San Jose Mall 3pcs Children Face Mask with Filters Temptation of Ice Cream Gir Ranking TOP19

Denver Mall This fits your . Make sure this fits by entering your model number. The Gryphon Guardian: Does so much more than traditional home WiFi routers. This wireless WiFi router offers MESH Wifi Connectivity, Intrusion amp; Malware Home Protection for all your devices (smart connected appliances too) and most importantly protects your family from unwanted influences. Imagine a secure WiFi router amp; knowing that your kids can surf the web with blazing fast speed and 24/7 protection. Competitively Fast Mesh WiFi Internet: MESH Router works by combining the power of each tower or guardian to provide seamless coverage for your space. No more dead zones. If you buy one Gryphon it’s a great wireless router, if you buy multiple Gryphons they work together and create a “MESH” of amazing WiFi coverage. Protect your peace of mind: A Gryphon parent control router comes with the Gryphon app which is easy to setup and manage. Setup a secure network, monitor parental controls amp; set bedtimes for all your devices across the whole home to protect from hackers and unwanted content, or limit time on the web. Un-Matched Advanced Internet Protection: This smart router features an arsenal of cyber-armour for your home, Free for the 1st Year then Optional /Year: Intelligent Intrusion Detection. Malware Filtering Protection by ESET. Daily Security Updates. AD Reduction. Device Scanning for IoT’s for Vulnerabilities. *Travel for Work? Kids going behind your back using mobile data? Try our Advanced Protection on the Go with Gryphon HomeBound Free 90 Day Trial! Brilliant Parental Control Device Too! Don’t let the internet rule you or your family time. Take back control with our included WiFi Parental Control App featureing content filtering, browsing history, safe search, and safe viewing for YouTube too. Suspend the internet amp; limit screen time with bed/homework times at the click of a button. Make good decisions easier to make. Product Description Gryphon Online Safety System Advanced Internet Protection System Home Network Security Automatic software security updates and Malware updates of the threat database from ESET provide the most current protection for your home network. WiFi amp; IoT Device Protection Every connected device on your Gryphon network is protected 24/7. No software installs needed on any of your devices. When you’re Gryphon connected, you’re Gryphon protected. Personal Data Security With Gryphon HomeBound, your smartphone data is encrypted and routed back to your Gryphon home router ensuring Internet safety everywhere you go. Advanced Parental Control System Content Filtering The support you need, with 1.2 million blocked sites stored locally on Gryphon, and aggregated website reputation ratings from multiple sources including other parents. View Browsing History Gryphon helps ensure a brighter future for your kids by monitoring their browsing history, even if they delete it. History is stored locally on Gryphon so you have full control of your privacy. Set Bedtimes/Homework Times No more nagging, negotiating or wiggle room. Gryphon helps you schedule screen time in the run up to automatically shutting off their internet for bedtime. Suspend the Internet Literally. Just a touch of a button allows you to take complete control of the internet, giving you instant and non-negotiable family time. Advanced Parental Controls Create multiple users - safe for kids, unrestricted for adults See website ratings with patented Crowd Ranking View browsing history even if your child surfs with Incognito Mode Limit Screen Time, Set Bedtimes/Homework Times Suspend the Internet for dinner time Enforce Safe Search amp; YouTube to hide inappropriate results Grant approval to website or bedtime extension requests from anywhere, in real time Advanced Internet Protection* Block ransomware and malware from coming in your network with ESET technology Protect your privacy with Intelligent Intrusion Detection Scan devices for vulnerabilities Daily security updates to prevent the latest threats with 24/7 protection while you sleep. AD Blocker amp; Automatic Firmware Updates Network Management Smart network throughput optimization amp; Separate Guest WiFi Intelligent hand offs for best coverage (requires WiFi mesh setup) Prioritize a device on the network for zero video buffering (QoS) Specifications AC1200 True Mesh WiFi - 802.11 b/g/n/AC Simultaneous Dual-Band Radios - 2.4 GHz amp; 5GHz 2x2 MU-MIMO amp; Antenna Beamforming, WPA3 Compatible 1.2 Gbps overall throughput with up to 5000 sqft of coverage 1 WAN Port + 1 Gigabit LAN port w/Ethernet Backhaul Mesh WiFi Expandable with any Gryphon Router Gryphon App requires iPhone/Android Mobile w/Bluetooth LE support Includes - 6 Month Trial of Advanced Internet Protection* - Comprehensive Security that keeps you safe. Includes - 3 Month Trial of Gryphon Homebound - Take your security and parental controls on the go. *Advanced Internet Protection is included for 6 months. After its only 22 cents a day billed annually at 89/year. Without it, Gryphon will still be a powerful Mesh WiFi router with parental controls and network management, but your network won't be protected from malware, ransomware, and intrusions. Gryphon Has You Covered Easy Setup amp; Installation Installs in minutes. Easy for anyone to setup and use. Get a Fast, Stable connection anywhere in or near your home. Enhanced Safety Features that give you peace of mind. Protection For All Your Connected Devices Comprehensive Internet security, yet simple enough for anyone to use. Gryphon uses machine learning technology to analyze every device connected on your Gryphon network to safeguard against hackers and online threats. Advanced Internet Protection with the latest in AI intelligent intrusion detection. 24/7 protection for every connected device on your Gryphon home WiFi network from vulnerabilities, dangerous hackers, and malware. We Believe in Protecting Your Privacy Gryphon is not in the business of collecting your data. We believe your data is your property and you should have total control of how it’s stored, accessed, and used. In addition to protecting your home WiFi, we’re equally committed to protecting your privacy. Expand Your Coverage amp; Protection Parental Controls amp; Advanced Security On the Go 3pcs Children Face Mask with Filters Temptation of Ice Cream Gir Electronics => Computers Accessories => Networking Products at sport part, we live sneakers, clothing, they are all we think about and nothing makes us more proud than being able to keep our followers up to date with the latest trends. Gryphon Guardian Router Mesh WiFi System – 1,800Sq Ft per Mesh San Jose Mall 3pcs Children Face Mask with Filters Temptation of Ice Cream Gir Ranking TOP19 As a senior network engineer and cybersecurity expert I am exposed to a lot of firewalls/routers/NGFW and UTM appliances. So when I tell you something is great, you can bet it is great! First we will run through the hardware of this device, followed by the setup/configuration of it, then the testing and result of it. Sit back and get ready for the ride!First things first.. The packaging is great, giving off a real premium feel. The box is so nice I think I want to put it on display. Hardware wise, this is a beast. Far above the most powerful consumer routers.Gryphon has a Quad Core Arm Cortex A7 processor with 1GB of RAM and 4GB of Flash ram802.11bgn802.11AC3000Mbps throughput3 Radios (2.4 and 2x5.0)4x4 MU-MIMOBeamforming and WiFi PriorityMesh (instant)Six AntennasIn comparison, a top of the line ASUS RT-AC3200 has a Broadcom BCM4709 dual-core 1GHz processor with 256MB of DDR 3 system memory and 128MB of flash storage. Which is absolutely ANEMIC compared to the Gryphon. Especially considering a Dual Core Broadcom will spike to 100% CPU use on anything over 500Mbps and will struggle to 900Mbps. Contrary to the Gryphon, which can run at wire-speed 1000/1000Mbps without breaking a sweat.Software: (the basics, more later)Gryphon runs on LuCI, which is a fork of OpenWRT - highly customized and locked down.Intrusion Protection isn't signature based, rather it works off traffic anomaly inspection.Web Filtration is by ESET, and ESET uses licensed zVelo web filtration. (one of the top 5 in the world)Speed testing of your connection along with Up/Down Status of your WANAnti-Spoofing (MAC/ARP), Rogue AP DetectionVulnerability ScansPrioritized DeviceExtreme Device and Parental ControlSetup is extremely easy and amounts to installing the iOS or Android App then following the instructions. Those instructions are, you register for an account, plug in the router, scan the QR code and the router is paired with your account and app and is ready to be configured. Initial setup from unboxing to an active WiFi signal ready for connection is less than 5 minutes. It should be noted that all of this is conducted over encrypted channels. There are a few things i would like to inform you of regarding setup;1) You should unplug and fully disconnect your existing router. (with the assumption you have a Modem+Router setup right now)2) The Gryphon plugs into the ethernet going to your modem.3) Gryphon defaults to a 192.168.1.1/24 network, you CAN change this now. (Gateway 192.168.9.1)4) Gryphon defaults to DNS 8.8.8.8/8.8.8.8, you CAN change this.5) Gryphon allows multiple SSID's and allows you to segregate them by bands.6) Gryphon has NO configuration via web portal. Hitting the firewall gateway of 192.169.1.1 yields a device (the one you are on) landing page with statistics, and the ability to request access to specific websites you are blocked from.After setup is completed you'll go into the app and start examining devices connecting to the Gryphon. Each new device connects automatically to the 'Guest' user profile. From there, it's up to you to select the device, label the type of device it is, then assign it to a user group for granular restrictions/control over the device. This is the meat and potatoes of the Gryphon because device assignment largely controls the type of protection a device will have. Some important information about this;1) Some devices can't be user assigned once you designate the type of device. This is by design. If you pause the internet for a user with 4 devices, you don't want to pause their camera, thermostat or alarm system! So specific, critical devices are outside of the user profile area and designed as 'Things' by Gryphon.2) Device designation controls the intrusion protection for the device. For example computers have a lot of random activity, so they will be 'softened' for IPS. While your thermostat essentially does the same thing, and the AI/Machine Learning knows what it does, so it has a hardened intrusion protection level. If you assign a computer to a thermostat category you are going to be bombarded with warnings about HTTP/HTTPS activity, open ports, etc.. Don't do this.3) Device categories are 'somewhat' limited, about 29 different types. But strangely, they are missing some basic types like DVR, Network Switch, Servers and Robotic Vacuums. I would recommend assigning DVR to 'TV' category and vacuums to 'Other' for now. I've notified them of my request to add additional categories for some common devices. Most folks probably won't have an issue here, as every other device is included.Once you assign each device to a category, and if it applies, to a user group then you can go in and configure the device access at the granular level and this is VERY powerful! Gryphon functions at the application layer, so it can determine application use on the individual device level, and control access to individual applications and when they can be used. For example if you don't want your kids on Snapchat after 10PM at night, you can control this with a simple slider. This is a very powerful system that far outstrips any other router in the world other than SMB/Corporate UTM offerings costings many times more money. We'll go into important points about parental control below;1) You can control 'Homework' hours. Which means only homework/educational sites can be visited during X to Y hours on a specific device.2) Actively PAUSE the internet for specific devices, anytime you wish. (and it does NOT use ARP poisoning like Fingbox and others)3) Schedule internet time of day. On/Off, specific times, etc.4) Enable safe-search for all search engines, and disable all youtube comments, automatically on all devices!5) Store browsing history, with a snapshot of each page browsed.6) Allow/Disallow VPN activity on each device.7) Control individual application use, when you want and how you want. (No snapchat after 10pm kids!)8) Click on the 'i' for age groups for more information and what is filtered. Adult 18+ will filter malware+porn only. Unfiltered will filter malware only. Unfiltered isn't clarified on the fact it still filters malware but it does. Toddler is the equivalent of full whitelisting mode. Essentially blocking everything except what you allow. That's a great profile age group for things like servers and limited IoT devices!9) Blocked sites bring up a portal page, from there your users can 'request' access. Which then sends a screen capture of the page they want access to and the ability for you to one-click allow/deny. Impressive!10) Users can go to the gateway IP on their device (192.168.9.1) and request a laundry list of sites for you to unblock.Security (my favorite category)Gryphon is an incredibly secure router/UTM. It's running LuCI on OpenWRT, completely custom designed. All of the common 'hacking' ingress on it are completely closed off. No SSH, no web admin access, no HTTP/HTTPS configuration panel access. No default passwords. No WAN OR LAN facing configuration AT ALL. This in and of itself closes off many thousands of potential attacks and cannot be overstated about why it is important. Your typical home router comes out of the box with a default password and HTTP WAN/LAN access. Your typical home consumer opens it up, plugs it in and leaves all of this alone, and in the process gives even the most basic hacker complete access to their router, home network, and potentially all devices on the home network. So right out of the gate Gryphon is incredibly hacker resistant, there just isn't anything to hack on it. I ran port scans and penetration testing. Gryphon does very well here with full stealth on all service ports right out of the box. Some highlights about security;1) All ports automatically stealthed.2) No SSH/Telnet/HTTP/HTTPS admin access (lan or wan) Config is only through app.3) No default passwords/logins. You setup a strong password for your account on the app, which is paired (encrypted) to the app. Only YOU can access your device, period. End of story.4) ESET Technology for Web Scanning (HTTP/HTTPS), which is a subset of the powerful zVelo web categorization system.5) Machine Learning/AI system for device anomalies with the capability to quarantine infected devices.6) ARP/MAC spoofing detection/blocking.7) New device control (including default blocking of new devices)and much more...With the bullet points out of the way, for security buffs I am going to tell you how to ramp this Gryphon up to new levels, essentially making it UTM-Like in functionality. First, I recommend instead of creating User Profiles, you create DEVICE profiles. This is easy to do, all you need to do is create a user profile for a specific goal you wish to accomplish. For example let's say you want to block some specific devices from ALL internet connectivity, let's say you run cameras with a local DVR or Blue Iris on the network and you DO NOT need your cameras talking to the internet. To accomplish this task with Gryphon all you need to do is create a 'Camera' user profile, assign a device type as 'Computer' to your cameras, move them to the Camera User Profile, then go in and edit the camera profile and pause the internet AND/OR set it to 'Toddler'. Your cameras will never be able to communicate outside of your network or be able to be hacked, or send telemetry to China, etc. This functions as a sort of policy based routing with some level of granular control and I feel is one of the most powerful aspects of Gryphon when configured correctly.Instead of user categories, I have: Tablets, Phones, Desktops, Laptops, Servers, Cameras. Then I group devices within those categories and assign specific rules/controls to control them on a more granular level. For example my 'Servers' user profile is set to Toddler, then I go for the first day of use, look at the pages the server is trying to access, and whitelist/blacklist based on the activity I want to permit. That way the servers still get windows updates, but can't do things like have ransomware on them dialing out, telemetry from installed applications, etc. This is exceptionally powerful and a largely undisclosed (but major) benefit of Gryphon. The best part, I can do all of this and manage my entire network from my phone laying in bed! Here are some security tips that would likely make the Gryphon one of the most secure routers in the world;1) Since all devices connect to 'Guest' user profile until you categorize them - I recommend restricting Guest Profile to Toddler and/or setting that profile to be permanently paused. That way it's a full lockdown on all new devices, until you approve those devices individually.2) I recommend device categories for user profiles over individual users in many cases. This allows you to group all devices, then control them. Servers with limited access out the WAN. Cameras or other junk you might want to totally block from the internet, etc.3) I recommend setting SCHEDULES for all computers. For example group your computers into a computer user profile, then set a schedule to disable the internet from 2AM-7AM each night. This will reduce your threat surface during off hours and provide additional security.4) Go into malware protection, and toggle it to 'All Threats'. There is no reason to degrade security in any way.Bottom line, out of the box this is one of the most secure router in the world. With minor tweaks, it IS the most secure one in the world, probably even above many SMB/Corporate offerings.Wireless (how good is it?)REALLY GOOD. My home is quite large, and this device covers all three floors and the entire floor plan with full bars in almost every area. To give you an idea of how good this is, I previously required 3 FortiAP units when I used Fortinet, and when I switched to Ubiquity I required a top of the line Unifi AC-HD Pro unit AND a Mesh Lite unit to cover the home. This unit performs better than any other wireless solution I have tested. Google WiFi, Velop, Orbi, all of them are childrens toys compared to this!Speed wise, it's 3000Mbps 'total' maximum throughput. Obviously you won't get that if your connection is 300 Mbps, what it means is the absolute maximum from all devices and radios combined will be 3000Mbps. That's throughput on the LAN, WAN, and all three radius. But it does live up to it's potential far better than any other router I have tested - you can trust me on that! Top of the line ASUS routers are nothing but trinkets compared to this. They've really done their homework regarding this system.Recommendations/ConsNo cons to this device at all. But I would recommend they implement a few basic things to take it to the next level. ICMP shouldn't respond from WAN. Even with ports all stealthed I'd like to see ICMP responsed blackholed. Not a huge issue. I'd like to see a 'custom' web filtration category where I can setup custom fields about what to block. A few more device categories would be nice.In close - this is the best possible router (hybrid UTM) device you can purchase for your home. Period. Bar none. Nothing else comes close. You can toss every other gadget out (Fingbox, Dojo, Norton Sphere, Cujo, etc), they're all basically junk compared to this. This is the only consumer router to get my 100% seal of approval. In fact, for prosumers, you can probably forget about your Sophos and Fortinet's and run with this. You won't be disappointed! Another recommendation to Gryphon Company would be to improve information and FAQ with more detailed question/answers, especially for the Prosumer market. I'd like to see whitepapers, some test results, and maybe technical documentation. Information is a bit too vague IMO, and I have provided more information in my review here than you'll ever find anywhere on Gryphon, and it was done through my own testing/research over a 24 hour period.UPDATED January 2019The Gryphon router is meh. It's not the stellar product that some of the reviews, or its own advertising, claim. And in many regards, I prefer my previous router (TP-Link Archer C9 AC1900), which yes I understand has the “vulnerability” which allows it to be compromised through the web interface… but even this is limited as you must have a physical (hard-wired) connection to the router from a compromised computer, and even then you can take steps to minimize your risk.Anyway, back to this Gryphon router…THE GOOD:• It’s really easy to set up.• Support Team is very responsive.THE BAD: (Read further below for details)• The app / user interface is way too simple.• Documentation is almost non-existent.• Browsing history is incredibly limited (only domain-level) and only the most recent entries• No browsing history is available for devices classified as “Things”.• Can’t check if you have the latest firmware version.• “Homework time” and “Bedtime” lack granularity.• Can’t check what’s blocked based on user account type.While the support team is very responsive and I usually get a response within minutes of submitting an issue, I find that I am frequently contacting support, with the general response that Gryphon hears customers' feedback and is working to improve the product. So I feel as though the product is more of a beta, and I'm part of the testing process. Contrast this with some of the other well-established router manufacturers where their product are mature from a development standpoint. I definitely like the very responsive support team, but wish that I didn't need to contact support so frequently.The app / user interface is way too simple. While it makes setup relatively easy (since there’s very few settings you can actually configure), I do wish they offered the option to view an “advanced” interface and customize many of the settings. I’m coming from a TP-Link Archer C9 AC1900 router, and that router gives both a simple interface and an advanced interface, with the user manual built into the interface, and myriads of configuration options.One user commented below that I have confused this device with a prosumer-level device… No, I didn’t confuse it with something else… Indeed, I expected more than what this Gryphon provides. An TP-Link router has advanced configuration settings. Even a Linksys provides more configuration options than this Gryphon… and if you don’t like the -router’s firmware, you can install your own open-source firmware. This Gryphon costs 0+ and you can configure only basic settings… So yes, I expected more from this router.The router can only be configured through a smartphone app, and your router needs to be connected to the Internet in order for you to be able to configure it. If your Internet connection goes down, you can’t configure the router even for local network purposes. There is no way to configure this router through a desktop (or laptop) user interface using a wired connection.When using the app to configure the router, presumably all of your configuration settings (including your WiFi passwords) are passed through the Gryphon “servers” prior to going to your router. The Privacy Policy states that network settings information is passed to Gryphon servers, but is stored only temporarily (although temporarily isn’t defined). You’ll just have to trust that they are being ethical about the information collected. If you disconnect the router from the Internet, you can no longer see the devices which are connected, but you can still see your WiFi passwords. So are your WiFi passwords stored on your smartphone app, or are they stored on the Gryphon servers? There’s no documentation on how this works. So much for temporarily storing your data…Furthermore, any useful documentation on this router is essentially non-existent. You can go to the Gryphon support webpage for some limited FAQs, or you can watch even further limited YouTube videos which explain to you how to do some of the most basic and self-explanatory tasks, and that’s about it. So there’s no good detailed documentation on this router.To further demonstrate the lack of documentation… consider the user types (toddler, elementary school, middle school , high school, adult 18+, unfiltered). All you are told regarding these user types is whether or not these user types filter out content for violence, guns, gambling, alcohol, and drugs. For example, elementary school and middle school user types appear to be exactly identical with regards to filtering out violence, guns, gambling, alcohol, drugs… but they are not. There’s definitely other filtering going on, but you don’t know what it is, and there’s no way to find out other than trail-and-error, which is very frustrating. There’s no way to understand beforehand the access privileges / whitelist / blacklist configuration of each user type. For example, my elementary-school child likes to play Minecraft… but the Minecraft program was blocked from connecting to the Internet, and the associated Mojang.com website was also blocked. Was this because of violence? Guns? Who knows… there was no documentation on this. I found out by trial-and-error. When I changed his user profile from “elementary school” to “middle school” Minecraft was able to connect to the Internet again. I shouldn’t have to change profiles in order to allow access… I should be able to configure the user profile appropriately the first time using documentation provided by Gryphon…You can configure “homework time” and “bed time” only to the extent that you are allowed to do so based on the user type (elementary vs middle school vs high school vs …). For example, if you want to set homework time, you can only do that for the “school” type of users, not for adult. However, the school type users filter out any websites flagged for violence, guns gambling, alcohol, and drugs, and some of the websites are (in my opinion) incorrectly flagged and therefore blocked. So if I want to allow my kids to access one of these websites, I have to set the setting to “Adult 18+” which grants them permission to view the website but then removes the “homework time” feature.If you have enabled “homework time” or “bed time”, you can select the days of the week that these times are enforced, but they are the same times for all days of the week selected. For example, you can’t set homework time to start at 4pm on Monday and 6pm on Tuesday. There’s no granularity for each day of the week.They advertise that you can “view your child’s browsing history.” This is misleading, as the browsing history available through the Gryphon app is not even close to the giving the same information as the browsing history of the internet browser. It only offers only domain-level browsing history. While some reviewers have pointed out that this is similar to business class UTM systems, I feel that if they’re going to advertise the ability to “view your child’s browsing history” then it should be a real browsing history as most of us consumers understand “browsing history” to mean. Or perhaps they can include an footnote that states "domain-level browsing history"... Otherwise, I feel I've been misled.More on the browsing history… you can only see the most recent timestamp that a specific domain was accessed. So if your child accessed 100 YouTube links in the last few hours, you only see the most recent entry. As far as you can tell, your child only accessed YouTube once just a few moments ago.Still more on the browsing history… I wish they would allow me to click on an item in the browsing history, and it takes me to the exact website that my child accessed. But you can’t do this… and if you could it wouldn’t be of any usefulness since they only collect domain-level information at the moment, and I have no interest in being directed to just the domain.Last thing to mention on browsing history… it’s collected based on users, not devices, which is a problem because some devices (like thermostats, NAS, etc) cannot be assigned to users, so for these devices there’s no browsing history collected. If you want to see what domains these devices are connecting to, you have to configure the device to be a computer or similar, and then assign it to a user. But what does this do to the AI monitoring… I don’t know because there’s no useful information on this… All you’re told is that the router is smart and can detect threats based on the device type… So if you follow this logic, you just configured your thermostat to act like a computer, which then tells the router to treat the network traffic to/from this device like a computer instead of a thermostat, all so that you can log browsing history?!?!? Does this expose you to threats? If I had to take an educated guess, I would say yes.There’s no way to check if you have the most recent firmware. It would be nice if they displayed on their support page the current firmware version and when it was issued so that you can compare with the firmware displayed in you Gryphon app. Alternatively, they could have an option within the Gryphon app to “check for firmware updates” which would give you feedback that you have the latest firmware… but again the interface is designed to be so simple that this feature isn’t available. You’ll just have to trust that you have the most recent firmware. When you finally receive a notification that firmware is available to be installed, you do get a list of changes that are included in the firmware update, but the list of changes is not comprehensive / all-inclusive.When the original review was written, there was a security issue… The router responded to ping requests coming from the Internet. So hackers scanning for responsive IP addresses could find your router to be present. I contacted support about this, and they indicated it would be fixed in the next firmware update coming in about a week’s time. The update actually came about a month later.Some (including the Gryphon Care Team) commented that ping response presents only a negligible risk. Maybe… but it’s easy enough to keep disable, and so why even allow a “negligible risk”.To re-iterate the last point about the router responding to ping requests, this is a big deal for me. The company boasts itself on having “UNMATCHED PROTECTION amp; SECURITY” per the product description above, and responses from the Gryphon team to many of these reviews state that the router has gone through extensive testing. My question is… how did they miss that the router responds to ping? And for so long? That they needed a customer to tell them that the router responds to ping in order for them to find the issue? And if they missed this issue, what other issues did they also miss that I don’t know about? And since the user interface is so dumbed down, I don’t know what configurations have been made without my consent. It really makes me doubt whether I made the right move to purchase this item.IN SUMMARY:• If you are the type of person with very little knowledge about home networking, and you want a secure device which you can set it up quickly and easily, and not worry about it again (except for your 0/yr fee for intrusion protection), then this is the router for you.• If you are a parent who wants parental controls, you will be frustrated at the constant need to switch user profiles, as there's no way to check for whitelist / blacklist / access privileges and your kids will complain that perfectly acceptable websites / videos are blocked.• If you are an advanced user who wants configuration options, or you want a mature product for which you don't want to repeatedly contact the support team, then this is not the router for you. Based upon the great reviews I had read about the Gryphon mesh routers, I ordered two units for our home. Despite trying everything I could think of for four or five hours, I could not install the Gryphon router. It simply would not work with my Apple wifi system and my Comcast Arris combo modem. With persistence, patience and knowledge over two days, Gryphon figured out the solution. They would not give up. The OLDER Apple Airport Extreme I had was causing a rare kind of conflict. Apple stuff does not always play nice with others. My problem was unique to the company. They had not seen it before, and will know what to do if it happens to anyone else.My wifi coverage is much better now. The safety and control features of the Gryphon are both excellent and very easy to set up. Great product.
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San Jose Mall 3pcs Children Face Mask with Filters Temptation of Ice Cream Gir Ranking TOP19

Siska et al. provide evidence for immunometabolic dysregulation in COVID-19, which can be mitigated by dexamethasone treatment. Image credit: Thomas Simeth.

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Commentaries
Abstract

Despite recent therapeutic gains in the treatment of advanced bladder cancer, the overall survival in patients with metastatic disease remains poor and further therapeutic discovery is needed. Advanced bladder cancer is a molecularly heterogeneous disease, and the identification of driver genetic alterations has led to effective targeted therapeutic agents, such as fibroblast growth factor receptor (FGFR) inhibitors. In this issue of the JCI, Bekele et al. identify a subtype of muscle-invasive bladder cancer (MIBC) that harbors RAF1 amplification. The authors showed that RAF1 inhibition, with pan-RAF inhibitors, and the combination of RAF1 inhibition with MEK inhibition were efficacious in preclinical models harboring RAF1 amplifications as well as in tumors with HRAS and NRAS mutations. This study highlights RAF1 amplification as a driver event in bladder cancer and establishes the central role of the MAPK pathway in bladder tumorigenesis.

Authors

Sean Clark-Garvey, William Y. Kim

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Abstract

Cannabinoid receptor 1 (CB-1) antagonists are potential candidates for treating obesity and metabolic complications. Despite clear metabolic benefits, unwanted side effects in the brain pose issues for patients. With the hope of overcoming this obstacle, CB-1 in peripheral tissues has become a potential drug target. Previous studies had suggested that liver CB-1 would be an excellent target to prevent development of nonalcoholic steatohepatitis (NAFLD). However, in this issue of the JCI, Wang et al. showed that CB-1 was barely detectable in the liver and deletion of CB-1 in hepatocytes provided no metabolic benefits against NAFLD. These contradictory results raise substantial concerns about the potential benefits of peripheral CB-1 blockers against NAFLD.

Authors

Beste Mutlu, Pere Puigserver

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Abstract

HIV and Mycobacterium tuberculosis (M. tuberculosis) coinfection increases the risk of active tuberculosis (aTB), but how HIV infection and medications contribute to drive risk remains unknown. In this issue of the JCI, Correa-Macedo and Fava et al. investigated alveolar macrophages (AMs) from people living with HIV (PLWH). To mimic the earliest event in tuberculosis (TB), the authors isolated AMs from broncheoalveolar lavage (BAL) of PLWH, healthy individuals, and healthy individuals taking antitretroviral therapy (ART) as preexposure prophylaxis (PrEP) to prevent HIV acquisition. These AMs were exposed to M. tuberculosis and epigenetic configuration, transcriptional responses, and cytokine production were assessed. M. tuberculosis–stimulated AMs from PLWH and from healthy individuals on PrEP showed blunted responses compared with healthy controls. While HIV infection is the major risk factor for TB, these findings suggest that ART may modulate AM responses and potentially contribute to residual risk of aTB in fully treated HIV.

Authors

Eileen P. Scully, Bryan D. Bryson

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Abstract

APOL1 G1 and G2 variants are established risk factors for nondiabetic kidney disease. The presence of two APOL1 risk variants in donor kidneys negatively impacts kidney allograft survival. Because of evolutionary pressure, the APOL1 risk variants have become common in people from Africa and in those with recent African ancestry. APOL1 risk variant proteins are expressed in kidney cells and can cause toxicity to these cells. In this issue of the JCI, Zhang, Sun, and colleagues show that recipient APOL1 risk variants negatively affect kidney allograft survival and T cell–mediated rejection rates, independent of donor APOL1 genotype or recipient ancestry. The authors provide evidence that APOL1 risk variants play an immunomodulatory role in T cells and NK cells in the setting of kidney transplantation. These findings have important clinical implications that require further investigation.

Authors

Andrew F. Malone

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Abstract

Hypertriglyceridemia is associated with obesity, diabetes, and atherosclerosis. While lipoprotein lipase (LPL) hydrolyzes triglyceride (TG) cargo into remnant lipoproteins with atherogenic properties, how remnant lipoprotein clearance relates to atherosclerosis in people with diabetes remains unclear. In this issue of the JCI, Shimizu-Albergine et al. examined the effects of the basic leucine zipper transcription factor CREBH, which induces genes that activate LPL in mouse models of type I diabetes. Overexpression of a CREBH fragment reduced apolipoprotein C3 (APOC3) levels, which reduced plasma TGs. Notably, the TGs were lowered by a mechanism that was independent of LPL, and atherosclerosis was alleviated by enhanced lipoprotein remnant clearance as opposed to increased lipolysis of TG-rich lipoprotein precursors. A proinflammatory mechanism likely underlies the atherogenicity of remnant lipoproteins. These findings suggest that modifying CREBH expression in the liver may ameliorate atherosclerosis and, perhaps, other diabetes complications.

Authors

Alan D. Attie

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Research Articles
Abstract

Epoxyeicosatrienoic acids (EETs) have potent antiinflammatory properties. Hydrolysis of EETs by soluble epoxide hydrolase/ epoxide hydrolase 2 (sEH/EPHX2) to less active diols attenuates their antiinflammatory effects. Macrophage activation is critical to many inflammatory responses; however, the role of EETs and sEH in regulating macrophage function remains unknown. Lung bacterial clearance of Streptococcus pneumoniae was impaired in Ephx2-deficient (Ephx2–/–) mice and in mice treated with an sEH inhibitor. The EET receptor antagonist EEZE restored lung clearance of S. pneumoniae in Ephx2–/– mice. Ephx2–/– mice had normal lung Il1b, Il6, and Tnfa expression levels and macrophage recruitment to the lungs during S. pneumoniae infection; however, Ephx2 disruption attenuated proinflammatory cytokine induction, Tlr2 and Pgylrp1 receptor upregulation, and Ras-related C3 botulinum toxin substrates 1 and 2 (Rac1/2) and cell division control protein 42 homolog (Cdc42) activation in PGN-stimulated macrophages. Consistent with these observations, Ephx2–/– macrophages displayed reduced phagocytosis of S. pneumoniae in vivo and in vitro. Heterologous overexpression of TLR2 and peptidoglycan recognition protein 1 (PGLYRP1) in Ephx2–/– macrophages restored macrophage activation and phagocytosis. Human macrophage function was similarly regulated by EETs. Together, these results demonstrate that EETs reduced macrophage activation and phagocytosis of S. pneumoniae through the downregulation of TLR2 and PGLYRP1 expression. Defining the role of EETs and sEH in macrophage function may lead to the development of new therapeutic approaches for bacterial diseases.

Authors

Hong Li, J. Alyce Bradbury, Matthew L. Edin, Joan P. Graves, Artiom Gruzdev, Jennifer Cheng, Samantha L. Hoopes, Laura M. DeGraff, Michael B. Fessler, Stavros Garantziotis, Shepherd H. Schurman, Darryl C. Zeldin

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Abstract

Cerebral small vessel disease (CSVD) causes dementia and gait disturbance due to arteriopathy. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. In CARASIL, arteriopathy causes intimal thickening, smooth muscle cell (SMC) degeneration, elastic lamina splitting, and vasodilation. The molecular mechanisms were proposed to involve the accumulation of matrisome proteins as substrates or abnormalities in transforming growth factor β (TGF-β) signaling. Here, we show that HTRA1−/− mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation. In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex. In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-β binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated. Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow. Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network. Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL.

Authors

Taisuke Kato, Ri-ichiroh Manabe, Hironaka Igarashi, Fuyuki Kametani, Sachiko Hirokawa, Yumi Sekine, Natsumi Fujita, Satoshi Saito, Yusuke Kawashima, Yuya Hatano, Shoichiro Ando, Hiroaki Nozaki, Akihiro Sugai, Masahiro Uemura, Masaki Fukunaga, Toshiya Sato, Akihide Koyama, Rie Saito, Atsushi Sugie, Yasuko Toyoshima, Hirotoshi Kawata, Shigeo Murayama, Masaki Matsumoto, Akiyoshi Kakita, Masato Hasegawa, Masafumi Ihara, Masato Kanazawa, Masatoyo Nishizawa, Shoji Tsuji, Osamu Onodera

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Abstract

Cutaneous leishmaniasis (CL) is caused by Leishmania donovani in Sri Lanka. Pentavalent antimonials (e.g., sodium stibogluconate [SSG]) remain first-line drugs for CL with no new effective treatments emerging. We studied whole blood and lesion transcriptomes from Sri Lankan patients with CL at presentation and during SSG treatment. From lesions but not whole blood, we identified differential expression of immune-related genes, including immune checkpoint molecules, after onset of treatment. Using spatial profiling and RNA-FISH, we confirmed reduced expression of programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) proteins on treatment in lesions of a second validation cohort and further demonstrated significantly higher expression of these checkpoint molecules on parasite-infected compared with noninfected lesional CD68+ monocytes and macrophages. Crucially, early reduction in PD-L1 but not IDO1 expression was predictive of rate of clinical cure (HR = 4.88) and occurred in parallel with reduction in parasite load. Our data support a model whereby the initial anti–leishmanial activity of antimonial drugs alleviates checkpoint inhibition on T cells, facilitating immune-drug synergism and clinical cure. Our findings demonstrate that PD-L1 expression can be used as a predictor of rapidity of clinical response to SSG treatment in Sri Lanka and support further evaluation of PD-L1 as a host-directed therapeutic in leishmaniasis.

Authors

Nidhi S. Dey, Sujai Senaratne, Vijani Somaratne, Nayani P. Madarasinghe, Bimalka Seneviratne, Sarah Forrester, Marcela Montes de Oca, Luiza Campos Reis, Srija Moulik, Pegine B. Walrad, Mitali Chatterjee, Hiro Goto, Renu Wickremasinghe, Dimitris Lagos, Paul M. Kaye, Shalindra Ranasinghe

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Abstract

Growing tumors exist in metabolically compromised environments that require activation of multiple pathways to scavenge nutrients to support accelerated rates of growth. The folliculin (FLCN) tumor suppressor complex (FLCN, FNIP1, FNIP2) is implicated in the regulation of energy homeostasis via 2 metabolic master kinases: AMPK and mTORC1. Loss-of-function mutations of the FLCN tumor suppressor complex have only been reported in renal tumors in patients with the rare Birt-Hogg-Dube syndrome. Here, we revealed that FLCN, FNIP1, and FNIP2 are downregulated in many human cancers, including poor-prognosis invasive basal-like breast carcinomas where AMPK and TFE3 targets are activated compared with the luminal, less aggressive subtypes. FLCN loss in luminal breast cancer promoted tumor growth through TFE3 activation and subsequent induction of several pathways, including autophagy, lysosomal biogenesis, aerobic glycolysis, and angiogenesis. Strikingly, induction of aerobic glycolysis and angiogenesis in FLCN-deficient cells was dictated by the activation of the PGC-1α/HIF-1α pathway, which we showed to be TFE3 dependent, directly linking TFE3 to Warburg metabolic reprogramming and angiogenesis. Conversely, FLCN overexpression in invasive basal-like breast cancer models attenuated TFE3 nuclear localization, TFE3-dependent transcriptional activity, and tumor growth. These findings support a general role of a deregulated FLCN/TFE3 tumor suppressor pathway in human cancers.

Authors

Leeanna El-Houjeiri, Marco Biondini, Mathieu Paquette, Helen Kuasne, Alain Pacis, Morag Park, Peter M. Siegel, Arnim Pause

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Abstract

High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we showed that LIN28B expression was associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7–independent enrichment of transcripts encoding components of the translational and ribosomal apparatus and depletion of transcripts of neuronal developmental programs. We further observed that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrated that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a posttranscriptional driver of the metastatic phenotype.

Authors

Pavlos Missios, Edroaldo Lummertz da Rocha, Daniel S. Pearson, Julia Philipp, Maria M. Aleman, Mehdi Pirouz, Dorian Farache, Joseph W. Franses, Caroline Kubaczka, Kaloyan M. Tsanov, Deepak K. Jha, Brian Pepe-Mooney, John T. Powers, Richard I. Gregory, Amy S.Y. Lee, Daniel Dominguez, David T. Ting, George Q. Daley

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Abstract

Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss, but whether recipient risk allele expression affects transplant outcomes is unclear. To test whether recipient APOL1 risk alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data on donors and recipients from 2 kidney transplant cohorts: Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 01/17 (CTOT-01/17). We estimated genetic ancestry (quantified as the proportion of African ancestry, or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we noted that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with an increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), as well as within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with an increased risk of any T cell–mediated rejection (TCMR) event. These associations were validated in CTOT-01/17. Ex vivo studies of PMBCs revealed, unexpectedly, high expression levels of APOL1 in activated CD4+/CD8+ T cells and NK cells. We detected enriched immune response gene pathways in risk allele carriers compared with noncarriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk alleles associated with TCMR and DCAL. We believe this finding has broader implications for immune-mediated injury to native kidneys.

Authors

San Jose Mall 3pcs Children Face Mask with Filters Temptation of Ice Cream Gir Ranking TOP19

Discount Wholesale Dealer the individuals behind my story remain true to the company's roots Vintage Wood Carved Corner Onlay Applique Frame Door Decorate Wa San Jose Mall 3pcs Children Face Mask with Filters Temptation of Ice Cream Gir Ranking TOP19 Tools Home Improvement => Building Supplies => Building Materials 3pcs Children Face Mask with Filters Temptation of Ice Cream Gir ✿ Safe material: wood carving decals are made of rubber wood, which is natural, environmentally friendly, safe and durable ✿Home decoration: Wooden decals blend Chinese and Western cultures, fully embody the beauty of cultural fusion, and make your home look new ✿Handmade: Wooden decals are wooden decorations, so they are easy to dye. You can paint with your favorite painful colors, creative and flexible ✿Easy to install: Our wood carving decals can be used for home decoration and can be pasted on walls, doors, furniture, cabinets, cabinets, windows and other areas ✿Quality: Natural wood products are hand-carved, and may have wood grain, knots, burrs, rough surface, and different shades of color. It is normal and will be covered by paint. Please make sure you don't mind before buying Product description Color:A Product features and functions:---1.✿ Safety material: wood carving appliques are made of rubber wood, natural, environmentally friendly, safe and durable---2. ✿Home decorations: Wooden decals integrate Chinese and Western cultures, fully reflect the beauty of cultural fusion, and make your home look new---3.✿Handmade: Wooden decals are wooden decorations, so it’s easy Dyeing, you can paint it with your favorite painful color, creative and flexible---4.✿Easy to install: our wood carving decals can be used for home decoration, and can be pasted on walls and doors , Furniture, cabinets, cabinets, windows and other areasPlease note:1. Color: The true color of the product is due to various factors such as the brightness of the computer screen or the light level. It may be slightly different from the picture displayed on the website2. Size: The size is manually measured, so please allow a slight deviation within 1 inch 3. Odor: All our items are new from the factory, So some may have a little smell is normal. But it will disappear soon, please don’t worry Tip: If we can’t satisfy you for any reason, please don’t worry and contact us for time, we promise to serve everyone Customers provide high-quality after-sales service. When you buy here, we will do our best to give you a pleasant shopping experience, thank you

Zhongyang Zhang, Zeguo Sun, Jia Fu, Qisheng Lin, Khadija Banu, Kinsuk Chauhan, Marina Planoutene, Chengguo Wei, Fadi Salem, Zhengzi Yi, Ruijie Liu, Paolo Cravedi, Haoxiang Cheng, Ke Hao, Philip J. O’Connell, Shuta Ishibe, Weijia Zhang, Steven G. Coca, Ian W. Gibson, Robert B. Colvin, John Cijiang He, Peter S. Heeger, Barbara Murphy, Madhav C. Menon

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Abstract

Genetic variants near the TRIB1 gene are highly significantly associated with plasma lipid traits and coronary artery disease. While TRIB1 is likely causal of these associations, the molecular mechanisms are not well understood. Here we sought to investigate how TRIB1 influences low density lipoprotein cholesterol (LDL-C) levels in mice. Hepatocyte-specific deletion of Trib1 (Trib1Δhep) in mice increased plasma cholesterol and apoB and slowed the catabolism of LDL-apoB due to decreased levels of LDL receptor (LDLR) mRNA and protein. Simultaneous deletion of the transcription factor CCAAT/enhancer-binding protein alpha (CEBPα) with TRIB1 eliminated the effects of TRIB1 on hepatic LDLR regulation and LDL catabolism. Using RNA-seq, we found that activating transcription factor 3 (Atf3) was highly upregulated in the livers of Trib1Δhep but not Trib1Δhep CebpaΔhep mice. ATF3 has been shown to directly bind to the CEBPα protein, and to repress the expression of LDLR by binding its promoter. Blunting the increase of ATF3 in Trib1Δhep mice reduced the levels of plasma cholesterol and partially attenuated the effects on LDLR. Based on these data, we conclude that deletion of Trib1 leads to a posttranslational increase in CEBPα, which increases ATF3 levels, thereby contributing to the downregulation of LDLR and increased plasma LDL-C.

Authors

Katherine Quiroz-Figueroa, Cecilia Vitali, Donna M. Conlon, John S. Millar, John W. Tobias, Robert C. Bauer, Nicholas J. Hand, Daniel J. Rader

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Abstract

Bladder cancer is a genetically heterogeneous disease, and novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes. Here, we identified a unique subset of urothelial tumors with focal amplification of the RAF1 (CRAF) kinase gene. RAF1-amplified tumors had activation of the RAF/MEK/ERK signaling pathway and exhibited a luminal gene expression pattern. Genetic studies demonstrated that RAF1-amplified tumors were dependent upon RAF1 activity for survival, and RAF1-activated cell lines and patient-derived models were sensitive to available and emerging RAF inhibitors as well as combined RAF plus MEK inhibition. Furthermore, we found that bladder tumors with HRAS- or NRAS-activating mutations were dependent on RAF1-mediated signaling and were sensitive to RAF1-targeted therapy. Together, these data identified RAF1 activation as a dependency in a subset making up nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rational therapeutic strategy.

Authors

Raie T. Bekele, Amruta S. Samant, Amin H. Nassar, Jonathan So, Elizabeth P. Garcia, Catherine R. Curran, Justin H. Hwang, David L. Mayhew, Anwesha Nag, Aaron R. Thorner, Judit Börcsök, Zsofia Sztupinszki, Chong-Xian Pan, Joaquim Bellmunt, David J. Kwiatkowski, Guru P. Sonpavde, Eliezer M. Van Allen, Kent W. Mouw

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Abstract

Persons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is often the result of recent infection with Mycobacterium tuberculosis (M. tuberculosis) followed by rapid progression to disease. Alveolar macrophages (AMs) are the first cells of the innate immune system that engage M. tuberculosis, but how HIV and antiretroviral therapy (ART) affect the anti-mycobacterial response of AMs is not known. To investigate the impact of HIV and ART on the transcriptomic and epigenetic response of AMs to M. tuberculosis, we obtained AMs by bronchoalveolar lavage from 20 PLWH receiving ART, 16 control subjects who were HIV-free (HC), and 14 subjects who received ART as preexposure prophylaxis (PrEP) to prevent HIV infection. Following in vitro challenge with M. tuberculosis, AMs from each group displayed overlapping but distinct profiles of significantly up- and downregulated genes in response to M. tuberculosis. Comparatively, AMs isolated from both PLWH and PrEP subjects presented a substantially weaker transcriptional response. In addition, AMs from HC subjects challenged with M. tuberculosis responded with pronounced chromatin accessibility changes while AMs obtained from PLWH and PrEP subjects displayed no significant changes in their chromatin state. Collectively, these results revealed a stronger adverse effect of ART than HIV on the epigenetic landscape and transcriptional responsiveness of AMs.

Authors

Wilian Correa-Macedo, Vinicius M. Fava, Marianna Orlova, Pauline Cassart, Ron Olivenstein, Joaquín Sanz, Yong Zhong Xu, Anne Dumaine, Renata H.M. Sindeaux, Vania Yotova, Alain Pacis, Josée Girouard, Barbara Kalsdorf, Christoph Lange, Jean-Pierre Routy, Luis B. Barreiro, Erwin Schurr

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Abstract

The tumorigenic mechanism for pancreatic ductal adenocarcinoma (PDAC) is not clear, although chronic inflammation is implicated. Here, we identified an inflammatory cytokine–regulated transfer RNA–derived (tRNA-derived) fragment, tRF-21-VBY9PYKHD (tRF-21), as a tumor suppressor in PDAC progression. We found that the biogenesis of tRF-21 could be inhibited by leukemia inhibitory factor and IL-6 via the splicing factor SRSF5. Reduced tRF-21 promoted AKT2/1-mediated heterogeneous nuclear ribonucleoprotein L (hnRNP L) phosphorylation, enhancing hnRNP L to interact with dead-box helicase 17 (DDX17) to form an alternative splicing complex. The provoked hnRNP L-DDX17 activity preferentially spliced Caspase 9 and mH2A1 pre-mRNAs to form Caspase 9b and mH2A1.2, promoting PDAC cell malignant phenotypes. The tRF-21 levels were significantly lower in PDACs than in normal tissues, and patients with low tRF-21 levels had a poor prognosis. Treatment of mouse PDAC xenografts or patient-derived xenografts (PDXs) with tRF-21 mimics repressed tumor growth and metastasis. These results demonstrate that tRF-21 has a tumor-suppressive effect and is a potential therapeutic agent for PDAC.

Authors

Ling Pan, Xudong Huang, Ze-Xian Liu, Ying Ye, Rui Li, Jialiang Zhang, Guandi Wu, Ruihong Bai, Lisha Zhuang, Lusheng Wei, Mei Li, Yanfen Zheng, Jiachun Su, Junge Deng, Shuang Deng, Lingxing Zeng, Shaoping Zhang, Chen Wu, Xu Che, Chengfeng Wang, Rufu Chen, Dongxin Lin, Jian Zheng

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Abstract

Metabolic pathways regulate immune responses and disrupted metabolism leads to immune dysfunction and disease. Coronavirus disease 2019 (COVID-19) is driven by imbalanced immune responses, yet the role of immunometabolism in COVID-19 pathogenesis remains unclear. By investigating 87 patients with confirmed SARS-CoV-2 infection, 6 critically ill non–COVID-19 patients, and 47 uninfected controls, we found an immunometabolic dysregulation in patients with progressed COVID-19. Specifically, T cells, monocytes, and granulocytes exhibited increased mitochondrial mass, yet only T cells accumulated intracellular reactive oxygen species (ROS), were metabolically quiescent, and showed a disrupted mitochondrial architecture. During recovery, T cell ROS decreased to match the uninfected controls. Transcriptionally, T cells from severe/critical COVID-19 patients showed an induction of ROS-responsive genes as well as genes related to mitochondrial function and the basigin network. Basigin (CD147) ligands cyclophilin A and the SARS-CoV-2 spike protein triggered ROS production in T cells in vitro. In line with this, only PCR-positive patients showed increased ROS levels. Dexamethasone treatment resulted in a downregulation of ROS in vitro and T cells from dexamethasone-treated patients exhibited low ROS and basigin levels. This was reflected by changes in the transcriptional landscape. Our findings provide evidence of an immunometabolic dysregulation in COVID-19 that can be mitigated by dexamethasone treatment.

Authors

Peter J. Siska, Sonja-Maria Decking, Nathalie Babl, Carina Matos, Christina Bruss, Katrin Singer, Jana Klitzke, Marian Schön, Jakob Simeth, Josef Köstler, Heiko Siegmund, Ines Ugele, Michael Paulus, Alexander Dietl, Kristina Kolodova, Louisa Steines, Katharina Freitag, Alice Peuker, Gabriele Schönhammer, Johanna Raithel, Bernhard Graf, Florian Geismann, Matthias Lubnow, Matthias Mack, Peter Hau, Christopher Bohr, Ralph Burkhardt, Andre Gessner, Bernd Salzberger, Ralf Wagner, Frank Hanses, Florian Hitzenbichler, Daniel Heudobler, Florian Lüke, Tobias Pukrop, Wolfgang Herr, Daniel Wolff, Rainer Spang, Hendrik Poeck, Petra Hoffmann, Jonathan Jantsch, Christoph Brochhausen, Dirk Lunz, Michael Rehli, Marina Kreutz, Kathrin Renner

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Abstract

Ribonuclease 7 (RNase 7) is an antimicrobial peptide that prevents urinary tract infections (UTI); however, it is yet unknown how RNASE7 genetic variations affect its antimicrobial activity and its mitigation of UTI risk. This study determined whether the RNASE7 SNP rs1263872 is more prevalent in children with UTI and defined how rs1263872 affects RNase 7’s antimicrobial activity against uropathogenic E. coli (UPEC). We performed genotyping for rs1263872 in 2 national UTI cohorts, including children enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux trial or the Careful Urinary Tract Infection Evaluation study. Genotypes from these cohorts were compared with those of female controls with no UTI. To assess whether rs1263872 affects RNase 7’s antimicrobial activity, we generated RNase 7 peptides and genetically modified urothelial cultures encoding wild-type RNase 7 and its variant. Compared with controls, girls in both UTI cohorts had an increased prevalence of the RNASE7 variant. Compared with the missense variant, wild-type RNase 7 peptide showed greater bactericidal activity against UPEC. Wild-type RNase 7 overexpression in human urothelial cultures reduced UPEC invasive infection compared with mutant overexpression. These results show that children with UTI have an increased prevalence of RNASE7 rs1263872, which may increase UTI susceptibility by suppressing RNase 7’s antibacterial activity.

Authors

Keith R. Pierce, Tad Eichler, Claudia Mosquera Vasquez, Andrew L. Schwaderer, Aaron Simoni, Steven Creacy, David S. Hains, John D. Spencer

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Abstract

Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.

Authors

Nan Jin, Bhumsuk Keam, Janice Cho, Michelle J. Lee, Hye Ryun Kim, Hayarpi Torosyan, Natalia Jura, Patrick K.S. Ng, Gordon B. Mills, Hua Li, Yan Zeng, Zohar Barbash, Gabi Tarcic, Hyunseok Kang, Julie E. Bauman, Mi-Ok Kim, Nathan K. VanLandingham, Danielle L. Swaney, Nevan J. Krogan, Daniel E. Johnson, Jennifer R. Grandis

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Abstract

We used human monoclonal antibodies (humAbs) to study the mechanism of neuron intoxication by tetanus neurotoxin and to evaluate these antibodies as a safe preventive and therapeutic substitute for hyperimmune sera to treat tetanus in mice. By screening memory B cells from immune donors, we selected 2 tetanus neurotoxin–specific mAbs with exceptionally high neutralizing activities and extensively characterized them both structurally and functionally. We found that these antibodies interfered with the binding and translocation of the neurotoxin into neurons by interacting with 2 epitopes, whose identification pinpoints crucial events in the cellular pathogenesis of tetanus. Our observations explain the neutralization ability of these antibodies, which we found to be exceptionally potent in preventing experimental tetanus when injected into mice long before the toxin. Moreover, their Fab derivatives neutralized tetanus neurotoxin in post-exposure experiments, suggesting their potential for therapeutic use via intrathecal injection. As such, we believe these humAbs, as well as their Fab derivatives, meet the requirements to be considered for prophylactic and therapeutic use in human tetanus and are ready for clinical trials.

Authors

Marco Pirazzini, Alessandro Grinzato, Davide Corti, Sonia Barbieri, Oneda Leka, Francesca Vallese, Marika Tonellato, Chiara Silacci-Fregni, Luca Piccoli, Eaazhisai Kandiah, Giampietro Schiavo, Giuseppe Zanotti, Antonio Lanzavecchia, Cesare Montecucco

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Abstract

Ferroptosis, an iron-dependent nonapoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA-binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here, we report that the RNA-binding protein RBMS1 participates in lung cancer development via mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 is a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3′- and 5′-UTR of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake, and promoted ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potential and clinical value.

Authors

Wenjing Zhang, Yu Sun, Lu Bai, Lili Zhi, Yun Yang, Qingzhi Zhao, Chaoqun Chen, Yangfan Qi, Wenting Gao, Wenxia He, Luning Wang, Dan Chen, Shujun Fan, Huan Chen, Hai-Long Piao, Qinglong Qiao, Zhaochao Xu, Jinrui Zhang, Jinyao Zhao, Sirui Zhang, Yue Yin, Chao Peng, Xiaoling Li, Quentin Liu, Han Liu, Yang Wang

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Abstract

Air pollution is a well-known contributor to asthma. Air toxics are hazardous air pollutants that cause or may cause serious health effects. Although individual air toxics have been associated with asthma, only a limited number of studies have specifically examined combinations of air toxics associated with the disease. We geocoded air toxic levels from the US National Air Toxics Assessment (NATA) to residential locations for participants of our AiRway in Asthma (ARIA) study. We then applied Data-driven ExposurE Profile extraction (DEEP), a machine learning–based method, to discover combinations of early-life air toxics associated with current use of daily asthma controller medication, lifetime emergency department visit for asthma, and lifetime overnight hospitalization for asthma. We discovered 20 multi–air toxic combinations and 18 single air toxics associated with at least 1 outcome. The multi–air toxic combinations included those containing acrylic acid, ethylidene dichloride, and hydroquinone, and they were significantly associated with asthma outcomes. Several air toxic members of the combinations would not have been identified by single air toxic analyses, supporting the use of machine learning–based methods designed to detect combinatorial effects. Our findings provide knowledge about air toxic combinations associated with childhood asthma.

Authors

Yan-Chak Li, Hsiao-Hsien Leon Hsu, Yoojin Chun, Po-Hsiang Chiu, Zoe Arditi, Luz Claudio, Gaurav Pandey, Supinda Bunyavanich

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Abstract

The endocannabinoid system regulates appetite and energy expenditure and inhibitors of cannabinoid receptor 1 (CB-1) induce weight loss with improvement in components of the metabolic syndrome. While CB-1 blockage in brain is responsible for weight loss, many of the metabolic benefits associated with CB-1 blockade have been attributed to inhibition of CB-1 signaling in the periphery. As a result, there has been interest in developing a peripherally restricted CB-1 inhibitor for the treatment of nonalcoholic fatty liver disease (NAFLD) that would lack the unwanted centrally mediated side effects. Here, we produced mice that lacked CB-1 in hepatocytes or stellate cells to determine if CB-1 signaling contributes to the development of NAFLD or liver fibrosis. Deletion of CB-1 in hepatocytes did not alter the development of NAFLD in mice fed a high-sucrose diet (HSD) or a high-fat diet (HFD). Similarly, deletion of CB-1 specifically in stellate cells also did not prevent the development of NAFLD in mice fed the HFD, nor did it protect mice from carbon tetrachloride–induced fibrosis. Combined, these studies do not support a direct role for hepatocyte or stellate cell CB-1 signaling in the development of NAFLD or liver fibrosis.

Authors

Simeng Wang, Qingzhang Zhu, Guosheng Liang, Tania Franks, Magalie Boucher, Kendra K. Bence, Mingjian Lu, Carlos M. Castorena, Shangang Zhao, Joel K. Elmquist, Philipp E. Scherer, Jay D. Horton

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Abstract

Emerging evidence has shown that open reading frames inside long noncoding RNAs (lncRNAs) could encode micropeptides. However, their roles in cellular energy metabolism and tumor progression remain largely unknown. Here, we identified a 94 amino acid–length micropeptide encoded by lncRNA LINC00467 in colorectal cancer. We also characterized its conservation across higher mammals, localization to mitochondria, and the concerted local functions. This peptide enhanced the ATP synthase construction by interacting with the subunits α and γ (ATP5A and ATP5C), increased ATP synthase activity and mitochondrial oxygen consumption rate, and thereby promoted colorectal cancer cell proliferation. Hence, this micropeptide was termed ATP synthase–associated peptide (ASAP). Furthermore, loss of ASAP suppressed patient-derived xenograft growth with attenuated ATP synthase activity and mitochondrial ATP production. Clinically, high expression of ASAP and LINC00467 predicted poor prognosis of colorectal cancer patients. Taken together, our findings revealed a colorectal cancer–associated micropeptide as a vital player in mitochondrial metabolism and provided a therapeutic target for colorectal cancer.

Authors

Qiwei Ge, Dingjiacheng Jia, Dong Cen, Yadong Qi, Chengyu Shi, Junhong Li, Lingjie Sang, Luo-jia Yang, Jiamin He, Aifu Lin, Shujie Chen, Liangjing Wang

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Abstract

Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the activity of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol. Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL, as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH’s ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in Apoe–/– mice. Importantly, individuals with CREB3L3 loss-of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOE-dependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM.

Authors

Masami Shimizu-Albergine, Debapriya Basu, Jenny E. Kanter, Farah Kramer, Vishal Kothari, Shelley Barnhart, Carissa Thornock, Adam E. Mullick, Noemie Clouet-Foraison, Tomas Vaisar, Jay W. Heinecke, Robert A. Hegele, Ira J. Goldberg, Karin E. Bornfeldt

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Corrigendum

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Abstract

Vast numbers of differentially expressed genes and perturbed networks have been identified in Alzheimer’s disease (AD), however neither disease- nor brain region-specificity of these transcriptome alterations have been explored. Using RNA sequencing data from 231 temporal cortex and 224 cerebellum samples of patients with AD and progressive supranuclear palsy (PSP), a tauopathy, we identify a striking correlation in the directionality and magnitude of gene expression changes between these two neurodegenerative proteinopathies. Further, the transcriptome changes in AD and PSP are highly conserved between the temporal and cerebellar cortices, indicating highly similar transcriptional changes occur in pathologically affected and grossly less affected, albeit functionally connected, areas of the brain. Shared up- or down-regulated genes in AD and PSP are enriched in biological pathways. Many of these genes also have concordant protein changes and evidence of epigenetic control. These conserved transcriptomic alterations of two distinct proteinopathies in brain regions with and without significant gross neuropathology have broad implications. AD and other neurodegenerative diseases are likely characterized by common disease or compensatory pathways with widespread perturbations in the whole brain. These findings can be leveraged to develop multifaceted therapies and biomarkers that address these common, complex and ubiquitous molecular alterations in neurodegenerative diseases.

Authors

Xue Wang, Mariet Allen, Özkan İş, Joseph S. Reddy, Frederick Q. Tutor-New, Monica Castanedes Casey, Minerva M. Carrasquillo, Stephanie R. Oatman, Yuhao Min, Yan W. Asmann, Cory Funk, Thuy Nguyen, Charlotte C.G. Ho, Kimberly G. Malphrus, Nicholas T. Seyfried, Allan I. Levey, Steven G. Younkin, Melissa E. Murray, Dennis W. Dickson, Nathan D. Price, Todd E. Golde, Nilufer Ertekin-Taner

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Abstract

While negative selection of developing B cells in the periphery is well described, yet poorly understood, evidence of naïve B cell positive selection remains elusive. Using two humanized mouse models, we demonstrate that there is strong skewing of expressed immunoglobulin repertoire upon transit into the peripheral naïve B cell pool. This positive selection of expanded naïve B cells in humanized mice resembled that in healthy donors and was independent of autologous thymic tissue. In contrast, negative selection of autoreactive B cells required thymic-derived regulatory T cells (Tregs) and MHC class II-restricted self-antigen presentation by B cells. Indeed, both defective MHC class II expression on their B cells in rare bare lymphocyte syndrome patients or prevention of self-antigen presentation via HLA-DM inhibition in humanized mice result in the production of autoreactive naïve B cells. These latter observations suggest that Tregs repress autoreactive naïve B cells continuously produced by the bone marrow. Thus, a model emerges in which both positive and negative selection shape the human naïve B cell repertoire and that each process is mediated by fundamentally different molecular and cellular mechanisms.

Authors

Jeff W. Chen, Jean-Nicolas Schickel, Nikolaos Tsakiris, Joel Sng, Florent Arbogast, Delphine Bouis, Daniele Parisi, Ruchi Gera, Joshua M. Boeckers, Fabien R. Delmotte, Margaret Veselits, Catharina Schuetz, Eva-Maria Jacobsen, Carsten Posovszky, Ansgar S. Schulz, Klaus Schwarz, Marcus R. Clark, Laurence Menard, Eric Meffre

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Abstract

In chronic lymphocytic leukemia (CLL), the B-cell receptor (BCR) plays a critical role in disease development and progression as indicated by the therapeutic efficacy of drugs blocking BCR signaling. However, the mechanism(s) underlining BCR responsiveness are not completely defined. Selective engagement of membrane IgM or IgD on CLL cells, each co-expressed by > 90% of cases, leads to distinct signaling events. Since both IgM and IgD carry the same antigen-binding domains, the divergent actions of the receptors are attributed to differences in immunoglobulin (IG) structure or the outcome of signal transduction. We showed that IgM, not IgD, level and organization linked with CLL-cell birth rate and the type and consequences of BCR signaling in humans and mice. The latter IgM-driven effects were abrogated when BCR signaling was inhibited. Collectively, these studies demonstrated a critical, selective role for IgM in BCR signaling and B-cell fate decisions, possibly opening new avenues for CLL therapy.

Authors

Andrea N. Mazzarello, Eva Gentner-Göbel, Marcus Dühren-von Minden, Tatyana N. Tarasenko, Antonella Nicolò, Gerardo Ferrer, Stefano Vergani, Yun Liu, Davide Bagnara, Kanti R. Rai, Jan A. Burger, Peter J. McGuire, Palash C. Maity, Hassan Jumaa, Nicholas Chiorazzi

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Abstract

Various population of cells are recruited to the heart after cardiac injury but little is known about whether the cardiomyocyte directly regulates heart repair. In a murine model of ischemic cardiac injury, we demonstrate that the cardiomyocyte plays a pivotal role in heart repair by regulating nucleotide metabolism and fates of non-myocytes. Cardiac injury induced the expression of the ectonucleotidase ENPP1 that hydrolyzes extracellular ATP to form AMP. In response to AMP, the cardiomyocyte released adenine and specific ribonucleosides that disrupted pyrimidine biosynthesis at OMP synthesis step, induced genotoxic stress and a p53 mediated cell death of cycling non-myocytes. As non-myocytes are critical for heart repair, we showed that rescue of pyrimidine biosynthesis by administration of uridine or by genetic targeting of ENPP1/AMP pathway enhanced repair after cardiac injury. We identified ENPP1 inhibitors on small molecule screening and showed that systemic administration of an ENPP1 inhibitor after heart injury rescued pyrimidine biosynthesis in non-myocyte cells, augmented cardiac repair and post infarct heart function. These observations demonstrate that the cardiac muscle cell by releasing adenine and specific nucleosides after heart injury regulates pyrimidine metabolism in non-muscle cells and provide insight into how inter-cellular regulation of pyrimidine biosynthesis can be targeted and monitored for augmenting tissue repair.

Authors

Shen Li, Tomohiro Yokota, Ping Wang, Johanna ten Hoeve, Feiyang Ma, Thuc M. Le, Evan R. Abt, Yonggang Zhou, Rimao Wu, Maxine Nanthavongdouangsy, Abraham Rodriguez, Yijie Wang, Yen-Ju Lin, Hayato Muranaka, Mark Sharpley, Demetrios T. Braddock, Vicky E. MacRae, Utpal Banerjee, Pei-Yu Chiou, Marcus Seldin, Dian Huang, Michael Teitell, Ilya Gertsman, Michael Jung, Steven J. Bensinger, Robert Damoiseaux, Kym Faull, Matteo Pellegrini, Aldons Lusis, Thomas G. Graeber, Caius G. Radu, Arjun Deb

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Abstract

BACKGROUND. Neoantigen-driven recognition and T cell-mediated killing contribute to tumor clearance following adoptive cell therapy (ACT) with Tumor-Infiltrating Lymphocytes (TILs). Yet, how diversity, frequency, and persistence of expanded neoepitope-specific CD8+ T cells derived from TIL infusion products affect patient outcome is not fully determined. METHODS. Using barcoded pMHC multimers, we provide a comprehensive mapping of CD8+ T cells recognizing neoepitopes in TIL infusion products and blood samples from 26 metastatic mela-noma patients who received ACT. RESULTS. We identified 106 neoepitopes within TIL infusion products corresponding to 1.8% of all predicted neoepitopes. We observed neoepitope-specific recognition to be virtually devoid in TIL infusion products given to patients with progressive disease outcome. Moreover, we found that the frequency of neoepitope-specific CD8+ T cells in TIL infusion products correlated with in-creased survival, and that detection of engrafted CD8+ T cells in post-treatment (i.e. originating from the TIL infusion product) were unique to responders of TIL-ACT. Finally, we found that a transcriptional signature for lymphocyte activity within the tumor microenvironment was associated with a higher frequency of neoepitope-specific CD8+ T cells in the infusion product. CONCLUSIONS. These data support previous case studies of neoepitope-specific CD8+ T cells in melanoma, and indicate that successful TIL-ACT is associated with an expansion of neoepitope-specific CD8+ T cells. FUNDING. NEYE Foundation; European Research Council; Lundbeck Foundation Fellowship; Carlsberg Foundation.

Authors

Nikolaj Pagh Kristensen, Christina Heeke, Siri A. Tvingsholm, Annie Borch, Arianna Draghi, Michael D. Crowther, Ibel Carri, Kamilla K. Munk, Jeppe Sejerø Holm, Anne-Mette Bjerregaard, Amalie Kai Bentzen, Andrea M. Marquard, Zoltan Szallasi, Nicholas McGranahan, Rikke Andersen, Morten Nielsen, Göran B. Jönsson, Marco Donia, Inge Marie Svane, Sine Reker Hadrup

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November 2021 JCI This Month

JCI This Month is a digest of the research, reviews, and other features published each month.

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Review Series - More

Circadian Rhythm

Series edited by Amita Sehgal

Animals, plants, and bacteria all display behavioral patterns that coincide with Earth’s light and dark cycles. These oscillating behaviors are the manifestation of the molecular circadian clock, a highly conserved network that maintains a near 24-hour rhythm even in the absence of light. In mammals, light signals are transmitted via the superchiasmatic nucleus (SCN) in the hypothalamus to synchronize peripheral clocks and coordinate physiological functions with the organism’s active period. This collection of reviews, curated by Amita Sehgal, considers the critical role of the circadian system in human health. Technology, work, and social obligations can disrupt optimal sleep and wake schedules, leaving humans vulnerable to diseases affecting the heart, brain, metabolism, and more. Sleep disorders as well as normal variations in human chronotype may exacerbate circadian disruptions, with profound consequences. These reviews emphasize that ongoing efforts to understand the complexities of human circadian rhythm will be essential for developing chronotherapies and other circadian-based interventions.

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