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Comment by Dr. Krishna Kumari Challa on February 9, 2024 at 9:59am

Researchers identify potential way to treat genetic epilepsy by replacing 'lost' enzyme

Scientists  have found a new treatment target for CDKL5 deficiency disorder (CDD), one of the most common types of genetic epilepsy.

CDD causes seizures and impaired development in children, and medications are limited to managing symptoms rather than tackling the root cause of the disease. The disorder involves losing the function of a gene producing the CDKL5 enzyme, which phosphorylates proteins, meaning it adds an extra phosphate molecule to alter their function.

Following recent research from the same lab showing that a calcium channel could be a target for therapy for CDD, the team has now identified a new way to potentially treat CDD by boosting another enzyme's activity to compensate for the loss of CDKL5.

In research published in Molecular Psychiatry, the scientists studied mice that don't make the CDKL5 enzyme. These mice show similar symptoms to people with CDD, such as impaired learning or social interaction.

The researchers first identified that CDKL5 is active in nerve cells in mice but not in another type of brain cell called an astrocyte. In the nerve cells, they measured the level of phosphorylation of EB2, a molecule known to be targeted by CDKL5, to understand what happens when CDKL5 isn't produced.

Interestingly, even in mice that don't produce CDKL5, there was still some EB2 phosphorylation taking place, which suggested that another similar enzyme must also be able to phosphorylate it.

By looking at enzymes similar to CDKL5, the researchers identified that one called CDKL2 also targets EB2 and is present in human neurons. In mice without both CDKL5 and CDKL2, the remaining EB2 phosphorylation almost fully dropped off.

The researchers concluded that although most activity comes from CDKL5, about 15% is from CDKL2, and the remaining < 5% from another enzyme yet to be identified.

Their research suggests that increasing the level of CDKL2 in people who are deficient in CDKL5 could potentially treat some of the effects on the brain in early development.

Margaux Silvestre et al, Cell-type specific expression, regulation and compensation of CDKL5 activity in mouse brain. Molecular Psychiatry. (2024). DOI: 10.1038/s41380-024-02434-7

Comment by Dr. Krishna Kumari Challa on February 9, 2024 at 8:54am

Patterns of brain connectivity found to differ between pre-term and term babies

A new scanning study of 390 babies has shown distinct patterns between term and pre-term babies in the moment-to-moment activity and connectivity of brain networks.

This is the first study to analyze how the communication between brain areas changes moment-to-moment in the first few weeks of life.

Published in Nature Communications, the study also found that these dynamic patterns of brain connectivity in babies were linked to developmental measures of movement, language, cognition, and social behavior 18 months later.

There is increasing awareness that conditions such as ADHD, autism, and schizophrenia have their origins early in life and that the development of these conditions may be linked to neonatal brain connectivity and its fluctuations over time.

The study identified six different brain states: three of these were across the whole brain, and three were constrained to regions of the brain (occipital, sensorimotor, and frontal regions). By comparing term and pre-term babies, the researchers showed that different patterns of connectivity are linked to pre-term birth; for example, pre-term babies spent more time in frontal and occipital brain states than term babies. They also demonstrated that brain state dynamics at birth are linked to various developmental outcomes in early childhood.

Dafnis Batallé et al, Neonatal brain dynamic functional connectivity: impact of preterm birth and association with early childhood neurodevelopment, Nature Communications (2024). www.nature.com/articles/s41467-023-44050-z

Comment by Dr. Krishna Kumari Challa on February 8, 2024 at 6:47am

Chronic jet lag leads to human liver cancer in a mouse model

When asked about what could cause cancer, people most likely think of chemicals like tobacco or radiation such as UV light in sunshine, but chronic jet lag probably does not come to mind. Human epidemiological studies have linked chronic jet lag, also known as chronic circadian dysfunction, to increased liver cancer risk. However, direct evidence that it leads to liver cancer has been lacking.

A recent study  by researchers  published in the Journal of Hepatology is the first to experimentally demonstrate that chronic circadian dysfunction is indeed a human carcinogen.

They worked with a humanized mouse model that was developed by one of the researchers. This animal model has both human and mouse liver cells in the animals' livers, which allowed them to study the effect of disrupting the circadian rhythm on cancer development in human cells.  

Circadian rhythm is the 24-hour internal timekeeper in our brain that regulates cycles of alertness, sleepiness and practically all functions of the body by being in sync with the planet's day-and-night cycle. Recent studies have uncovered that when the internal clock goes out of sync, disease has a better chance of developing.

Humanized mice were exposed to two different conditions. One group of animals was maintained in sync with the natural day-and-night cycle. For the other group, the researchers changed the light and dark periods the animals were exposed to, to create the equivalent of the changes a person experiences when flying back and forth from San Francisco to London every week for many weeks.

 They found that compared to mice kept in normal light/dark cycles, mice in the jet-lagged group had a shorter lifespan as well as increased cirrhosis, jaundice (when skin or the white of the eyes turns yellow) and also developed cancer in both mouse and human liver cells. Importantly, chronic jet lag also induced metastasis from humanized livers.

Blood analyses and microscopy studies of the livers revealed multiple commonalities between humanized mice and patients with liver cancer, including glucose intolerance, abnormal fat accumulation in the liver, inflammation and fibrosis. This supports the validity of this model to study the human condition.

The study showed that as the tumor progresses, biomarker profile and genetic expression patterns in the cells change.

Chronic jet-lagged humanized mice spontaneously developed liver cancer in human liver cells following the same process and molecular pathways as those in humans. Gene expression studies reveal that spontaneous cancer development in this model is driven by changes in the expression of thousands of genes which depend on cell type, time and disease stage.

One of the important findings of the paper is that once the tumors spontaneously develop in response to chronic circadian disruption, returning the mice to a normal circadian clock slows tumor development and prevents metastasis.

When the animals reenter normal circadian rhythm, the gene expression pattern is restored to what it was before.

Jennifer Padilla et al, Circadian dysfunction induces NAFLD-related human liver cancer in a mouse model, Journal of Hepatology (2023). DOI: 10.1016/j.jhep.2023.10.018

Comment by Dr. Krishna Kumari Challa on February 8, 2024 at 6:37am

Can an experimental cell phone app screen coughs for TB? Scientists say 'yes'

What telltale features—many inaudible to the human ear—separate one kind of cough from another? Scientists are on the verge of finding out with a new machine learning tool aimed at identifying the signature sounds of tuberculosis.

Cough is a leading symptom of respiratory infections. And because the pattern and frequency of cough episodes differ from one disease to the next, an effort is underway to develop a smartphone app that is sensitive enough to accurately discern coughs associated with TB.

An international team of researchers is testing the hypothesis that TB's unique pattern and frequency of coughing can provide sufficient data to screen for the highly infectious bacterial disease using technology engineered into a smartphone app.

Currently in the investigational phase, the app is not yet ready for distribution. At present it is a machine-learning tool called TBscreen, but given the rising numbers of TB cases around the globe, its development couldn't have arrived at a more opportune time.

The research team includes engineers and computer scientists as well as physicians and experts in infectious diseases.

When they entered audio of coughs through various microphones into TBscreen, the team found that TBscreen—the investigational app—and a smartphone mic identified active TB more accurately than when cough audio was fed through expensive microphones.

The machine-learning tool is being "trained" to recognize pattern and frequency in coughs caused by TB. The investigational app also is being trained to distinguish TB-related coughs from those caused by other respiratory disorders.

Researchers have found that there are numerous factors affecting the basic patterns of coughing, nuances—some inaudible to the human ear—that the tool must discern as a way to accurately screen for TB.

The mechanism of cough production varies according to mucus properties, respiratory muscle strength, mechanosensitivity, chemosensitivity of airways, and other factors resulting in diverse cough sounds.

Manuja Sharma et al, TBscreen: A passive cough classifier for tuberculosis screening with a controlled dataset, Science Advances (2024). DOI: 10.1126/sciadv.adi0282

Comment by Dr. Krishna Kumari Challa on February 8, 2024 at 6:31am

Study finds that microglia could regulate sleep via the modulation of norepinephrine transmission

Sleep is known to play a key role in facilitating various physiological processes, while also contributing to the healthy functioning of the brain. Lack of sleep and poor sleep quality have been linked to various chronic health and mental health issues, including high blood pressure, depression, stroke, obesity, and heart disease.

Sleep disturbances have also been implicated in the development of neurodegenerative diseases. Interestingly, neurodegenerative diseases have also been associated with the dysfunction of microglia, the primary mammalian immune cells, yet the link between microglia and sleep has not been thoroughly studied yet.

Researchers recently carried out a study exploring the potential role of microglia in regulating sleep. Their findings, published in Nature Neuroscience, suggest that microglia regulate sleep by modulating the transmission of the neurotransmitter norepinephrine, which is known to contribute to arousal, attention and stress reactions.

These initial observations could soon pave the way for further studies investigating the role of microglia in sleep regulation, focusing on norepinephrine transmission.

As microglia dysfunction and sleep disturbances have been linked to Alzheimer's and other neurodegenerative diseases, this work may also broaden neuroscientists' understanding of these diseases, potentially aiding the future development of new therapeutic strategies.

 Chenyan Ma et al, Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission, Nature Neuroscience (2024). DOI: 10.1038/s41593-023-01548-5.

Comment by Dr. Krishna Kumari Challa on February 7, 2024 at 9:05am

The team says they weren't expecting this evolution and decrease in metabolic coupling, and it's far from clear as to why these changes occur in the way they do.

But it's easy to see why they think this drastic reprogramming could go awry, perhaps leading to some of the metabolic conditions that arise during pregnancy. The roles of all 91 pregnancy-adaptive metabolites were verified in human cell models and in 32 pregnant human's blood serum samples.

Those pregnant women with pre-eclampsia – a dangerous natal condition characterized by high blood pressure, severe swelling, and protein-laden urine – had a huge drop in levels of the metabolite corticosterone, which is involved in maturing the placenta.

Another key metabolite during pregnancy appears to be palmitoylcarnitine, which regulates immunity and is involved in processing fatty acids. Levels were up in the tissues of early- and mid-pregnant monkeys, across a range of organs including the liver, pancreas, heart, and kidney.

The researchers think that this metabolic shift may have some link to gestational diabetes, but more research is needed to confirm this. 

This research was published in Cell.

https://www.cell.com/cell/fulltext/S0092-8674(23)01329-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867423013296%3Fshowall%3Dtrue

Part 3

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Comment by Dr. Krishna Kumari Challa on February 7, 2024 at 9:03am

The samples from the non-pregnant monkeys provided a reference point for how certain metabolic pathways interact prior to pregnancy, with the other samples revealing the drastic extent to which these 'trade routes' changed course as the monkey's pregnancies progressed.

In fact, during pregnancy, 91 metabolites changed consistently across all 23 tissues sampled.

In non-pregnant monkeys, the metabolomes of skeletal muscles were highly correlated with tissues from the heart, spinal cord, adrenal gland, and uterus. But in the first and second trimesters, their coupling with heart tissues decreased.

In early pregnancy, the samples indicated that the uterus backs off from its ongoing metabolic 'agreement' with the heart and skeletal muscles, coupling with the developing placenta instead.

Fully formed by the second trimester, the placenta appeared to be sending metabolites to the pregnant monkey's heart, ovaries, and liver. Weirdly, the uterus, seemingly done with getting the placenta established, shifts its focus to a metabolic exchange with scalp skin tissue, of all things.

And for those monkeys in their third trimester, the samples showed the skeletal muscles had developed a significant exchange with the spinal cord.
Part 2

Comment by Dr. Krishna Kumari Challa on February 7, 2024 at 9:03am

Monkey Study Reveals 91 Changes in Virtually Every Body Organ During Pregnancy

Scientists have mapped out the drastic changes pregnancy makes to the body's metabolic pathways in a closely related primate, and it could guide the way to better understanding pregnancy problems like recurrent miscarriage, pre-eclampsia, and gestational diabetes.

Little is known about this major disruption to the body's metabolic flow, but now a team of biologists from the Chinese Academy of Sciences in Beijing has studied crab-eating macaques (Macaca fascicularis) to create a map that charts at least some of the changes that occur during pregnancy.
These monkeys are one of the primates most closely related to humans, so they're often used as a proxy in experiments that can't be done on humans.

The researchers collected 273 tissue samples from 12 captive-bred monkeys – three each that were not pregnant, in early pregnancy (5–8 weeks), in mid-pregnancy (12–15 weeks) and in late pregnancy (18–20 weeks).

This included a blood serum sample taken from each monkey before they were euthanized, when a further 22 tissue samples were collected from different body systems, including the uterus, liver, spinal cord, skin, blood, and five different heart regions.

The metabolism is made up of thousands of different chemical pathways, like a bustling port city where a log of imports and exports wouldn't suffice to capture the complex ecosystem of logistics.

It's business as usual for the myriad cells, tissues, and organs that trade the raw materials of life until, as always, a baby comes along and changes everything.

The researchers were able to identify the full set of small-molecule chemicals within each sample, which is known as a 'metabolome'.

Part 1

Comment by Dr. Krishna Kumari Challa on February 7, 2024 at 8:51am

There's just one problem: alkali metals are highly reactive with liquid water, sometimes even to the point of explosivity.

The research team found a very nifty way to solve this problem. What if, rather than adding the metal to water, water was added to the metal?

In a vacuum chamber, the team started by extruding from a nozzle a small blob of sodium-potassium alloy, which is liquid at room temperature, and very carefully added a thin film of pure water using vapor deposition.

Upon contact, the electrons and metal cations (positively charged ions) flowed into the water from the alloy.

Not only did this give the water a golden shine, it turned the water conductive – just like we should see in metallic pure water at high pressure.

This was confirmed using optical reflection spectroscopy and synchrotron X-ray photoelectron spectroscopy. The two properties – the golden sheen and the conductive band – occupied two different frequency ranges, which allowed them both to be identified clearly.

https://www.nature.com/articles/s41586-021-03646-5

Part 2

Comment by Dr. Krishna Kumari Challa on February 7, 2024 at 8:49am

Scientists Transformed Pure Water Into a Metal

Water found in nature conducts electricity – but that's because of the impurities therein, which dissolve into free ions that allow an electric current to flow. Pure water only becomes "metallic" – electronically conductive – at extremely high pressures, beyond our current abilities to produce in a lab.

But, as researchers demonstrated for the first time back in 2021, it's not only high pressures that can induce this metallicity in pure water.

By bringing pure water into contact with an electron-sharing alkali metal – in this case an alloy of sodium and potassium – free-moving charged particles can be added, turning water metallic.

The resulting conductivity only lasts a few seconds, but it's a significant step towards being able to understand this phase of water by studying it directly.

You can see the phase transition to metallic water with the naked eye! The silvery sodium-potassium droplet covers itself with a golden glow, which is very impressive.

Metallic water prepared for first time under terrestrial conditions

The idea is that if you squeeze the atoms together tightly enough, the orbitals of the outer electrons would start to overlap, allowing them to move around. For water, this pressure is around 48 megabars – just under 48 million times Earth's atmospheric pressure at sea level.

While pressures exceeding this have been generated in a laboratory setting, such experiments would be unsuitable for studying metallic water. So a team of researchers turned to alkali metals.

These substances release their outer electrons very easily, which means they could induce the electron-sharing properties of highly pressurized pure water without the high pressures.

Part 1

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