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Comment by Dr. Krishna Kumari Challa on January 19, 2023 at 10:37am

 How iron dysregulation might contribute to neurodegenerative diseases

Past neuroscience research consistently found a link between deviations from the "normal" iron metabolism, also known as iron dysregulation, and different neurodegenerative diseases, including Parkinson's disease (PD) and Multiple Sclerosis (MS). Specifically, brain regions associated with these diseases have been found to be often populated by microglia (i.e., resident immune cells) packed with Iron.

While the association between iron dysregulation and neurodegenerative diseases is well documented, the ways in which iron accumulation affects the physiology of microglia and neurodegeneration are yet to be fully grasped. Researchers  have recently carried out a study aimed at filling this gap in the literature, by better understanding how microglia respond to iron.

For years it has been known that iron accumulates in affected brain regions in PD, MS and other neurodegenerative diseases.

The key objective of the recent work  was to better understand how iron accumulation in microglia affects these cells' functioning and health. Their work builds on their previous studies, and on the 2012 discovery of an iron-dependent form of cell death, known as ferroptosis.

Ferroptosis is a form of cell death that is mediated by iron-dependent lipid peroxidation, a process that damages lipids by oxidizing them. In their paper, the researchers' hypothesized that iron-laden microglia are susceptible to ferroptosis and that this might play a role in neurodegenerative diseases.

To conduct their experiments, the researchers grew microglia in a tri-culture system. Using a series of genetic and experimental techniques, they then showed that these microglia are highly responsive to iron and also susceptible to ferroptosis.

In addition, the team showed that an overload of iron causes a shift in the microglial transcriptional state, which overlaps with a transcriptomic signature observed in microglia in brain tissue from deceased patients with PD. When they removed microglia from their tri-culture system, the researchers observed that iron-induced neurotoxicity in the system significantly slowed down. This suggests that microglia responses to iron overload play a crucial role in neurodegeneration.

Sean K. Ryan et al, Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration, Nature Neuroscience (2022). DOI: 10.1038/s41593-022-01221-3

Jonathan D. Proto et al, Disrupted microglial iron homeostasis in progressive multiple sclerosis, bioRxiv (2021). DOI: 10.1101/2021.05.09.443127

Comment by Deepak Menon on January 19, 2023 at 5:53am

Dear Doctor Krishna - the years pass - I encountered your kkartlab in 2016 - thought I'd let you know that my son also completed his P Hd from Stanford in 2017 and set up his own Robotics Company soon after. https://www dexterity.ai
You never post your poetry here ... please do so - 'twill be nice
Cheers
Deepak Menon (Author on Amazon)

Comment by Deepak Menon on January 18, 2023 at 9:51pm

Aww - wonderful insights Dr Krishna.

Comment by Dr. Krishna Kumari Challa on January 18, 2023 at 11:35am

Unusual compound found in Rembrandt's The Night Watch

An international team of scientists from the Rijksmuseum, the CNRS, the ESRF the European Synchrotron, the University of Amsterdam and the University of Antwerp, have discovered a rare lead compound (named lead formate) in Rembrandt's masterpiece The Night Watch. This discovery, which is a first in the history of the scientific study of paintings, provides new insight into 17th-century painting technique and the conservation history of the painting. The study is published in Angewandte Chemie International Edition.

Comment by Dr. Krishna Kumari Challa on January 18, 2023 at 11:13am

Eating one wild fish same as month of drinking tainted water: study

Eating one freshwater fish caught in a river or lake in the United States is the equivalent of drinking a month's worth of water contaminated with toxic "forever chemicals", new research said recently.

The invisible chemicals called PFAS were first developed in the 1940s to resist water and heat, and are now used in items such as non-stick pans, textiles, fire suppression foams and food packaging.

But the indestructibility of PFAS, per- and polyfluoroalkyl substances, means the pollutants have built up over time in the air, soil, lakes, rivers, food, drinking water and even our bodies.

There have been growing calls for stricter regulation for PFAS, which have been linked to a range of serious health issues including liver damage, high cholesterol, reduced immune responses and several kinds of cancer.

To find out PFAS contamination in locally caught fish, a team of researchers analyzed more than 500 samples from rivers and lakes across the United States between 2013 and 2015.

The median level of PFAS in the fish was 9,500 nanogrammes per kilogram, according to a new study published in the journal Environmental Research.

Eating just one freshwater fish equalled drinking water with PFOS at 48 parts per trillion for a month, the researchers calculated.

Nadia Barbo et al, Locally caught freshwater fish across the United States are likely a significant source of exposure to PFOS and other perfluorinated compounds, Environmental Research (2022). DOI: 10.1016/j.envres.2022.115165

Comment by Dr. Krishna Kumari Challa on January 18, 2023 at 10:55am

Study finds that UV-emitting nail polish dryers damage DNA and cause mutations in cells

The ultraviolet nail polish drying devices used to cure gel manicures may pose more of a public health concern than previously thought. Researchers at the University of California San Diego have studied these ultraviolet (UV) light emitting devices, and found that their use leads to cell death and cancer-causing mutations in human cells.

The devices are a common fixture in nail salons, and generally use a particular spectrum of UV light (340-395nm) to cure the chemicals used in gel manicures. While tanning beds use a different spectrum of UV light (280-400nm) that studies have conclusively proven to be carcinogenic, the spectrum used in the nail dryers has not been well studied.

If you look at the way these devices are presented, they are marketed as safe, with nothing to be concerned about. But to the best of our knowledge, no one has actually studied these devices and how they affect human cells at the molecular and cellular levels until now.

Using three different cell lines—adult human skin keratinocytes, human foreskin fibroblasts, and mouse embryonic fibroblasts—the researchers found that the use of these UV emitting devices for just one 20-minute session led to between 20 and 30 percent cell death, while three consecutive 20-minute exposures caused between 65 and 70 percent of the exposed cells to die.

Exposure to the UV light also caused mitochondrial and DNA damage in the remaining cells and resulted in mutations with patterns that can be observed in skin cancer in humans.

Researchers observed multiple things:

DNA gets damaged,  some of the DNA damage does not get repaired over time, and it does lead to mutations after every exposure with a UV-nail polish dryer, exposure may cause mitochondrial dysfunction, which may also result in additional mutations.

The researchers caution that while the results show the harmful effects of the repeated use of these devices on human cells, a long-term epideomological study would be required before stating conclusively that using these machines leads to an increased risk of skin cancers. However, the results of the study were clear: The chronic use of these nail polish drying machines is damaging to human cells.

Maria Zhivagui et al, DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer, Nature Communications (2023). DOI: 10.1038/s41467-023-35876-8

Comment by Deepak Menon on January 17, 2023 at 9:41pm

Very interesting posts! As regards the use of human excreta for fertilizer - we have a soak pit system, and the municipality sends a tank to empty it by suction - I've never thought about what they do with it....?

Comment by Dr. Krishna Kumari Challa on January 17, 2023 at 12:08pm

How the last 12,000 years have shaped what humans are today

How the last 12,000 years have shaped what humans are today

While humans have been evolving for millions of years, the past 12,000 years have been among the most dynamic and impactful for the way we live today, according to an anthropologist who organized a special journal feature on the topic in the Proceedings of the National Academy of Sciences.

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Our toilets can yield excellent alternatives for widespread polluti...

To tackle the climate crisis, biodiversity loss, and pollution, humanity will need to move to a circular economy, where all resources are recycled. Why not recycle our own body waste too as fertilizer, provided there is no risk that harmful microbes or traces from pharmaceuticals end up in the consumed crops? Most nutrients needed for plant growth occur in human urine and feces. Urine is especially rich in nitrogen and potassium, and also contains trace amounts of metals such as boron, zinc, and iron. Feces could in theory supply other nutrients such as phosphorus, calcium, and magnesium or valuable organic carbon to soils.

Comment by Dr. Krishna Kumari Challa on January 17, 2023 at 11:47am

Blood vessel protein found to reduce mortality in infectious disease

The vascular system plays an essential role in carrying oxygen and nutrients throughout the body, but too much vascular permeability, or space between the cells lining the blood vessels, can have devastating results. Recently, researchers  have shed new light on a key protein involved in vascular permeability and its impact on mortality in infectious disease.

In a new study published in PNAS, researchers  have demonstrated the potential of endothelial cell-specific protein Roundabout4 (Robo4) as a therapeutic target to reduce mortality resulting from severe infection. Robo4 is expressed by endothelial cells that line the blood vessels. These cells regulate vascular permeability and allow for the exchange of substances from the blood vessels into the surrounding tissue and vice versa.

During the body's immune response, vascular permeability facilitates the movement of important immune cells and the elimination of dangerous pathogens. However, in severe immune responses, such as may occur in infectious diseases like COVID-19, an excessive increase in vascular permeability, known as vascular hyperpermeability, may lead to organ damage and death.

Currently, no drugs directly suppress vascular hyperpermeability. Because Robo4 has been previously shown to play a role in vascular permeability, the researchers  set out to explore Robo4 as a potential target to reduce vascular permeability in severe infection.

To investigate the effects of Robo4 on vascular hyperpermeability, researchers generated an endothelial cell-specific mouse model of conditional Robo4 overexpression. Upon exposing these mice to lipopolysaccharide (LPS), which induces a severe immune response, the mice exhibited decreased vascular permeability and increased rates of survival.

 Researchers found  that treatment with ALK1 inhibitor increases Robo4 expression and reduces mortality in mice under sepsis and SARS-CoV-2 conditions. Increasing Robo4 expression may represent a strategy to reduce vascular permeability and alleviate severe infections.

The researchers screened a library of drugs using a mouse endothelial cell line to identify pathways that are involved in the regulation of Robo4 and found that two competitive SMAD signaling pathways appear to regulate Robo4 expression. When the researchers treated LPS-injected mice with a drug that inhibits ALK1-SMAD signaling, they observed increased Robo4 expression, decreased vascular permeability, and reduced mortality. A reduction in mortality was also observed in mice exposed to SARS-CoV-2, the virus that causes COVID-19.

Maaya Morita et al, Upregulation of Robo4 expression by SMAD signaling suppresses vascular permeability and mortality in endotoxemia and COVID-19 models, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2213317120

Comment by Dr. Krishna Kumari Challa on January 17, 2023 at 11:34am

Highly accurate test for common respiratory viruses uses DNA as 'bait'

Researchers have developed a new test that "fishes" for multiple respiratory viruses at once using single strands of DNA as bait and gives highly accurate results in under an hour.

The test uses DNA "nanobait" to detect the most common respiratory viruses—including influenza, rhinovirus, RSV and COVID-19—at the same time. In comparison, PCR (polymerase chain reaction) tests, while highly specific and highly accurate, can only test for a single virus at a time and take several hours to return a result.

While many common respiratory viruses have similar symptoms, they require different treatments. By testing for multiple viruses at once, the researchers say their test will ensure patients get the right treatment quickly and could also reduce the unwarranted use of antibiotics.

In addition, the tests can be used in any setting, and can be easily modified to detect different bacteria and viruses, including potential new variants of SARS-CoV-2, the virus which causes COVID-19. 

The researchers based their test on structures built from double strands of DNA with overhanging single strands. These single strands are the "bait": they are programmed to "fish" for specific regions in the RNA of target viruses. The nanobaits are then passed through very tiny holes called nanopores. Nanopore sensing is like a ticker tape reader that transforms molecular structures into digital information in milliseconds. The structure of each nanobait reveals the target virus or its variant.

The researchers showed that the test can easily be reprogrammed to discriminate between viral variants, including variants of the virus that causes COVID-19. The approach enables near 100% specificity due to the precision of the programmable nanobait structures.

Ulrich Keyser, Simultaneous identification of viruses and viral variants with programmable DNA nanobait, Nature Nanotechnology (2023). DOI: 10.1038/s41565-022-01287-x. www.nature.com/articles/s41565-022-01287-x

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