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Knowing This Specific Gene Can Cause Endometriosis Could Lead Us to Better Treatments

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A rigorous international inquiry into the genetics of endometriosis has revealed a potential new drug target for what remains a very common and incurable disease.

Endometriosis occurs when tissue similar to the uterus grows outside of the womb, oftentimes leading to chronic pain, although not in every case.

 

After decades of neglect from researchers and doctors alike, the reality is we still know very little about this inflammatory condition, which predominantly impacts women of reproductive age. 

Treatments currently include surgery to remove the endometrial lesions and hormones to control their growth, but both have imperfect results and come with their own risks and side effects.

Alternative treatments are desperately needed, and because endometriosis is commonly inherited, drug researchers are turning to genetics for clues.

The first parallel investigation of both humans and rhesus macaques (Macaca mulatta) has now revealed a possible focus for future drug treatment; it’s one that isn’t based on hormones, which can come with a whole lot of side effects.

It began with a 2015 study at Oxford University on 32 families containing three or more endometriosis patients. Here, researchers found a genetic link between stage III/IV endometriosis and a region of the human chromosome called 7p13-15.

That was a good starting point, but this region alone holds hundreds of genes. In the end, it took several more years of research at the Baylor College of Medicine in Texas to locate the specific gene researchers were looking for.

 

When researchers sequenced the DNA of 849 macaques – 135 of which had developed spontaneous endometriosis – they noticed a variation in the gene NPSR1, which is located on the chromosome 7p13-15 and seems to increase the risk of suffering from late-stage endometriosis. 

Back at Oxford, researchers sequenced the DNA of more than 11,000 women, including 3,000 women with endometriosis, to see if they could find a similar genetic variation in humans.  Their results ultimately found stage III/IV endometriosis is associated with the same specific variant in the NPSR1 gene as found in macaques.

In the past, variations of the NPSR1 gene have been linked to several other inflammatory conditions, such as asthma, allergies, inflammatory bowel disease (IBD), rheumatoid arthritis, and recurrent abdominal pain – some of which are known to co-occur with endometriosis.

But the variation, in this case, was slightly different from what has been found before with, say, IBD.

“This is one of the first examples of DNA sequencing in nonhuman primates to validate results in human studies and the first to make a significant impact on understanding the genetics of common, complex metabolic diseases,” says Jeffrey Rogers from the Baylor College of Medicine.  

 

“The primate research really helped to provide confidence at each step of the genetic analysis in humans and gave us motivation to carry on chasing these particular genes.”

In recent years, a growing number of researchers have come to suspect that endometriosis is not just one disease, but is in fact made up of several different subtypes.

There’s even been some preliminary evidence that the various stages of endometriosis are genetically distinct, but at the moment, there are no drugs available that target these specific variations.

The late stages of endometriosis are usually defined by a higher number of lesions with deeper infiltration, and yet that doesn’t always correlate with greater pain or worsening symptoms.

The way that endometriosis presents can vary quite a lot from patient to patient, and no one really knows why or how best to treat the various symptoms.

Even in the current research, not every endometriosis patient studied at Oxford University had an NPSR1 variant, which means that if a drug can be developed to target this subtype, it probably won’t work for everyone.

 

Still, that doesn’t mean it’s not worth pursuing. When researchers inhibited the NPSR1 gene’s expression in mice, which had little pieces of uterine lining implanted into their abdomens to simulate endometriosis, the animals showed signs of reduced inflammation and abdominal pain.

“We need to do further research on the mechanism of action and the role of the genetic variants in modulation of the gene’s effects in specific tissues,” says genetic epidemiologist Krina T. Zondervan from Oxford University.

“However, we have a promising new non-hormonal target for further investigation and development that appears to address directly the inflammatory and pain components of the disease.”

Just like in any emerging field, this study has limitations. A relatively small number of patients were initially studied at Oxford University and the functional effects of the NPSR1 gene changes weren’t able to be investigated.

While mice seemed to have their pain decreased somewhat when this genetic variant was turned off, Stacy McAllister, an endometriosis researcher at Emory University who was not involved in the study, told Science Magazine she’d like to know if the results can be extended from acute pain relief to chronic pain relief, which is the main complaint among patients with endometriosis.

What’s more, because mice do not menstruate, their models of this suspected inflammatory disease can only tell us so much. The authors of the current study admit their results do not feature the ‘full disease spectrum’ or the ‘pathological nuances’ we seen in humans.

As such, they hope to conduct further research on NPSR1 variants and their functional effects among macaques. If researchers can target the gene in monkeys in a similar way to mice, we can begin to test out certain drug treatments, working our way up to clinical trials in humans.

That reality is still a ways off, but given the debilitating toll endometriosis can take on the lives and livelihoods of women around the world, it’s vital we find a better way to treat this disease.

The study was published in Science Translational Medicine.

 

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Indian Coast Guard to get three more pollution control vessels to enhance capabilities

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Panaji: As a marine pollution control response, three more pollution control vessels (PCVs) will be added to the Indian Coast Guard’s (ICG) fleet, Union Defence Secretary Ajay Kumar said on Tuesday.

Speaking to reporters on the sidelines of the 8th National Pollution Response Exercise currently taking place in Goa, Kumar said that India is also willing to help friendly countries in upgrading their capabilities.

Around 19 friendly countries are participating in the exercise.

The Union government is continuously trying to upgrade the ICG’s capabilities to face pollution hazards in the ocean.

“Today, the Indian Coast Guard is capable of handling the highest level of oil spills in this region, which is 700 tonnes and above. Only a few countries in the world have this capability,” Kumar said.

Currently, the ICG has two dedicated vessels for pollution response, while three more will be added to its fleet to enhance its capability, he said.

The Indian Ocean is one of the busiest routes in the world and half of the trade takes place in the region, the senior official said, adding that oil exploration has also increase and accidents can happen anywhere.

Countries are also battling with the issue of plastic waste being dumped in the ocean, he said.

“We need to fight this (plastic pollution) collectively. It cannot be done by one country. All the coastal countries in the region need to make efforts,” Kumar said.

The defence secretary lauded the Punit Sagar Mission launched by Prime Minister Narendra Modi to clear plastic from the coastline.

“We should ensure that plastic waste is not washed into the ocean. Every year, 15,000 million tonnes of plastic washes into the Indian Ocean from different countries. If this continues, our marine life, environment, ecology and health will be affected,” he said.

Asked about cooperation from Pakistan and China over the pollution response, Kumar said, “This is an environmental issue and all countries should contribute towards it.” Several treaties have been signed to reduce pollution in the Indian Ocean, and friendly nations will have to collectively ensure that these are observed, he said.(GoaNewsHub)

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Brain Implant Translates Paralyzed Man’s Thoughts Into Text With 94% Accuracy

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A man paralyzed from the neck down due to a spinal cord injury he sustained in 2007 has shown he can communicate his thoughts, thanks to a brain implant system that translates his imagined handwriting into actual text.

 

The device – part of a longstanding research collaboration called BrainGate – is a brain-computer interface (BCI), that uses artificial intelligence (AI) to interpret signals of neural activity generated during handwriting.

In this case, the man – called T5 in the study, and who was 65 years of age at the time of the research – wasn’t doing any actual writing, as his hand, along with all his limbs, had been paralyzed for several years.

But during the experiment, reported in Nature earlier in the year, the man concentrated as if he were writing – effectively, thinking about making the letters with an imaginary pen and paper.

As he did this, electrodes implanted in his motor cortex recorded signals of his brain activity, which were then interpreted by algorithms running on an external computer, decoding T5’s imaginary pen trajectories, which mentally traced the 26 letters of the alphabet and some basic punctuation marks.

“This new system uses both the rich neural activity recorded by intracortical electrodes and the power of language models that, when applied to the neurally decoded letters, can create rapid and accurate text,” says first author of the study Frank Willett, a neural prosthetics researcher from Stanford University.

 

Similar systems developed as part of the BrainGate have been transcribing neural activity into text for several years, but many previous interfaces have focused on different cerebral metaphors for denoting which characters to write – such as point-and-click typing with a computer cursor controlled by the mind.

It wasn’t known, however, how well the neural representations of handwriting – a more rapid and dexterous motor skill – might be retained in the brain, nor how well they might be leveraged to communicate with a brain-computer interface, or BCI.

Here, T5 showed just how much promise a virtual handwriting system could offer for people who have lost virtually all independent physical movement.

BrainImpantDevice2A diagram of how the system works. (F. Willett et al., Nature, 2021, Erika Woodrum)

In tests, the man was able to achieve writing speeds of 90 characters per minute (about 18 words per minute), with approximately 94 percent accuracy (and up to 99 percent accuracy with autocorrect enabled).

Not only is that rate significantly faster than previous BCI experiments (using things like virtual keyboards), but it’s almost on par with the typing speed of smartphone users in the man’s age group – which is about 115 characters or 23 words per minute, the researchers say.

 

“We’ve learned that the brain retains its ability to prescribe fine movements a full decade after the body has lost its ability to execute those movements,” Willett says.

“And we’ve learned that complicated intended motions involving changing speeds and curved trajectories, like handwriting, can be interpreted more easily and more rapidly by the artificial-intelligence algorithms we’re using than can simpler intended motions like moving a cursor in a straight path at a steady speed.”

Basically, the researchers say that alphabetical letters are very different from one another in shape, so the AI can decode the user’s intention more rapidly as the characters are drawn, compared to other BCI systems that don’t make use of dozens of different inputs in the same way.

BrainImpantDevice2The man’s imagined handwriting, as interpreted by the system. (Frank Willett)

Despite the potential of this first-of-its-kind technology, the researchers emphasize that the current system is only a proof of concept so far, having only been shown to work with one participant, so it’s definitely not a complete, clinically viable product as yet.

The next steps in the research could include training other people to use the interface, expanding the character set to include more symbols (such as capital letters), refining the sensitivity of the system, and adding more sophisticated editing tools for the user.

There’s plenty of work to still be done, but we could be looking at an exciting new development here, giving the ability to communicate back to people who lost it.

“Our results open a new approach for BCIs and demonstrate the feasibility of accurately decoding rapid, dexterous movements years after paralysis,” the researchers write.

“We believe that the future of intracortical BCIs is bright.”

The findings are reported in Nature.

 

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Astronomers Detect a ‘Tsunami’ of Gravitational Waves. Here’s Where They’re Coming From

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The most recent gravitational wave observing run has netted the biggest haul yet.

In less than five months, from November 2019 to March 2020, the LIGO-Virgo interferometers recorded a massive 35 gravitational wave events. On average, that’s almost 1.7 gravitational wave events every week for the duration of the run.

 

This represents a significant increase from the 1.5-event weekly average detected on the previous run, and a result that has plumped up the number of total events to 90 since that first history-making gravitational wave detection in September 2015.

“These discoveries represent a tenfold increase in the number of gravitational waves detected by LIGO and Virgo since they started observing,” said astrophysicist Susan Scott of the Australian National University in Australia.

“We’ve detected 35 events. That’s massive! In contrast, we made three detections in our first observing run, which lasted four months in 2015-16. This really is a new era for gravitational wave detections and the growing population of discoveries is revealing so much information about the life and death of stars throughout the Universe.”

Of the 35 new detections, 32 are most likely the result of mergers between pairs of black holes. This is when pairs of black holes on a close orbit are drawn in by mutual gravity, eventually colliding to form one single, more massive black hole.

That collision sends ripples through space-time, like the ripples generated when you throw a rock in a pond; astronomers can analyze those ripples to determine the properties of the black holes.

mergersAn infographic showing the masses of all black hole mergers announced to date. (LIGO-Virgo/Aaron Geller/Northwestern University)

The data revealed a range of black hole masses, with the most massive clocking in at around 87 times the mass of the Sun. That black hole merged with a companion 61 times the mass of the Sun, resulting in a single black hole 141 times the mass of the Sun. That event is named GW200220_061928.

Another merger produced a black hole 104 times the mass of the Sun; both of these are considered intermediate mass black holes, a mass range between 100 and around a million solar masses, in which very few black holes have been detected.

 

GW200220_061928 is also interesting, because at least one of the black holes involved in the merger falls into what we call the upper mass gap. According to our models, black holes over about 65 solar masses can’t form from a single star, as stellar mass black holes do.

That’s because the precursor stars are so massive that their supernovae – known as pair-instability supernovae – ought to completely obliterate the stellar core, leaving nothing behind to gravitationally collapse into a black hole.

This suggests that the 87 solar mass black hole might be the product of a previous merger. GW200220_061928 isn’t the first that’s involved a black hole in the upper mass gap, but its detection does suggest that hierarchical black hole mergers are not uncommon.

And another event includes an object in the lower mass gap – a gap of black holes between 2.5 and 5 times the mass of the Sun. We’ve not conclusively found a neutron star larger than the former, or a black hole smaller than the latter; the event named GW200210_092254 involved an object clocking in at 2.8 solar masses. Astronomers have concluded that it’s probably a very small black hole.

 

“Looking at the masses and spins of the black holes in these binary systems indicates how these systems got together in the first place,” Scott said.

“It also raises some really fascinating questions. For example, did the system originally form with two stars that went through their life cycles together and eventually became black holes? Or were the two black holes thrust together in a very dense dynamical environment such as at the centre of a galaxy?”

The other three events out of the 35 involved a black hole and something else much less massive, likely a neutron star. These events are of great interest to astronomers, since they might reveal the stuff that’s inside a neutron star – if we ever detect one that emits light. By finding more of these mergers, we can start to build a better understanding of how they actually occur.

“Only now are we starting to appreciate the wonderful diversity of black holes and neutron stars,” said astronomer Christopher Berry of the University of Glasgow in the UK

“Our latest results prove that they come in many sizes and combinations – we have solved some long-standing mysteries, but uncovered some new puzzles too. Using these observations, we are closer to unlocking the mysteries of how stars, the building blocks of our Universe, evolve.”

The team’s paper has been submitted for publication, and can be found on preprint server arXiv.

 

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