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The key to a universal cancer therapy is to find a vulnerability that is (a) common to all cancers, something fundamental to cancer as a class, (b) nowhere near as prevalent in normal cells, and (c) can be cost-effectively exploited as a basis for treatment. Lengthening of telomeres is a good example, and an area in which at least a few groups are working at an early stage. Cancer cells must employ telomerase or alternative lengthening of telomeres mechanisms to evade the Hayflick limit on replication, triggered by short telomeres, as telomere length is reduced with each cell division. Other examples include other mechanisms related to cell replication, unsurprisingly given that unfettered replication is a defining characteristic of cancer. Today’s research materials discuss an interesting example of this type of approach.

Inhibition of Mitochondrial DNA Transcription as an Approach to Universal

Image credit: Pixabay (Free Pixabay license)

Researchers here note that production of proteins from mitochondrial DNA is critical to cell replication. Yet their experiments in interfering in that process demonstrate that mitochondrial gene expression is not so critical that it can’t be turned off for a while in normal tissues, given a normal rate of cell division. Cancerous cells, on the other hand, with their rampant pace of replication, run into issues if their ability to produce proteins from mitochondrial DNA is impaired. Reducing the ability of cancerous cells to replicate is a promising way to improve the effectiveness of any treatment based on killing cancerous cells, and particularly if it can be applied to any cancer by virtue of the universality of the underlying mechanism.

Novel principle for cancer treatment shows promising effect

Mitochondria are the power plants of our cells. They are essential for converting the energy in the food we eat into the common energy currency that is required for a variety of cellular functions. Cancer cells are critically dependent on mitochondria, not only for providing energy but also for producing a variety of building blocks needed to make more cells as the cancer cells divide. The continuous cell division means that a cancer cell must constantly make new mitochondria in order to grow.

Previous attempts to target mitochondria for cancer treatment have focused on acutely inhibiting mitochondrial function. However, this strategy has often resulted in severe side effects due to the crucial role of mitochondria for normal tissue function. As an alternative, researchers developed a novel strategy that does not directly interfere with the function of existing mitochondria. Instead, they designed highly selective inhibitors that target the mitochondria’s own genetic material, mtDNA, which has a critical role in the formation of new mitochondria.

When investigating the mechanism of action of these novel inhibitors, the researchers observed that the inhibitors put cancer cells into a state of severe energy and nutrient depletion. This leads to loss of necessary cellular building blocks, reduced tumour cell growth and ultimately cell death. “Previous findings from our research group have shown that rapidly dividing cells, such as cancer cells, are crucially dependent on mtDNA to form new functional mitochondria. Consequently, treatment with our inhibitors specifically affects proliferation of tumour cells, whereas healthy cells in tissues such as skeletal muscle, liver, or heart remain unaffected for a surprisingly long time.”

Small-molecule inhibitors of human mitochondrial DNA transcription

Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration, and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system. The IMTs efficiently impair mtDNA transcription and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines.

The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease.

Source: Fight Aging!




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‘Junk DNA’ plays a key role in regulating circadian clocks

Drosophila circadian rhythm

If you’ve ever had a bad case of jet lag, you know how a disruption to your body’s circadian rhythm makes it difficult to function. Molecular circadian “clocks” exist in cells throughout the body, governing more than just sleep and wake cycles — they are crucial to many aspects of human health. For more than a decade, researchers have been trying to figure out what makes them tick, in search of new insights into diseases like Alzheimer’s, cancer and diabetes.

Until now, that research has focused on what is known as clock genes, which encode proteins that drive oscillating cycles of gene expression affecting physiology and behavior. But research just published in the Proceedings of the National Academy of Sciences reveals the discovery of a new cog in the circadian clock — a genome-wide regulatory layer made up of small chains of non-coding nucleotides known as micro RNAS (miRNAs).

Junk DNA plays a key role in regulating circadian clocks

Drosophila ciacadian rhythm. Credit: Chhandama via Wikimedia Commons, CC-BY-SA-4.0

“We’ve seen how the function of these clock genes are really important in many different diseases,” said Steve Kay, PhD, Provost Professor of neurology, biomedical engineering and quantitative computational biology at the Keck School of Medicine of USC. “But what we were blind to was a whole different funky kind of genes network that also is important for circadian regulation and this is the whole crazy world of what we call non-coding microRNA.”

‘Junk DNA’ proves to be a valuable tool in circadian rhythms

Formerly thought to be “junk DNA,” miRNAs are now known to affect gene expression by preventing messenger RNA from making proteins. Past research has indicated miRNAs may have a role in the function of circadian clocks but determining which of the hundreds of miRNAs in the genome might be involved remained a problem.

Kay and his team, led by Lili Zhou, a research associate in the Keck School’s Department of Neurology, turned to the Genomics Institute of the Novartis Research Foundation (GNF) in San Diego, which has created robots capable of high throughput experiments. Working with scientists at the institute, Zhou developed a high throughput screen for a robot to test the close to 1000 miRNAs by individually transferring them into cells the team had engineered to glow on and off, based on the cell’s 24-hour circadian clock cycle.

“The collaboration with GNF made it possible for us to conduct the first cell-based, genome-wide screening approach to systematically identify which of the hundreds of miRNAs might be the ones modulating circadian rhythms,” said Zhou.

“Much to our surprise,” said Kay, “we discovered about 110 to 120 miRNAs that do this.”

With the help of Caitlyn Miller, a biochemistry undergraduate from USC Dornsife, researchers then verified the impact on circadian rhythms by inactivating certain miRNAs identified by the screen in their line of glowing cells. Knocking out the miRNAs had the opposite effect on the cells’ circadian rhythm as adding them to the cells.

Physiologic and behavioral impacts  of miRNAs

Researchers also focused on the physiologic and behavioral impacts of miRNAs. They analyzed the behavior of mice with a particular cluster of miRNAs inactivated – miR 183/96/182 – and saw that inactivating the cluster interfered with their wheel-running behavior in the dark compared with control mice. They then examined the impact of the miRNA cluster on brain, retina and lung tissue, and found that inactivating the cluster affected circadian rhythms in a different way in each tissue type – suggesting that the way the miRNAs regulate the circadian clock is tissue specific.

Understanding the impact of miRNAs on the circadian clock in individual tissue could reveal new ways of treating or preventing specific diseases.

“In the brain we’re interested in connecting the clock to diseases like Alzheimer’s, in the lung we’re interested in connecting the clock to diseases like asthma,” said Kay. “The next step I think for us to model disease states in animals and in cells and look at how these microRNAs are functioning in those disease states.”

Source: USC




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Samsung Galaxy F62, Samsung Galaxy M02 Spotted on India Support Page; Hints at Imminent Launch

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Samsung Galaxy F62 and Samsung Galaxy M02 have leaked in the past on several occasions, and now the model numbers associated with these phones have been spotted on Samsung’s official support page in India as well. This indicates that both the phones’ launches could be inching closer and Samsung is gearing up to introduce them in the Indian market. Samsung Galaxy F62 is also reported to be called the Samsung Galaxy E62. In some markets, this phone may likely be also called the Samsung Galaxy M62.

MySmartPrice spotted two model numbers – SM-E625F/DS and SM-M022G/DS – on the Samsung India support page. The support page doesn’t offer any details about the phone, and it doesn’t even reveal the commercial name of the phone, but the SM-E625F/DS model number is largely associated with Samsung Galaxy F62, or Samsung Galaxy E62, in the past. Likewise, the SM-M022G/DS is associated with the anticipated Samsung Galaxy M02 handset.

Samsung introduced the Galaxy M02s in the Indian market earlier this month, but the Galaxy M02 still remains in the rumour mill. As per a Geekbench listing, Samsung Galaxy M02 may run on Android 10 and come with 3GB of RAM. The smartphone could also come with the Qualcomm Snapdragon SoC that is clocked at 1.8GHz.

The rumoured Samsung Galaxy F62 has also leaked in images, hinting at a square shaped module on the back. The phone has also been spotted on BIS website and an earlier report also claims that the production of the rumoured Samsung Galaxy F62 has begun at the company’s Greater Noida facility in the Delhi-NCR region. The Galaxy F62 could be one of the slimmest phones from Samsung and it is expected to launch in the first quarter of 2021. Specifications leaked in the past include Exynos 9825 SoC, have 6GB of RAM and Android 11.


Is this the end of the Samsung Galaxy Note series as we know it? We discussed this on Orbital, our weekly technology podcast, which you can subscribe to via Apple Podcasts, Google Podcasts, or RSS, download the episode, or just hit the play button below.

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The new Microsoft Edge browser will warn you if your password has been leaked online

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The new Edge 88 browser includes tough new security features, including a password generator and a tool for monitoring whether your login details have been exposed to the dark web.

Edge 88 began rolling out on 21 January.

Image: Microsoft

Microsoft Edge 88 is rolling out to users in the Stable channel alongside some new privacy-focused features, including a long-awaited credentials monitor and a built-in password generator.

The first of these features, Password Monitor, will help users stay protected against data breaches involving passwords. If Edge determines that a user’s login credentials have been exposed on the dark web (or elsewhere), it will notify them within the browser and advise them to update their passwords.

SEE: Identity theft protection policy (TechRepublic Premium)    

Password monitor was
announced by Microsoft last year,

and began rolling out yesterday (January 21) with the release of Edge 88, though it may take a week or two to reach Edge users, Microsoft said.

The latest version of Microsoft Edge, which is based on the open-source Chromium architecture, also features a built-in password generator. When users sign up to a new account on a website, Edge will automatically generate a strong password for the user, which is then automatically saved and synced across their devices.

The feature is similar to the one available on Google Chrome, and helps ensure users are using strong passwords for their accounts, while taking away the onus of having to memorize (or worse, write down) lists of complex, unique passwords for each service they sign up for. This is particularly important when creating accounts for financial services and other websites that require valuable information, Microsoft said.

Password Monitor is available for Windows 7, 8 and 10 users. Password Generator is available to the same Windows users, in addition to being available on macOS. Both features require users to be signed into Edge with a work or school account, and password sync turned on.

Microsoft has made additional privacy tweaks under the hood of Edge 88. This includes more transparent options around data collection, with users now able to dip into the permissions settings and control which sites have access to location, camera and microphone functions. Customers also have more control over how cookies are stored, specifically by allowing them to delete unnecessary third-party cookies while hanging onto ones they want to keep: say, for keeping certain settings in place for websites they visit regularly.

SEE: Top Windows 10 run commands (free PDF) (TechRepublic)

Edge 88 also adds features for making browsing in private mode even more private. Users can now toggle a ‘Strict’ mode within the InPrivate browser that will block any trackers that personalize content and ads. This will prevent users from being shown personalized ads based on their browsing history, which Microsoft said would be useful when shopping for gifts or planning a surprise. This could be inadvertently ruined by an ad that gives the game away, particularly on a shared computer.

For times when even more privacy is needed, Microsoft Edge 88 features Secure DNS. This bolsters security by looking up website addresses over the more secure HTTPS protocol, ensuring data remains encrypted and protecting it from attackers who might try to modify or eavesdrop on the connection.

Users can configure a different secure DNS provider or disable it altogether within the Edge 88 privacy settings. Strict mode and Secure DNS is available on Edge 88 for Windows 7, 8 and 10 users, and on macOS. 

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