![]() We can make a copy of this file (using the redmine user): ![]() There is an example of the database connection configuration file with all supported databases in the config subdirectory of the extracted archive. Now we have all information needed to tell the application where and how will it find the database.With that in place, we need to restart the database for the settings to take effect:.If you have such line, comment it out, it will conflict with the login we plan to set up. The redmine user will connect locally, so we add the following line to the pg_hba.conf file, located by default at /var/lib/pgsql/data by default on RHEL based distributions:Ĭheck your configuration file for the following: # IPv4 local connections: Now that the user is set up, we need to allow login for it on the database server.We’ll need the username, password, encoding and database name in a later step. We also create a new database with the owner created above: postgres=# CREATE DATABASE rmdb WITH ENCODING='UTF8' OWNER=redmine We’ll create a role that will be used by the application (note down the username and password): postgres=# CREATE ROLE redmine LOGIN ENCRYPTED PASSWORD 'R3DM1N3' NOINHERIT VALID UNTIL 'infinity' We’ll login to psql as the superuser of the database: $ psql To do so, we’ll switch to the postgres operating system user created by default at database installation: We’ll need to create an empty database where the application will store it’s data.To setup the database for the application’s connection, we have to start it up if it isn’t running already:.Now we can set the redmine user as the owner of the extracted directory hierarchy, recursively: # chown -R redmine:redmine /opt/redmine* Optionally we can also create a symlink for easier access – this way we don’t need to remember the exact version: # ln -s /opt/redmine-4.0.3 /opt/redmine We’ll switch to this directory, and extract the archive: # cd /opt From here we can download the compressed tarball with wget to the target system:Īs the above command suggests, we’ll install the application under the /opt directory. To obtain the application, visit the the official download site (which is running on Redmine).# dnf install kernel-devel kernel-headers gcc postgresql-devel ruby ruby-devel rubygems To install the packages the operating system will provide, we’ll use dnf:.With the above configuration in place, all we need to do is add the redmine user to the wheel group: # usermod -a -G wheel redmine The second line with the NOPASSWD option is commented out, which will suit our needs. To check that this group is set up as sudoer, we can grep the /etc/sudoers file: # grep "%wheel" /etc/sudoers On RHEL based distributions, there is a wheel user group, who is allowed to use sudo to run privileged commands. We have to set a password for the new user, which we will use when using sudo: # passwd redmine We can revoke this access once the installation is complete. We’ll create a user who will be the owner of the application, and we’ll give it temporary sudo access.If the database setup is new, don’t forget to complete the initdb step in the mentioned guide, or the startup of the database will fail. You can refer to the PostgreSQL installation guide on RHEL8 for the detailed setup of the database in general, in this article we’ll cover only the steps needed for Redmine. We’ll use the Red Hat repositories available after enabling subscription management to solve the operating system dependencies. For the installation we’ll have to use rubygems and bundler, and compile a lot of dependencies, so it will take a while. How to install redmine on Redhat 8 step by step instructions $ – requires given linux commands to be executed as a regular non-privileged user # – requires given linux commands to be executed with root privileges either directly as a root user or by use of sudo command Privileged access to your Linux system as root or via the sudo command. Requirements, Conventions or Software Version Used Software Requirements and Conventions Used Software Requirements and Linux Command Line Conventions Category
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![]() Outdated Hide Online - Hunters vs Props Ver. Open Request Hide Online - Hunters vs Props *How to install (click the spoilers to read)* Stay away from harmful malicious mods that fill your device with UNWANTED ADS! I always provide quality service with no such malicious tricks to earn money. Thus, the identification of the sender and the recipient of the payment becomes impossible, regardless of the source and the form of the request.Game Name: Hide Online - Hunters vs Props Using cryptocurrency as the primary payment method allows you to hide the transaction participants.As a result, users receive an archive of the following targets files: incoming and outgoing text messages, current GPS coordinates of the device, audio and video calls history, contact lists, as well as received and sent photo and video files.The battery power is consumed as usual without any additional operations on the device. It is undetectable to any malware scanner and antivirus. AppMessenger Tracker works in full invisible mode and does not affect the normal operation of the device.Since the archive size can exceed 2 GB of disk space, its downloading time depends on your Internet connection specs. As a rule, a full operation cycle (from launching to archive downloading) takes no more than 20 minutes. WhatsApp hacking time may vary depending on AppMessenger server load.The main requirements are the presence of a stable Internet connection and one of the following browsers: last version of Google Chrome, Safari, Mozilla Firefox, Internet Explorer, MS Edge or Opera. ![]() Online WhatsApp hacking tool can be used on any modern mobile device.Please consider these few important things when using the AppMessenger SS7 Tracker: We accept only the most anonymous and secure payment methods. Client Security and Highest Anonymity Level - Our Main PriorityĪny data our clients specify at sign-up or when using this service undergoes two-factor encryption that entirely rules out the possibility of further identification. Service administration never shown any interest in exact purposes this software is used for. Moreover, you can always restore the history of your own WhatsApp account, in case of losing control over your phone number. It is worth noting that, spared from necessity to confirm a device owner's consent, you can use software in line with your individual needs. The Main Scenarios for Using WhatsApp Hacking Tool:Īny client independently determines AppMessenger Tracker field of use, which is most often remote monitoring (family members, significant others or company employees). AppMessenger developers fully automated a complex algorithm and created the most user-friendly service interface, which will be accessible and understandable to any client. This is needed to log into a specified account via a specially configured WhatsApp emulator, which allows, in a few minutes time, creating an archive containing the following: incoming and outgoing text messages, current location data, call history with the indication of a dialog partner and conversation duration, contact lists, as well as received and sent photo and video files. When exploiting the SS7 vulnerability, a message to a specified phone number is being intercepted remotely. ![]() How to Intercept a Verification SMS without Physical Access to Device? ![]() Therefore, there's only one way to hack WhatsApp – by intercepting a service message containing a verification code when your target's account is being transferred to some new device. For obvious reasons, app developers properly worked through its security system making available a two-factor authentication system. WhatsApp has over 1.5 billion daily active users worldwide. Get access online without detection risk thanks to the full-stack implementation of advanced cyber-security and encryption technologies. Consequently, any software package for WhatsApp hacking becomes a relic of the past. Our developers created an absolutely unique method of obtaining personal information being free from uploading and running spyware on a target device. ![]() Be sure to keep your software and programs up to date to avoid future problems caused by corrupted files. You should not delete a safe executable file without a valid reason, as this may affect the performance of any associated programs that use that file. When there, you can run a security program and a complete system analysis. In this case, you must enable Safe Mode with Networking - a secure environment that disables most processes and loads only the most required services and drivers. In addition, the functionality of the virus may itself affect the deletion of duckcapture.exe. Note that not all tools can detect every type of malware, so you may need to try several options before you're successful. To delete the duckcapture.exe virus, you should download and install a full security application like Malwarebytes. If you suspect that you may be infected with a virus, then you must attempt to fix it immediately. To do this, find this process in Task Manager.įind its location (it should be in C:\Program Files\DuckLink\DuckCapture\) and compare the size etc with the above facts. If you had any difficulties with this executable, you should determine if it's trustworthy before deleting duckcapture.exe. Known to be up to 29.01 MB in size on most Windows.Full Path: C:\Program Files\ducklink\duckcapture\duckcapture.exe.Located in C:\Program Files\DuckLink\DuckCapture\ subfolder.The most important facts about duckcapture.exe: Not all good Windows processes have a Verified Signature label, but neither do any of the bad ones. If the "Verified Signer" status of a process is listed as "Unable to Verify", you should take a moment look at the process. Now go to View -> Select Columns and add "Verified Signer" as one of the columns. Start the program (it does not require installation) and activate "Check Legends" under Options. ![]() If you find a suspicious directory here, it may be a good idea to investigate this process further.Īnother tool that can sometimes help you detect bad processes is Microsoft's Process Explorer. To confirm, open the Task Manager, go to View -> Select Columns and select "Image Path Name" to add a location column to your Task Manager. For example, a process like duckcapture.exe should run from C:\Program Files\ducklink\duckcapture\duckcapture.exe and not elsewhere. The first thing that will help you determine if a particular file is a legitimate Windows process or a virus, is the location of the executable itself. Is duckcapture.exe safe, or is it a virus or malware? (optional offer for Reimage - Website | EULA | Privacy Policy | Uninstall) Recommended: Identify duckcapture.exe related errors Please read the following to decide for yourself whether the duckcapture.exe file on your computer is a virus or trojan horse that you should delete, or whether it is a valid Windows operating system file or a reliable application. In some cases, executable files can damage your computer. exe extension of a file name displays an executable file. The software is usually about 29.01 MB in size. Repair the exe errors with software toolĭuckcapture.exe is an executable file that is part of the DuckLink Screen Capture 2.5 program developed by DuckLink.Updated July 2022: Here are three steps to using a repair tool to fix exe problems on your computer: Get it at this link ![]() Please direct correspondence to Building sustainable global collaborative networks: Recommendations from music studies and the social sciences. to Please note: We welcome questions, comments, citation, and constructive criticism, bearing in mind that this is a draft preprint subject to revision. As researchers in music and the social sciences with experience building and sustaining such networks, we participated in a virtual symposium on February 7, 2021. Global collaborative networks have been established in multiple fields to move beyond research that over-relies on "WEIRD" participants and to consider central questions from cross-cultural and epistemological perspectives. These divergent perspectives create an ethical and legal quandary, and further empirical and normative work is needed to fully characterize the implications of substantive differences in participant rights and protections. However, the extent to which they perceived such variability as problematic differed, as did their perceptions of stakeholder roles and responsibilities for addressing state law variation, and their estimations of requisite knowledge among IRBs and researchers. ![]() Interviewees were aware of state-based variation in laws that could be applied to research. Our goal was to better understand their experiences with choice of law issues, the effects of state law variation on research practices and stakeholder groups, and approaches to addressing such variation. To shed light on this topic, we conducted interviews with experts in law, human research protections, and precision medicine research. Thus, the determination of which state's laws apply, and under what circumstances, can substantially alter participant rights and protections. Precision medicine research in particular implicates state laws that govern an array of topics, including human subjects research, genetic testing, and both general and genetic privacy and discrimination. ![]() Pharmaceutical industry research spending exceeds the National Institutes of Health (NIH) budget, which increased from approximately $1 billion in 1970 to $30 billion in 2010.2 Multisite research, expansion into international and community settings, novel scientific opportunities, freezers of stored samples, expanded categories of researchers, and entities including contract research organizations, data and safety monitoring committees, clinical trial coordinating centers, and commercial IRBs have transformed the clinical research enterprise.įederal law establishes minimum standards for protecting human research participants, but many states have enacted laws that may apply to research. Institutional review boards were initially created to provide independent review of research conducted by researchers at their own institutions, impartial assessment of the ethical acceptability of proposed research, and a check on investigators' interests.1 Subsequently, advances in knowledge, technology, and resources have changed the face of research. Unregulated (Facebook) and regulated (Cornell University) activities were combined in the PNAS publication ( 1), the former by experimenting with large numbers of unwitting participants, the latter by approving the use of preexisting experimental data as exempt from the university’s ethical review.Institutional review boards (IRBs) are the core of the well-established US system for the protection of human research participants. One might well wonder why academic research is more subject to ethical review than that of business enterprises. In contrast, academic research is almost always governed by the provisions of the “Common Rule,” the US Department of Health and Human Services’ Code of Federal Regulations Title 45 Part 46 (45CFR46), “common” because it has been adopted by numerous federal agencies and applied to many research institutions. In commerce and on the Internet, experimentation is ubiquitous and invisible, and there are no protections for human participants beyond typically unread use agreements. Those events were recognized in an Expression of Concern in PNAS ( 2). Facebook’s experimental manipulation of newsfeed content and the subsequent PNAS publication of significant findings from it ( 1) have drawn attention to the regulation of human participation in academic research and to the differences between commercial and academic research. ![]() Take advantage of procedurally generated maps, characters, and challenges, to tell memorable stories.Ĭhoose to let defeated characters die in a deed of epic heroism, or live to fight on.Įvolve your plans and strategies as unpredictable moments alter your world. Unique as a Thing That's Just Very Unique In addition, the hero can gain wings, a tail, or a pet. Themes can change the appearance of a heros head, left arm, right arm, left leg, right leg, torso, or skin. Preserve the memory of your favorite heroes to live on as legends, and join your story again. Here's every currently confirmed game arriving on Game Pass day one in 2022 and beyond: Starfield November 11, 2022. A theme consists of a set of related modifications that can change a heros appearance, abilities, and stats. Guide these heroes as they enjoy triumph and love, or as they endure rivalry and loss. Meet dynamic characters, all generated with life histories and personalities. Kicking off 2020 with a strong start, the game we Cant Stop Playing this January is Wildermyth. Its good to know that the rest of RPS will play anything if I call them 'cowards' enough. Watch out for more articles on it throughout the month. Invest in the stories of heroes through dialogue-rich events, relationships, and personal quests. This time were weaving a narrative tapestry in the character-led tactical RPG Wildermyth. Thrive in tactical turn-based combat with deep and surprising advancement opportunities. Forge new stories in Wildermyth where any tale has the chance to live forever.Įxplore the wilderness, claim mysterious sites, and fight back against an oppressive enemy. Meet your heroes before they are anyone, and grow them into a roster of legends who shape the course of their own Yondering, and the worlds that come after. The Yondering Lands are wild, filled with beauty and magic, but also rife with threats that lurk and muster. ![]() ![]() ![]() Save Time and Labor: Steel City boxes and covers are a complete solution for mounting devices and fixtures in walls and ceilings. In manufacturing quality and innovative design, Steel City has no peer. Having said that unless you are removing coverplates (which I sometimes do) you aren’t going to find it.Since 1904, Steel City ® products have set the standard as the leading brand in electrical construction. Michael, I can think of only 2 reasons for extending a J box, the first is to correct the relative depth of the box to the drywall, the second possibility is to increase the boxes fill capacity.Īs an inspector I would make no note of them unless I felt there was something weired going on (such as a second layer of drywall installed over existing to hide something) I have seen that done. Are there any sparkies left on the message board? If what I’m asking is not clear to you then that’s OK, I probably don’t need to know that (Bob), perhaps only the sparkies will now what I’m referring to and can explain it. ![]() Now, certainly that would seem like it would be outside the scope of a typical home inspection to even think about something like that but, trust me, I have ulterior motives for understanding this concept better. A wall constructed of metal studs but finished with wood panels requires that the outlet boxes be mounted flush with the combustible material."Ĭan someone please explain the requirements and use of ‘spacers’ at electrical outlet boxes? My understanding is that in certain instances a trim ring of sorts may be needed at a j-box, that is recessed too much into the wall, to maintain the gap (1/4"?) caused by that recessing of the box and the cover plate. “A wall constructed of wood but sheathed with an outer layer of gypsum board is permitted to contain boxes set back or recessed not more than 1/4”. In walls and ceilings constructed of wood or other combustible surface material, boxes, plaster rings, extension rings, or listed extenders shall be flush with the finished surface or project therefrom." “In walls or ceilings with a surface of concrete, tile, gypsum, plaster, or other noncombustible material, boxes employing a flush-type cover or faceplate shall be installed so that the front edge of the box, plaster ring, extension ring, or listed extender will not be set back of the finished surface more than 6mm (1/4”). Note: I think I have subsequently found the answer to my question and would delete this post if it allowed me to. Can someone please explain the requirements and use of ‘spacers’ at electrical outlet boxes? My understanding is that in certain instances a trim ring or extender of sorts may be needed at a j-box, that is recessed too much into the wall, to maintain the gap (1/4"?) caused by that recessing of the box and the cover plate. After you collect your key on Autokey, you will be presented with your unique activation code. After your payment, you can then collect your code from our Autokey system. How does the purchasing process work?įirst, simply check-out using any of our easy payment methods. The game can be activated from anywhere in the world. As a result, it is completely region free and includes all languages upon installation. This activation code is sourced from the EU. This is an unused, brand new CD Key for the season pass, which can be used on Steam to activate the season pass. Once activated, you can enter the code into the Steam client in order to activate a full digital download of the season pass. This means that after your payment, you can go to our Autokey page and collect your CD Key. The activation code will be sent via our online Autokey system. You must already own Bioshock Infinite in order to use this key. 357 uses a break-action reload system with a removable cylindrical magazine based on the Dardick Tround concept, and not the traditional swing-out revolving cylinder it uses in Team Fortress 2.This is a brand new, genuine, and unused Bioshock Infinite Season Pass Steam Key. In Deus Ex: Human Revolution, the Diamond Back.357 looks when it is upgraded with a Laser Sight and Explosive Rounds, instead of its default, unmodified appearance. The Diamondback's design in Team Fortress 2 resembles how the Diamond Back.There are unused particles that resemble the particles used for Marked for Death.The crits counter overlaps with the Cloak meter when using the Minimal HUD advanced option.Like all of the Spy's secondary weapons except the Revolver and the Enforcer, the Spy does not actually put any bullets into the cylinder while reloading.Firing once sets the counter to the correct value. Destroying a building with a guaranteed-critical Diamondback shot earns another guaranteed crit however, the counter displays as having 0 stored crits.However, picking up another secondary weapon while having a picked up Diamondback results in the stored crits disappearing.If a Spy performs backstabs or saps buildings with a different secondary weapon equipped, the crits are retroactively awarded as soon as the Spy switches to the Diamondback via a Resupply locker or by picking up a dropped Diamondback.Players do not earn any critical hits for sapped buildings destroyed with non-critical Diamondback shots.Fixed the Diamondback accumulating crits for backstabbing ÜberCharge players.Backstab kills now gains a critical attack. ![]()
![]() I created the seeds of RequireJS as RunJS. Some environments, like Adobe AIR do not allow eval() and most developers are taught that eval() is evil and should be avoided. It can also be slower than plain script tag loading. Using synchronous XHR is not very friendly for new developers or people who want ease of debugging across browsers. However, I was mostly concerned with something that worked well in the browser, and that meant needing a function wrapper so we could use script tags. I originally wanted something that would work with CommonJS modules, but those modules seemed to be structured assuming a synchronous module loader, which is possible in server-side JavaScript environments. I also liked explicitly passing the dependent modules as arguments to the function definition, since it allowed linting tools like JSLint to be more effective. I believe RequireJS is more generic, since YUI seems to use labels for their modules that do not directly correspond to file paths. YUI 3's use() function is also very similar to require, and use()'s API (but not code) also informed RequireJS' structure. I fleshed out some of the details for RequireJS (then called RunJS) on the dojo-contributors list, and Mike Wilson originally pushed for a more generic loader that could load plain files as well as allow for different contexts. The Dojo community seemed more amenable to considering a function wrapper, particularly since we are considering a Dojo 2.0 that can break some APIs. This can cause errors if the module references a dependency as part of the module's definition. In 2009, David Mark suggested that Dojo use document.write() to load modules before the page loads to help with that issue, but it meant required dependencies would not load until after the current module executes. ![]() However, the sync XHR loader has other issues, like making debugging harder. Because of the more complex i18n and requireIf requirements and the existence of many dojo modules already out in the world, I did not feel like the Dojo community would consider writing modules with function wrappers manually. So I created the xdomain loader that required a build step to inject function wrappers similar to what RequireJS uses, but more complex, due to i18n bundle loading and dojo.requireIf behavior. However, the XHR loader couldn't load Dojo modules from other domains because of the same-origin restrictions. The normal dojo loader used to use synchronous XMLHttpRequest (XHR) calls. Plus, Pitch Perfect was a welcome surprise, so I'm curious to see Moore's take on the material. Shouldn't entertaining stories be more than "Just Add Zombies"? However, I haven't read Afterlife with Archie, so I'll give Aguirre-Sacasa the benefit of the doubt. But they can also function as a complete gimmick, and I'm worried we're basically seeing Pride and Prejudice and Zombies but with Archie instead of Jane Austen. Zombies have become an increasingly pointless go-to because they allow for horror with easy gore and violence even though there's always potential for the undead to transcend their physical traits and become a potent symbol. What irritates me about Afterlife with Archie is that it looks like it's going for the zombie crutch. I love Mystery Team and that movie is PG characters in an R-rated film. I personally have no attachment to the comics, and I'm not opposed to mixing goofy elements with horror. Yet for a cold-hearted and remorseless killer like Jason, the powers of the TV demon Samara from The Ring wont do much. It's not matter of being an Archie "purist" or anything like that. And since it could be a bit complicated to fully remove Jason vs Zombies 1.5, Ill explain the how this application is installed and how the system manages the. The ability to scare someone to death is definitely a handy and worthwhile tool for a horror villain to possess, either against helpless victims or other villains. However, I'm wary of this take on Archie. He was brought in to help fix the Broadway musical Spider-Man: Turn off the Dark, and he wrote the screenplay for the upcoming remake of Carrie. Aguirre-Sacasa is no stranger to tweaking premises and updating properties. Version 1.5: Note: 1.2 is the version number of the free version the commercial version is at 1.5. Note: In the current free version you are only able to play the first mission.The concept is to balance the gore with "elements that are quintessentially Archie," according to Archie creator/publisher/editor John L. Jason vs Zombies is a Zombie action game starring Jason of Friday the 13th. A team of Navy SEALS quickly discovers it is facing a growing horde of zombies when it is sent into a city in Louisiana to find the vice president after. Your Level-Kill-Points will always be saved and you can play every level for new if it's unlocked once. ![]() You can also earn Bonus-Kill-Points if you cut the arms and heads of aggressively zombies with your different weapons. It’s not brilliant, it’s not essential, but it’s decent fun, and the fact it was able to be sold at all is a glowing reflection on the opportunities the Apple App store provides to up-and-coming developers. Jason vs Zombies is a Zombie action game starring Jason of Friday the 13th. And, for a one man effort, Jason vs Zombies is admirable. License 9.99 version 1.5 File Size 57. So you need many Kill-Points to unlock new weapons for free. There are two major reasons that Ted White didnt want to be credited for playing Jason Voorhees in Friday the 13th: The Final Chapter.The first is that he just wasnt a big horror fan, especially of the slasher sub-genre, and felt uneasy about his name being associated with one of its biggest icons. Killing zombies with Jason even more cool. Jason vs Zombies The First-Jason-3D-Action GameIt’s not Friday the 13th but you can feel like Jason as a Zombie Kille Info. It's a long way to the last level called "Zombie City". You have to be a very good Zombie Killer for surviving 5 amazing Levels and Missions. The world is full of zombies and you (Jason) are the only man who can save the world if you find and kill all zombies. Get also the FREE iPhone-, iPad- and iPod - version here: They have to find their way through an island full of undead, its your task to help them and defeat all undeads Category: Shooting. ![]() ***PLAY WITH JOYSTICK OR KEYBOARD AND MOUSE*** Pirates found a treasure map and need your help to find it. Killing zombies with Jason even more cool. In the game, youll also find picture puzzles zombie vs jason. Let’s face it, pitting Jason Vorhees against hordes of zombies is a genius idea. Friends You have to solve a lot of exciting levels, to cope with all the puzzles and be on the alert. ![]() NOW AVAILABLE FOR YOUR iMAC WITH AMAZING PERFORMANCE AND SPECIAL 3D EFFECTS Bonus level - jason vs zombies Works without Internet Freddy vs Jason games with puzzle horror elements help to develop motor skills and memory. It's not Friday the 13th but you can feel like Jason as a Zombie Killer! ***FREE VERSION*** The First-Jason-3D-Action Game It's not Friday the 13th but you can feel like Jason as a Zombie Killer! NOW AVAILABLE FOR YOUR iMAC WITH AMAZING PERFORMANCE AND SPECIAL 3D EFFECTS ***PLAY WITH JOYSTICK OR KEYBOARD AND MOUSE***. ![]() As Christian De Duve suggested ( 151), this might have happened as a consequence of the selective pressure provided by the transition from “the primordial soup to oceans,” i.e., from environments in which nutrients were present in a concentrated form to diluted environments. As prokaryotes evolved to eukaryotes, more complex “entry portals” began to appear. Early prokaryotic life forms used relative simple devices, such as pumps or channels, to transport essential molecules, such sugars, amino acids, and ions, through the PM. For the sake of clarity, however, we would be wise to take things from the beginning. This is because the past is paradoxically the best bridge between the present and the future, or, in other words, because the evolutionary perspective, though speculative, can help us to rationalize a number of heterogeneous observations and can indicate which experimental strategies might serve to achieve a coherent biological picture of endocytosis. The attentive reader will notice that this review ends where it should have started, i.e., with a discussion of the evolution of endocytosis and of the endomembrane system. The declared intent of this review is to illustrate how we have moved, in the course of the past 15 years or so, from one outlook to the other. ![]() ![]() Its evolution constitutes, arguably, the major driving force in the evolution of prokaryotic to eukaryotic organisms.” A shorter version might read as follows: “Endocytosis is the logistics of the cell,” where logistics (again as defined by Wiki) “involves the integration of information, transportation, inventory, warehousing, material handling and packaging, and security,” or in brief “having the right thing, in the right place, at the right time.” This latter definition of endocytosis underscores a shift from a limited perspective (what we might call a “traditional view”) to a much wider one, in which endocytosis is the cornerstone of the eukaryotic cell project. As such, it governs almost all aspects of the relationships of the cell with the extracellular environment and of intracellular communication. Based on present knowledge, a more precise definition of endocytosis should read: “a vast program, deeply ingrained in the cellular master plan and inextricably intertwined with signaling, which constitutes the major communications infrastructure of the cell. However, this is only a fragment of the whole picture. Indeed, endocytosis most likely evolved for this purpose. I. Introduction: The Vantage Point of Endocytosis on Signaling (and Vice Versa)Ī search for the term endocytosis in any major cell biology textbook, in the Encyclopedia Britannica, or even in Wikipedia will result in a definition corresponding to a more or less sophisticated version of the following (taken from Wiki): “Endocytosis is the process by which cells absorb molecules … that cannot pass through the plasma membrane.” This is indeed true endocytosis serves to bring nutrients and/or other types of molecules into the cell and, at the same time, to regulate the composition of the plasma membrane (PM). By combining the analysis of biochemical, biological, and evolutionary evidence, we propose herein that endocytosis constitutes one of the major enabling conditions that in the history of life permitted the development of a higher level of organization, leading to the actuation of the eukaryotic cell plan. A possible framework, to rationalize all this new knowledge, requires us to “upgrade” our vision of endocytosis. In addition, many newly discovered functions of endocytic proteins are not immediately interpretable within the classical view of endocytosis. A wealth of new evidence is uncovering the surprisingly pervasive nature of endocytosis in essentially all aspects of cellular regulation. Although this may seem revolutionary, it is still likely to be only a small part of the entire story. In essence, endocytosis provides the communications and supply routes (the logistics) of the cell. This led to the notion that endocytosis is actually the master organizer of cellular signaling, providing the cell with understandable messages that have been resolved in space and time. Although endocytosis was initially discovered and studied as a relatively simple process to transport molecules across the plasma membrane, it was subsequently found to be inextricably linked with almost all aspects of cellular signaling. This is the result not only of advances in our knowledge of its molecular and biological workings, but also of a true paradigm shift in our understanding of what really constitutes endocytosis and of its role in homeostasis. Our understanding of endocytosis has evolved remarkably in little more than a decade. |
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