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Senolytic drugs are those capable of selectively destroying senescent cells. A range of such therapies are at various stages of development, including those that have reached initial human clinical trials.

Senescent cell accumulation is an important cause of degenerative aging, and the removal of such cells via senolytic treatments has been shown to produce rejuvenation and extension of life in animal models of age-related disease. Senescent cells, while never very large in numbers relative to other cells in the body, secrete a potent mix of molecules that spurs chronic inflammation and degrades tissue structure and function. The more senescent cells, the worse the outcome.

A Proof of Concept Attempt to Assess the Impact of

Image credit: Pixabay (Free Pixabay license)

At present assessment of senolytics in human medicine is still at a comparatively early, albeit promising, stage. Data will emerge at the usual glacial pace characteristic of the highly regulated medical industry. It may be possible to extract some data on the performance of first generation senolytic drugs in advance of clinical trials, however. Many of these drugs have been widely used for years in patient populations, as treatments for various age-related conditions, and all of that data still exists, there to be analyzed.

The primary challenge here is that most such first generation senolytic drugs are chemotherapeutics. Firstly the patients in question were not in good shape at all, exhibiting significant mortality and loss of function due to cancer and its complications, making it hard to pick out benefits to health. Secondly chemotherapeutic doses are higher and more sustained than senolytic doses, causing significant additional cell death and dysfunction. Is it possible to work around these issues by picking a comparatively isolated part of the body, such as the retina, as is the case in today’s open access paper? Maybe, but I think that there remain sizable issues that would need to be addressed before one could take any such data at face value. Particularly given the very small sample size used here as a proof of concept for the ability to gather and analyze a broader range of data. For now, this is an interesting idea, perhaps worthy of further exploration.

Evaluating the neuroprotective impact of senolytic drugs on human vision

Based on neuropathological similarities of glaucoma with other age-related neurodegenerative diseases such as Alzheimer’s and the involvement of the ubiquitin-proteasome and chaperone systems, researchers have hypothesized a cellular senescence contribution to glaucoma pathogenesis. Preclinical evidence has supported the cellular senescence hypothesis as a contributor to glaucoma pathogenesis. Senescent cells secrete a plethora of molecules known as senescence associated secretory proteins (SASP), which affect surrounding cells by inducing either apoptosis or senescence, thus propagating the phenotype. There are several senolytic drugs that are able to specifically target senescent cells to overcome the apoptosis block to remove them, presenting an attractive hypothesis for potential treatment of glaucoma.

Indeed, our recent study has shown that targeting senescent retinal ganglion cells (RGCs) in a mouse model of glaucoma using the senolytic drug dasatinib protected the remaining RGCs and visual function from glaucomatous injury. These data are also supported by evidence from human studies, as a bioinformatics analysis of genes associated with primary open angle glaucoma suggested senescence as a key factor in pathogenesis.

Little is known about the neuroprotective effects or safety of senolytic drugs on vision in human patients, however. Clinical management of glaucoma involves acquisition of extensive longitudinal data including visual acuity, intraocular pressure (IOP), visual field sensitivity, and retinal nerve fiber thickness. Compared to other neurodegenerative diseases that often lack objective standardized metrics of clinical progression, some of these ophthalmic data are readily available and amenable to investigations of novel therapeutics, including senolytic drugs. To this end, we performed a retrospective analysis of existing clinical data to evaluate the effect of senolytics on vision and glaucoma progression. For the current study, we queried the electronic health record (EHR) system of a large academic medical center to identify glaucoma and glaucoma suspect patients exposed to at least one senolytic drug and conducted several analyses of visual data.

Senolytic exposure was not associated with decreased visual acuity, elevated intraocular pressure, or documentation of senolytic-related adverse ocular effects by treating ophthalmologists. Additionally, patients exposed to senolytics (n = 9) did not exhibit faster progression of glaucomatous visual field damage compared to matched glaucoma patients (n = 26) without senolytic exposure. These results suggest that senolytic drugs do not carry significant ocular toxicity and provide further support for additional evaluation of the potential neuroprotective effects of senolytics on glaucoma and other neurodegenerative diseases.

Source: Fight Aging!




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New computational method detects disrupted pathways in cancer

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Cancer is a notoriously complex disease, in part because it may be caused by mutations among hundreds or even thousands of genes. In addition, most cancers exhibit an extraordinary amount of variation among genetic mutations, even between patients with the same types of cancers.

Consequently, cancer researchers have chosen to study interactions among groups of genes in certain biological pathways that are disrupted.

When genes in certain pathways are frequently mutated or disrupted, that pathway may play a critical role in the initiation or development of cancer. But unravelling the molecular mechanisms underlying those disruptions is extremely complex.

Nw, University at Buffalo researchers have developed a new, statistically more powerful method called FDRnet that can more effectively detect key functional pathways in cancer using genomics data generated by next-generation sequencing technology.

Published in Nature Computational Science, the new method has the potential to give biologists more precise data with which to zero in on therapeutic targets.

“Using the new method, we can find biological pathways in which genes are significantly mutated or disrupted,” explained Yijun Sun, PhD, associate professor of bioinformatics in the Department of Microbiology and Immunology in the Jacobs School of Medicine and Biomedical Sciences at UB and the corresponding author. “It addresses some key challenges in molecular pathway analysis in cancer studies. Once the tumor biologists obtain this information, they can use it to verify our findings, and from there develop new cancer treatments,” he said.

“By overcoming the limitations of existing approaches, FDRnet can facilitate the detection of key functional pathways in cancer and other genetic diseases,” said Sun.

When Sun and his co-authors tested FDRnet on simulation data and on breast cancer and B-cell lymphoma data, they found that FDRnet was able to detect which subnetworks or pathways are significantly perturbed in these cancers, potentially leading tumour biologists to identify new therapeutic targets.

Source: State University of New York at Buffalo




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Tom & Jerry Release Date in India Set for February 19, a Week Before the US

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Tom & Jerry will now release February 19 in cinemas in India, a full week earlier than originally announced. Warner Bros. India revealed the new release date on Thursday via its social media channels. That puts the Indian release date a week prior to the US, where Tom & Jerry releases February 26 on (US-exclusive streaming service) HBO Max and in cinemas. In India, the hybrid live-action/ animated Tom and Jerry movie will be available in English (the original language), in addition to three local-language dubs: Hindi, Tamil, and Telugu.

The 42 Most Anticipated Movies of 2021, Including Tom & Jerry

However, India won’t be the first market to catch the big-screen return of the iconic cat and mouse duo. Tom & Jerry premieres February 10 in Netherlands, followed by Brazil and Singapore on February 11. India is among the next wave of markets on February 19, alongside Iceland and Lithuania. Russia and Slovakia will follow on February 25, before Tom & Jerry arrives in the US on February 26. Argentina, Czechia, Croatia, and Portugal follow on March 4, with Spain and France release set for March 5. In the UK, Ireland, and Japan, Tom & Jerry is due March 19.

Of course, whether any of this goes according to plan depends on how the COVID-19 situation fares locally. For instance, around 65 percent of theatres remain closed in the US (including the major metropolitan hubs of New York and Los Angeles). Theatres are indefinitely shut across the UK where a third stringent nationwide lockdown is in effect. That is also the case in France, at least until the end of January. In Spain, cinemas are operating at 30–50 percent capacity. But while Americans have the option to watch Tom & Jerry at home (on HBO Max), others do not.

Tom & Jerry Hindi trailer

Tom & Jerry Tamil trailer

Tom & Jerry Telugu trailer

Chloë Grace Moretz (Kick-Ass) is the human lead as event planner Kayla opposite Tom and Jerry in the new movie, alongside the likes of Michael Peña (Ant-Man and the Wasp) the hotel’s deputy general manager Terrance, Rob Delaney (Catastrophe) as the hotel manager Mr. DuBros, Ken Jeong (Community) as the hotel chef Jackie, Colin Jost (Saturday Night Live) as wedding groom Ben, and Pallavi Sharda (Besharam) as the bride Preeta.

William Hanna, Mel Blanc, and June Foray provide vocal effects for Tom and Jerry through archival audio recordings. Hanna is the co-creator of Tom and Jerry along with Joseph Barbera. Tim Story (Ride Along) is directing Tom & Jerry off a script by Kevin Costello (Brigsby Bear). Tom & Jerry is a production of Warner Animation Group, Turner Entertainment Company, and The Story Company.

Watch the First Trailer for the Tom & Jerry Movie

Here’s the official synopsis of Tom & Jerry, from Warner Bros.:

One of the most beloved rivalries in history is reignited when Jerry moves into New York City’s finest hotel on the eve of “the wedding of the century,” forcing the event’s desperate planner to hire Tom to get rid of him, in director Tim Story’s “Tom & Jerry.” The ensuing cat and mouse battle threatens to destroy her career, the wedding and possibly the hotel itself. But soon, an even bigger problem arises: a diabolically ambitious staffer conspiring against all three of them. An eye-popping blend of classic animation and live action, Tom and Jerry’s new big-screen adventure stakes new ground for the iconic characters and forces them to do the unthinkable… work together to save the day.

Tom & Jerry is out February 19 in India in English, Hindi, Tamil, and Telugu.

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How to install Eternal Terminal for persistent SSH connections

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If you have trouble with SSH connections breaking, Jack Wallen shows you how you can enjoy a bit more persistence with the help of Eternal Terminal.

Image: iStock/vadimrysev

If you’re an admin with Linux servers in your data center or cloud hosted account (such as AWS and Google Cloud), chances are pretty good you connect to those machines via SSH. Sometimes you need to remain connected for a good amount of time. You could be debugging code, working on containers or Kubernetes, or just about a thousand other reasons.

Thing is, sometimes those SSH connections get disconnected. This could occur because of a change in IP address or a host of reasons. When that happens, you have to re-connect. I’ve had experiences where SSH was constantly losing its connection, causing me to have to constantly reconnect.

That’s frustrating and time consuming. What can you do to avoid it?

One way around this problem is by using Eternal Terminal (ET), in place of SSH. Eternal Terminal does a great job of re-establishing a connection to a remote machine, without user intervention. That means once you’ve connected, you’ll stay connected until you break the connection manually.

I want to show you how to install and use Eternal Terminal. You can use this tool on Linux, macOS, and even Windows (using WSL). 

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What you’ll need

To make use of Eternal Terminal, you’ll need at least two systems that support the software and you must use Eternal Terminal on both remote and local machines. I’ll be installing ET on Ubuntu Server 20.04 and Ubuntu Desktop 20.04. As far as Linux is concerned, it can be installed on Debian-based distributions and CentOS (via the epel-release repository).

How to install Eternal Terminal

On Ubuntu (both server and desktop), the installation of Eternal Terminal is quite simple. Log in to either the server or desktop and install the software that allows you to add new repositories from PPAs with the command:

sudo apt-get install -y software-properties-common

Next, add the necessary repository:

sudo add-apt-repository ppa:jgmath2000/et

Update apt and install Eternal Terminal with the commands:

sudo apt-get update
sudo apt-get install et -y

Make sure to run through the above process on both the server and the desktop.

To install Eternal Terminal on CentOS 8 Stream, first install the epel-release with the command:

sudo dnf install epel-release -y

Install Eternal Terminal with the command:

sudo dnf install et -y

How to use Eternal Terminal

Using Eternal Terminal is exactly the same as using SSH, only you use the et command like so:

et SERVER

Where SERVER is the IP address or domain of the remote server.

Or:

et USER@SERVER

Where USER is the username on the remote server and SERVER is the IP address or domain of the remote server.

Eternal Terminal uses port 2022 by default–you’ll need to make sure that port is available. 

As you use Eternal Terminal, you won’t find anything different than working with SSH, until a connection is broken, at which point ET will appear to be non-responsive. However, it will cache all keystrokes made at this point and, as soon as the connection is re-established, it will execute the cached commands.

Note: This only works if the connection is terminated on the remote side of things. 

The caveat

Of course there’s a caveat. If your connection is broken by the client machine, and not the remote server, an orphaned session is created and you cannot reconnect to that orphaned session. In order to reconnect to the remote server, you’ll have to manually kill the orphan first. This is done with the command:

et -x USER@SERVER

Where USER is the username on the remote server and SERVER is the IP address or domain of the remote server.

And that’s the gist of using Eternal Terminal for persistent SSH connections to your remote Linux servers.

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