragments in complex with TGFβ2. We reported the crystal structure of the h4A11.v7 Fab in complex with TGFβ2 recently1. To investigate any structural differences in the TGFβ2:Fab complexes for both v2 and v7 variants, we crystallized and solved the x-ray crystal structure of TGFβ2 in a complex with Fab from h4A11.v2 to 2.9 Å resolution (Table 2). The overall structures of both v7 and v2 complexes are very similar, with two Fab fragments binding to two TGFβ2 molecules and the epitope of each Fab containing contributions TidyTabs Professional Crack 1.18.0 With License Key [2021] both TGFβ2 monomers in the dimer for the h4A11.v2-Fab, as previously reported for the h4A11.v7-Fab (Fig. 2). The overall RMSD for all atoms in TGFβ2 and the variable regions (Fv) of the complexes is 1.04 Å. The constant regions of the Fabs were excluded from these calculations because the wide variation in elbow angle of Fabs distorts the overall alignments in an irrelevant way7.

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The structures of h4A11.v2 and h4A11.v7 Fabs in complex with TGFβ2 are similar. Overall structures of (A) TGFβ2-dimer:h4A11-v2 Fab complex and (B) TGFβ2-dimer:h4A11-v7 Fab complex are very similar with RMSD of 1.04 Å for all atoms (only VH-VL regions in the Fab are shown for clarity).

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An analysis of TGFβ2:h4A11.v2-Fab and TGFβ2:h4A11.v7-Fab crystal structures revealed that the epitopes of both h4A11.v2 and h4A11.v7 antibodies on the TGFβ2 dimer are identical (Fig. 3). This, along with identical CDRs between the two variants, suggested that the functional differences observed between the two variants cannot be explained by a potentially altered epitope. Further analysis of the two structures revealed an intriguing interaction of the 2 heavy chain molecules in the TGFβ2:h4A11.v2-Fab complex with each other, which was not present in the TGFβ2:h4A11.v7-Fab complex. In the TGFβ2:h4A11.v2-Fab complex structure, Y79, R19 from one heavy chain molecule form a ternary π-stacking interaction with Q81 from the other heavy chain molecule and vice versa, resulting in a pseudo-symmetric interaction (Fig. 4A), which likely orients the relative positions of the two heavy chains and the conformation of the Fabs relative to TGFβ2 and alters the dynamics of the h4A11.v2 Fab when bound to TGFβ2 in solution, compared to the h4A11.v7 Fab. Supporting this hypothesis, in the TGFβ2:h4A11.v7-Fab complex structure, the corresponding residues in the heavy chain framework region are S19, S79 and K81, which do not allow for the specific interactions observed in the TGFβ2:h4A11.v2-Fab complex (Fig. 4B). Although the distances between the Cα atoms of the respective residues at each position (19–19, 79–79, 81–81) in the heavy chains of both the h4A11.v2 and h4A11.v7 Fabs are almost identical in the two structures, we hypothesized that in solution, the interactions between the side chains at 19, 79 and 81 among the 2 heavy chain molecules and subtle effects on the conformations of the Fabs may be the difference between a functional ‘complete blocker’ and an ‘incomplete blocker’, where the slight differences induced in the dynamics of the TGFβ2 dimer itself due to the presence or absence of the subtle Fab–Fab interaction could play a role. For such an interaction, we assume that two Fabs from the same antibody molecule would bind to a TGFβ2 dimer in solution since the rbt4A11 antibodies have monovalent interactions with dimeric TGFβ2 and TGFβ3. To test this hypothesis, we performed step by step mutagenesis to try and convert a v2-like function (incomplete blocking) to a v7-like function (complete blocking) with an increasing number of mutations listed in Table 3. We hypothesized that a simple R19S substitution in h4A11.v2 would disrupt the π-stacking interaction, and so would Q81N or Q81A. In addition, to convert a v7-like function to a v2-like function, we hypothesized that we would need to introduce a greater number of mutations at positions 19, 79, 81 to re-build the stabilizing interactions of a v2-like molecule. In this process, we also included pc cleaner pro free download aromatic sidechain W at position 79, as it could result in a π-stacking interaction similar to Y in the TGFβ2:h4A11.v2-Fab structure (Fig. 4).

The epitopes of h4A11.v2 and h4A11.v7 on TGFβ2 are identical. The residues in TGFb2 dimer that form the epitopes of (A) h4A11.v2 and (B) h4A11.v7 are highlighted as sticks and labelled.

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Molecular interactions between h4A11.v2 and h4A11.v7 Fabs bound to TGFβ2. (A) π-stacking between Y79 and R19 from one heavy chain A and Q81 from the second heavy chain B and vice versa results in a stable interaction between the two heavy chains of the Fabs in the h4A11.v2:TGFβ2 complex. (B) Aforementioned π-stacking is disrupted in h4A11.v7:TGFβ2 complex because of the substitution in the framework region of the heavy chain residues to S79, S19 and K81.

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Generation and functional characterization of structure-guided h4A11.v2 and h4A11.v7 heavy chain framework variants

To test the advanced systemcare pro 12.5.0.354 key - Free Activators in accordance with our structural analysis, a new panel of variants was generated with single or multiple mutations at position 19 (HC-FWR1), 79 and 81 (HC-FWR3) of h4A11.v2 and h4A11.v7. Following expression and purification, all variants were fully characterized and compared with parental rbt4A11, h4A11.v2 and h4A11.v7. As predicted from our structural analysis, all h4A11.v2-based variants (h4A11.v2.1–h4A11.v2.6) demonstrated binding affinity improvement as well as regained complete blocking activity in the cell-based assay against TGFβ2 and TGFβ3 (Table 3). All three single mutation variants (v2.1_R19S; v2.2_Q81N; v2.3_Q81A) were sufficient to restore complete blocking function similar to rbt4A11 (v2.1 in Fig. 5). Furthermore, by adding other mutations to R19S (v2.4_ R19S, Y79S; v2.5_ R19S, Q81S; v2.6_ R19S, Y79S, Q81S), did not further change the effect of the individual mutations, suggesting the critical role of positions 19, 79 and 81 in the observed h4A11.v2 heavy-chain interactions upon TGFβ2 and TGFβ3 binding. In contrast, all h4A11.v7-based variants (h4A11.v7.1–h4A11.v7.6) with double mutations (v7.1_S19R, S79Y; v7.2_S19R, S79W) and triple mutations (v7.3_S19R, S79Y, K81Q; v7.4_S19R, S79Y, K81R; v7.5_S19R, S79W, K81Q; v7.6_S19R, S79W, K81R) appeared to have a broad range of affinity drop (4–34 fold) compared to rbt4A11 and turned into incomplete blockers against TGFβ2 and TGFβ3 (v7.1 in Fig. 5). These results supported the important functional role of short sidechain amino acids at human framework positions 19 and 79 in the active h4A11.v7 molecule.

Dose-dependent inhibition of TGFβ by humanized 4A11 variants in HEK Blue™ TGFβ reporter cell-based assay. Human mature TGFβ2 (left) or TGFβ3 (right) isoform was incubated with a serial dilution of humanized 4A11 variants in quadruplicate to generate a dose-dependent inhibition curve. The response was normalized to maximum TGFβ activity (%) and mean activity ± standard deviation was plotted as a function of antibody concentration. The variants exhibiting less than 10% of maximum TGFβ activity at the highest antibody concentration were complete blocker (e.g., rbt4A11, h4A11.v2.1, h4A11.v7), whereas those reaching greater than 30% of maximum TGFβ activity were incomplete blockers (e.g., h4A11.v2, h4A11.v7.1).

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Discussion

In our current work, we identified a unique and interesting phenomenon during humanization of an allosteric antibody against TGFβ2 and TGFβ3, where a single amino acid in the framework region regulates antibody function. This work highlights how subtle differences in framework regions with no effect on antigen binding can dramatically alter antibody function in allosteric ligand blocking. We also demonstrate that it is possible to convert the inhibitory properties of the humanized antibodies by a single amino acid change in framework.

Functional antibodies impart their effects on their targets primarily through the interaction of their CDRs with the antigen. For symmetric, multimeric antigens, where appropriate relative orientations of each monomer are important for binding to partner proteins and for signaling, the existence of multiple epitopes of the antibody (Fab) and the multimeric nature of the interaction between antigens and Fabs could have consequences for signaling. This may offer clues to further design favorable properties for antibodies by varying the regions of antibodies beyond CDRs. As illustrated in this report, the interactions (or lack thereof) between the heavy chain framework regions in two Fabs can have a profound impact on signaling.

Although humanization is a well-established art in the field of antibody engineering, potential learnings especially from allosteric antibodies against antigens that function as multimers could be useful in improved antibody design. In this work, we have introduced and demonstrated an effective approach to humanize the rabbit monoclonal antibody 4A11 using the combinations of CDR grafts and framework shuffling. This approach has been successful in our humanization of multiple rabbit mAbs (data not shown). During the humanization process, we usually select the variants with activities similar to parental antibodies to move forward. However, in the humanization of 4A11, the variants displayed intriguing properties with similar binding affinity, but dramatically different blocking activity in cell based activity assays. The crystal structures of h4A11.v2 and h4A11.v7 Fabs bound to TGFβ2 have further delineated the mechanism of the allosteric inhibition that is dependent on homotypic interactions between framework regions of heavy chains. The subtle difference in the human framework impacts the interactions between the heavy chains framework regions of the two Fabs of humanized 4A11 that leads to the loss of activity in h4A11.v2, but not h4A11.v7.

Interaction between framework regions of the heavy chain of Fabs within a functional antibody has been observed before, for example, the anti-HIV-gp120 neutralizing Fab, 2G12 which was isolated from a patient that was resistant to several strains of HIV8. In the case of 2G12, the variable domain of one heavy chain undergoes a domain exchange with the variable domain of the 2nd light chain in the antibody and vice versa resulting in a dimerized Fab9. In addition, in 2G12, the typically surface exposed framework regions of the heavy chain are also extensively modified to form a specific stable interaction between the framework regions of the two heavy chains. This places the paratopes of the antibody in a defined, rigid geometry, that allows specific recognition of the carbohydrate clusters on the HIV gp120, which would not be possible with a typical IgG scaffold, where there are no stabilizing interactions between the heavy chain variable domains.

Our work, in addition to the 2G12 example above, suggests that the framework regions offer yet another region in an antibody for engineering interactions between Fabs and modulating antibody function. This could especially be useful where antigens are multimeric and restricting the paratopes on Fabs in a defined orientation to match a geometrically restricted and repeated epitope in a multimeric target could be useful to impart agonistic or antagonistic properties to the antibody, on top of binding properties imparted by CDRs, based on the molecular mechanism of signaling of the driverpack solution 18 - Crack Key For U and its effector molecules.

Methods

Humanization, IgG variants cloning, expression and purification

The variable regions of rabbit antibody 4A11 (rbt4A11) amino acid sequence were aligned to its closest human germlines using informatics tool (AbGrafter, Genentech) which covered all available immunoglobulin IGKV and IGHV mammalian human germline genes (Homo sapiens) in the international immunogenetics information system10. The closest human IGKV and IGHV germline frameworks identified through the process were then served as the acceptor frameworks for grafting rbt4A11 light chain and heavy chain hypervariable regions with the corresponding rabbit framework residues at the Vernier zone respectively3. By mixing and matching these grafting acceptor frameworks, a total combination of eight humanized 4A11 variants (h4A11.v1–h4A11.v8) were generated.

The coding sequences of each humanized variant’s variable region were generated by DNA synthesis and cloned into human IgG1 expression vectors (Genewiz). Small-scale IgG expressions and purifications were done in a high-throughput format. Briefly, IgG expressions were transiently conducted in Expi293F cells (Thermal Fisher Scientific), followed by a 2-step purification using Protein A affinity chromatography (MabSelect SuRe™, Cytiva) and analytical size exclusion chromatography (SEC, Cytiva). Quality control of antibody’s purity was determined by SDS-PAGE with Coomassie blue staining, A280 absorbance to measure protein concentration and aggregation analysis by SEC, as previously described11,12.

Expression, purification and crystallization of human TGFβ2 and h4A11.v2 /h4A11.v7 Fab

The mature form of human TGFβ2 was produced as previously reported13. LAP-TGFβ2 was expressed with a CHO TI stable cell line. Protein was purified with Ni–NTA, then was acidified and dialyzed in 0.1 M sodium citrate, pH 3 and loaded onto a 5 ml SP HP column. The fractions that contained the protein of interest from the SP pool were then further purified with Vydac C4 RP-HPLC. The fraction containing mature TGFβ2 was dialyzed directly into 1 mM HCl pH 3.0.

The Fab fragments of anti-TGFβ2 (h4A11.v2 and h4A11.v7) were expressed in E. coli overnight at 30ºC under the control of the PhoA promoter. The cells were pelleted by centrifugation at 6000 rpm for 15 min and lysed by microfluidization in PBS supplemented with 25 mM EDTA and 1 mM PMSF. Cell debris was removed by centrifugation at 10,000 rpm for 1 h at 4 °C. The resulting supernatant was run through a Protein G column equilibrated in PBS, and eluted with 0.58% acetic acid. Protein fractions were further purified by ion exchange chromatography (SP-sepharose) in 20 mM MES (pH 5.5) and eluted with a gradient from 0 to 250 mM NaCl.

The TGFβ2 and h4A11.v2 Fab complex was mixed at 1:1 molar ratio and further purified using a Superdex-200 column equilibrated in 25 mM Tris–HCl (pH 7.5) and 200 mM NaCl. For crystallization, the complex samples were concentrated to 10 mg/ml. The h4A11.v2 Fab/TGFβ2 crystals were obtained by vapor diffusion at 19 °C with mixing equal volumes of protein plus 15% PEG 4000 and 0.1 M Na Cacodylate pH 6.0 well solution. Crystals were cryoprotected with 25% glycerol. Data set was collected at the Advanced Light Source beamline 5.0.2 and processed with the HKL package14. Crystal structures were solved by molecular replacement using Phaser15. The refined coordinates of the TGFβ2 structure PDB file (6I9J) served as the search probe for the structure for TGFβ216. Subsequently, the constant (Fc) and variable (Fv) portions of the Fab were placed separately using Phaser and underwent initial rounds of rigid-body refinement with Phenix17. The model went through several iterative rounds of adjustment with Coot18. Atomic models were then built and refined with Phenix17.

TGFβ binding affinity measurement

The binding affinity of each humanized 4A11 (h4A11) variant was determined by surface plasmon resonance (SPR) technology (Biacore™-T200, Cytiva). Briefly, Series S sensor chip Protein A (Cytiva) was utilized to capture each version of h4A11 antibody on a different flow cell (FC) to achieve approximately 90 response units (RU), followed by the injection of five-fold serial dilutions of each human mature TGFβ isoform (PeproTech; 0.008 nM to 5 nM) in HBS-EP buffer (100 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% (v/v) Surfactant P20) with a flow rate of 100 μl/min at 37 °C to reach a relative low maximum binding response (Rmax) around 30 RU. The association was monitored by a standard 3 min observation, whereas the dissociation was extended to a much longer time (60 min) to receive sufficient decay for accurate off-rate measurement. The sensorgrams were recorded, processed by reference and blank subtraction, and evaluated by a simple one-to-one Langmuir binding model (Biacore T200 evaluation software version 2.0) to determine the equilibrium dissociation constant (KD).

TGFβ inhibition cell-based assay

The blocking potency of each h4A11 variant against each human mature TGFβ isoform was evaluated by a HEK-Blue™ TGFβ cell-based reporter assay. HEK-Blue™ TGFβ cells (InvivoGen) were generated by stable transfection of HEK293 cells with the human TGFβ receptor 1, Smad3, and Smad4 genes, and further expressed a Smad3/4-binding elements (SBE)-inducible secreted embryonic alkaline phosphatase (SEAP) reporter gene. Before experiments, cells were maintained in DMEM high glucose medium containing 10% fetal bovine serum (VWR), 2 mM L-glutamine, 50 units/mL penicillin, 50 μg/mL streptomycin, 100 μg/ml Normocin™, 30 µg/ml of blasticidin, 200 µg/ml of Hygromycin B Gold and 100 µg/ml of Zeocin™ (InvivoGen) at 37 °C ± 0.5 °C with 5% CO2. On the assay day, cells were seeded in cells were seeded in Greiner Bio-One™ CellStar™ 384-Well, cell culture-treated, flat-bottom microplates at a density of 9000 cells per well in the test medium (DMEM high glucose supplemented with 10% heat inactivated fetal bovine serum, 50 units /mL penicillin, 50 μg/mL streptomycin, and 2 mM glutamine) and incubated for 15 min at the condition described above. Each antibody variant, fourfold serially diluted for 12 points (final 0.000159 nM to 667 nM), was incubated with each human mature TGFβ isoform (PeproTech; final 20 pM) for 1 h, followed by transferring to the plates containing cells. The SEAP in the supernatant was measured with Quanti-Blue (InvivoGen) per manufacturer’s instructions after advanced systemcare pro 12.5.0.354 key - Free Activators incubation for 18–22 h. All experiments were done in quadruplicates, and the maximum or minimum response was determined by TGFβ or test media only respectively for normalization. The half maximal inhibitory concentration (IC50) values were then calculated by fitting the titration curves ([Antibody variant] vs. % Maximum TGFβ activity) using a Prism variable slope four parameters model (GraphPad Software).

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Acknowledgements

We thank Tianhe Sun, Joe Aaron, Ryan Kelly and Matthieu Masureel for discussions and Genentech protein production group for technical assistance and support. The coordinates and structure factors of the crystal structure of the h4A11.v2-Fab:TGFb2 complex were deposited in the Protein Data Bank with Accession Number 7RCO.

Funding

All authors are employees at Genentech Inc.

Author information

Affiliations

  1. Department of Antibody Engineering, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Wei-Ching Liang & Yan Wu

  2. Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Jianping Yin, Patrick Lupardus & Jawahar Sudhamsu

  3. Department of Biochemical and Cellular Pharmacology, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA

    Jianhuan Zhang & Kelly M. Loyet

  4. Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Jawahar Sudhamsu

Contributions

W.C.L., P.L., J.S. and Y.W. designed the research, interpreted the data and wrote the paper. W.C.L, J.Y., J.Z. and K.M.L. performed the experiments.

Corresponding authors

Correspondence to Jawahar Sudhamsu or Yan Wu.

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Liang, WC., Yin, J., Lupardus, P. et al. Dramatic activation of an antibody by a single amino acid change in framework. Sci Rep11, 22365 (2021). https://doi.org/10.1038/s41598-021-01530-w

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  1. I started a new job where I have to use a Mac for work. This video was really helpful in getting me to grips with the basics. I still struggle with the Mac keyboard though (it simply doesn't have the depth of a good ThinkPad).

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