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Comment by Dr. Krishna Kumari Challa on January 26, 2023 at 12:18pm

Drug pollution: What happens to drugs after they leave your body?

Swallowing a pill only seems to make it disappear. In reality, the drug eventually leaves your body and flows into waterways, where it can undergo further chemical transformations. And these downstream products aren't dead in thewater.

Many pharmaceuticals, for example, are designated as contaminants of emerging concern, or CECs, because they alter hormone levels or otherwise harm wildlife. Some downstream products formed during drug breakdown are even more harmful than their parent molecule. It's critical, then, to chart out the chemical course of drugs to assess risk, but this is a daunting task because it depends on myriad hard-to-predict reaction patterns that are difficult to observe.

In a new study published in Water Resources Research, researchers devise a new method to chart these reaction possibilities. The newly proposed method is based on a multimodel global sensitivity analysis. This balances model fit and mathematical complexity: It generates a well-fitting model by simplifying it.

The researchers estimated how the arthritis drug diclofenac breaks down upon entering groundwater. First, using existing chemical transformation data, they built a comprehensive model of breakdown that included the gamut of possible chemical reactions. However, the estimates from this model were highly uncertain.

To adjust the model to better fit their data, the researchers quantified the relative importance of each possible chemical process and removed the least relevant ones.

This led to three simplified yet plausible models of drug breakdown. They ranked these models on the basis of their fit with the data and showed that a simplified model outperformed the most complex one.

The method yielded a flexible and accurate model. The team says their new method is especially useful when data are limited. Applying it to other drugs, they say, could reveal the full toll that pharmaceutical pollution takes on the planet.

More information: Laura Ceresa et al, On Multi‐Model Assessment of Complex Degradation Paths: The Fate of Diclofenac and Its Transformation Products, Water Resources Research (2023). DOI: 10.1029/2022WR033183

Comment by Dr. Krishna Kumari Challa on January 26, 2023 at 12:12pm

Scientists discover evolutionary secret behind different animal life cycles

Why do some animals become larvae before growing into adults while some embryos directly  develop into miniature version of the adult?

In a new paper, scientists prove that the timing of activation of essential genes involved in embryogenesis—the transformation of a fertilized egg into an organism—correlates with the presence or absence of a larval stage and with whether the larva feeds from their surroundings or relies on nourishment the mother deposited in the egg.

It's impressive to see how evolution shaped the way animal embryos 'tell the time' to activate important groups of genes earlier or later in development. Suppose a larval stage is no longer essential for your survival. In that case, it might be evolutionarily advantageous to, for example, activate the genes to form the trunk earlier and develop straight into an adult instead.

This new study used state-of-the-art approaches to decode the genetic information, activity, and regulation in three species of marine invertebrate worms called annelids. They combined these with public datasets from other species in a large-scale study involving more than 600 datasets of more than 60 species separated by more than 500 million years of evolution.

Only by combining experimental datasets generated in the lab and systematic computational analyses were we able to unravel this new undiscovered biology.

José Martín-Durán, Annelid functional genomics reveal the origins of bilaterian life cycles, Nature (2023). DOI: 10.1038/s41586-022-05636-7. www.nature.com/articles/s41586-022-05636-7

Comment by Dr. Krishna Kumari Challa on January 26, 2023 at 11:42am

Cancer cells may shrink or super-size to survive

Cancer cells can shrink or super-size themselves to survive drug treatment or other challenges within their environment, researchers have discovered.

Scientists combined biochemical profiling technologies with mathematical analyses to reveal how genetic changes lead to differences in the size of cancer cells—and how these changes could be exploited by new treatments.

The researchers think smaller cells could be more vulnerable to DNA-damaging agents like chemotherapy combined with targeted drugs, while larger cancer cells might respond better to immunotherapy. The study combines innovative high-powered image analysis with examination of DNA and proteins to study size control in millions of skin cancer cells.

The skin cancer melanoma is driven by two different genetic mutations—60% of cases are caused by a BRAF gene mutation, while 20% to 30% of cases are caused by an NRAS mutation. The researchers set out to investigate the differences in size and shape of skin cancer cells harboring the two mutations, by using mathematical algorithms to analyze huge amounts of data on DNA and proteins. The major difference was cell size.

BRAF-mutant cancer cells were very small whereas NRAS-mutant cancer cells were much bigger. Drug resistant NRAS cells were even bigger. Smaller cells appear to be able to tolerate higher levels of DNA damage, as they are very concentrated with proteins that repair DNA—like PARP, BRCA1, or ATM1 proteins. The researchers think that this could make them more vulnerable to drugs like PARP inhibitors—drugs blocking proteins responsible for repairing DNA damage—especially when combined with DNA-damaging agents such as chemotherapy.

In contrast, the larger NRAS-mutant cancer cells contained damage to their DNA instead of repairing it, accumulating mutations and enlarging. These larger cells were not as reliant on DNA repair machinery, so using chemotherapy and PARP inhibitors against them might not be as effective. Scientists think larger cells could be more responsive to immunotherapy—because their larger number of mutations could make them look more alien to the body.

They are already exploring this theory with further studies. The researchers think BRAF and NRAS mutations may be driving the differences in cell size by regulating levels of a protein known as CCND1—which is involved in cell division, growth and maintaining the cytoskeleton—and its interactions with other proteins.

While the study focused on skin cancer cells, researchers suspect that this size-shifting ability and its impact on treatment response is common to multiple cancer types. They have already identified similar mechanisms in breast cancer and are now investigating whether the findings could apply to head and neck cancers.

The discovery provides new insight into how the size of cancer cells affects the overall disease, allowing for better predictions of how people with cancer will respond to different treatments simply by analyzing cell size.

Existing drugs could even be used to force cancer cells into a desired size prior to treatments like immunotherapy or radiotherapy, which could improve their effectiveness.

Ian Jones et al, Characterization of proteome-size scaling by integrative omics reveals mechanisms of proliferation control in cancer, Science Advances (2023). DOI: 10.1126/sciadv.add0636. www.science.org/doi/10.1126/sciadv.add0636

Comment by Dr. Krishna Kumari Challa on January 26, 2023 at 11:37am

Self-suppression associated with exercise dependence
The team recruited 227 recreational runners, half men and half women, with widely varying running practices. They were asked to fill out questionnaires which investigated three different aspects of escapism and exercise dependence: an escapism scale which measured preference for self-expansion or self-suppression, an exercise dependence scale, and a satisfaction with life scale designed to measure the participants' subjective well-being.

The scientists found that there was very little overlap between runners who favored self-expansion and runners who preferred self-suppression modes of escapism. Self-expansion was positively related with well-being, while self-suppression was negatively related to well-being. Self-suppression and self-expansion were both linked to exercise dependence, but self-suppression was much more strongly linked to it. Neither escapism mode was linked to age, gender, or amount of time a person spent running, but both affected the relationship between well-being and exercise dependence. Whether or not a person fulfilled criteria for exercise dependence, a preference for self-expansion would still be linked to a more positive sense of their own well-being.

Although exercise dependence corrodes the potential well-being gains from exercise, it seems that perceiving lower well-being may be both a cause and an outcome of exercise dependency: the dependency might be driven by lower well-being as well as promoting it.

Similarly, experiencing positive self-expansion might be a psychological motive that promotes exercise dependence.

These findings may enlighten people in understanding their own motivation, and be used for therapeutical reasons for individuals striving with a maladaptive engagement in their activity.

 Frode Stenseng et al, Running to Get "Lost"? Two Types of Escapism in Recreational Running and Their Relations to Exercise Dependence and Subjective Well-Being, Frontiers in Psychology (2023). DOI: 10.3389/fpsyg.2022.1035196

Part 2

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Comment by Dr. Krishna Kumari Challa on January 26, 2023 at 11:35am

Using running to escape everyday stresses may lead to exercise dependence instead of mental well-being

Recreational running offers a lot of physical and mental health benefits—but some people can develop exercise dependence, a form of addiction to physical activity which can cause health issues. Shockingly, signs of exercise dependence are common even in recreational runners. A study published in Frontiers in Psychology investigated whether the concept of escapism can help us understand the relationship between running, well-being, and exercise dependence.

Escapism is an everyday phenomenon among humans, but little is known regarding its motivational underpinnings, how it affects experiences, and the  psychological outcomes from it.

Escapism is often defined as 'an activity, a form of entertainment, etc. that helps you avoid or forget unpleasant or boring things. In other words, many of our everyday activities may be interpreted as escapism. The psychological reward from escapism is reduced self-awareness, less rumination, and a relief from one's most pressing, or stressing, thoughts and emotions.

Escapism can restore perspective, or it can act as a distraction from problems that need to be tackled. Escapism which is adaptive, seeking out positive experiences, is referred to as self-expansion. Meanwhile maladaptive escapism, avoiding negative experiences, is called self-suppression. Effectively, running as exploration or as evasion.

These two forms of escapism are stemming from two different mindsets, to promote a positive mood, or prevent a negative mood.

Escapist activities used for self-expansion have more positive effects but also more long-term benefits. Self-suppression, by contrast, tends to suppress positive feelings as well as negative ones and lead to avoidance.

Part 1

Comment by Dr. Krishna Kumari Challa on January 26, 2023 at 8:30am

Expert analysis refutes claims that humans are colonized by bacteria before birth

Scientific claims that babies harbor live bacteria while still in the womb are inaccurate, and may have impeded research progress, according to University College Cork (UCC) researchers at APC Microbiome Ireland, a world-leading Science Foundation Ireland (SFI) Research Center, which led a perspective published today in the journal Nature.

Prior claims that the human placenta and amniotic fluid are normally colonized by bacteria would, if true, have serious implications for clinical medicine and pediatrics and would undermine established principles in immunology and reproductive biology.

To examine these claims, UCC & APC Principal Investigator Prof. Jens Walter assembled a trans-disciplinary team of 46 leading experts in reproductive biology, microbiome science, and immunology from around the world to evaluate the evidence for microbes in human fetuses.

A healthy human fetus is sterile

The team unanimously refuted the concept of a fetal microbiome and concluded that the detection of microbiomes in fetal tissues was due to contamination of samples drawn from the womb. Contamination occurred during vaginal delivery, clinical procedures or during laboratory analysis.

In the report in Nature, the international experts encourage researchers to focus their studies on the microbiomes of mothers and their newborn infnats and on the microbial metabolites crossing the placenta that prepare the fetus for post-natal life in a microbial world.

The expert international authors also provide guidance on how scientists in the future can avoid pitfalls of contamination in the analysis of other samples where microbes are expected to be absent or present at low levels, such as internal organs and tissues within the human body.

Jens Walter, Questioning the fetal microbiome illustrates pitfalls of low-biomass microbial studies, Nature (2023). DOI: 10.1038/s41586-022-05546-8. www.nature.com/articles/s41586-022-05546-8

Comment by Dr. Krishna Kumari Challa on January 25, 2023 at 9:38am

Study shows how cells prevent harmful extra copies of DNA

A protein that prepares DNA for replication also prevents the replication process from running out of control, according to a new study.

 The cells of humans and all other higher organisms use a complex system of checkpoints and "licensing" proteins to ensure that they replicate their genomes precisely once before dividing. In preparation for cell division, the licensing proteins attach to specific regions in the DNA, designating them as replication origins. When the DNA synthesis phase of the cell cycle begins, replication begins only at those licensed sites, and only initiates, or "fires" once, according to the current model.

That model was missing a crucial point, though. The same factor that is allowing for this licensing to happen is only degraded after these replication origins have fired. In principle, the cell could load these licensing machines onto DNA that's already replicated, so, instead of two copies, you're getting three or four copies of that segment of the DNA, and these cells would be expected to lose genome integrity and die or become cancerous.

Figuring out how cells avoid that fate has been tricky.  Scientists needed to be studying events in the first minutes of the DNA synthesis phase of the cell cycle, so it's a very transient period. 

 To solve this difficult experimental problem, researchers used computer-aided microscopy to monitor thousands of growing cells simultaneously, catching the replicating cells in the act and analyzing the activities of their licensing and replication factors.

The work revealed that a well-known licensing factor, CDT1, not only licenses a segment of DNA to become a replication origin, but also acts as a brake for DNA replication, preventing an essential replication enzyme called CMG helicase from functioning. To start synthesizing DNA, the cell's enzymes must first break down CDT1.

Nalin Ratnayeke et al, CDT1 inhibits CMG helicase in early S phase to separate origin licensing from DNA synthesis, Molecular Cell (2023). DOI: 10.1016/j.molcel.2022.12.004

Comment by Dr. Krishna Kumari Challa on January 25, 2023 at 9:32am

Earth's inner core may have started spinning other way: Study

Earth's inner core, a hot iron ball the size of Pluto, has stopped spinning in the same direction as the rest of the planet and might even be rotating the other way, recent research suggested.

 

Roughly 5,000 kilometers (3,100 miles) below the surface we live on, this "planet within the planet" can spin independently because it floats in the liquid metal outer core.

Exactly how the inner core rotates has been a matter of debate between scientists—and the latest research is expected to prove controversial.

What little is known about the inner core comes from measuring the tiny differences in seismic waves—created by earthquakes or sometimes nuclear explosions—as they pass through the middle of the Earth.

Seeking to track the inner core's movements, new research published in the journal Nature Geoscience analyzed seismic waves from repeating earthquakes over the last six decades.

The study's authors said they found that the inner core's rotation "came to near halt around 2009 and then turned in an opposite direction".

Researchers think the inner core rotates, relative to the Earth's surface, back and forth, like a swing.

One cycle of the swing is about seven decades", meaning it changes direction roughly every 35 years, they added.

They said it previously changed direction in the early 1970s, and predicted the next about-face would be in the mid-2040s.

The researchers said this rotation roughly lines up with changes in what is called the "length of day"—small variations in the exact time it takes Earth to rotate on its axis.

So far there is little to indicate that what the inner core does has much effect on surface dwellers.

But the researchers said they think there were physical links between all Earth's layers, from the inner core to the surface.

However, experts not involved in the study expressed caution about its findings, pointing to several other theories and warning that many mysteries remain about the center of the Earth. None of the models made so far explain all the data very well, according to them.

Other researchers published research last year suggesting that the inner core oscillates far more quickly, changing direction every six years or so. Their work was based on seismic waves from two nuclear explosions in the late 1960s and early 1970s.

Another theory has some good evidence supporting it—is that the inner core only moved significantly between 2001 to 2013 and has stayed put since.

These mathematical models are most likely all incorrect because they explain the observed data but are not required by the data.

So scientists keep guessing and make more efforts to gather more data till evidence becomes more convincing.

Yi Yang et al, Multidecadal variation of the Earth's inner-core rotation, Nature Geoscience (2023). DOI: 10.1038/s41561-022-01112-z

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Comment by Dr. Krishna Kumari Challa on January 25, 2023 at 9:15am

Study shows that the lateral orbitofrontal cortex 'writes' cognitive maps in the brain

The orbitofrontal cortex (OFC) is a region in the frontal lobe of the brain known to be involved in decision-making and information processing. The lateral part of this brain region, known as the lOFC, has been identified as a particularly salient region for the creation of so-called "cognitive maps."

Cognitive maps are mental representations of the world that are thought to guide human behaviour. While past studies have linked the lOFC to the brain's use of these maps, it is still unclear whether it creates these maps or merely deploys them when necessary.

Researchers have recently carried out a study exploring these two hypotheses, with the hope of better understanding the functions of the lOFC. Their findings, published in Nature Neuroscience, suggest that the lateral OFC is directly involved in the writing of cognitive maps.

Scientists reasoned that if the lOFC is needed for updating maps, then it would also be critical for the creation of new maps during the initial learning of a new association, i.e., the creation of a new cognitive map.

They conducted experiments using rats and the findings gathered by them provide additional evidence for the cartographer hypothesis, suggesting that the lOFC plays a key role in writing cognitive maps. However, they also show that blocking activity in the lOFC does not fully disrupt model-based behavior, but rather prevents the rats from incorporating all aspects of the task they are learning to complete into cognitive maps.

Overall, it now seems that the lOFC is most important for incorporating, or updating, information that is related to the specific identity of predicted outcomes. This represents a new and more nuanced hypothesis for lOFC function, and really of how the brain parses information when learning about the structure of reality.

Kauê Machado Costa et al, The role of the lateral orbitofrontal cortex in creating cognitive maps, Nature Neuroscience (2022). DOI: 10.1038/s41593-022-01216-0

Comment by Dr. Krishna Kumari Challa on January 25, 2023 at 8:34am

In addition to their role in cancer-cell death via pyroptosis, pore-forming gasdermins are a family of proteins also implicated in the immune response. One of these proteins, gasdermin D, has held sway in cancer-cell death when induced by the formation of caspase-1–activating inflammasomes. But the story of pyroptosis apparently doesn't begin and end with gasdermin D or or its close cousin, gasdermin E. It is a molecular saga that is far more complex than other studies have reported, scientists say.

Caspase-1 activates gasdermin D under inflammatory conditions, whereas caspase-3 activates gasdermin E under apoptotic conditions, such as those induced by chemotherapy, scientists asserted. These pathways are thought to be separate.

However, researchers found that they are part of an integrated network of gatekeepers that enables pyroptotic cell death. They observed that gasdermin D was the primary pyroptotic mediator in cultured blood cells in response to doxorubicin and etoposide, two common chemotherapies for hematopoietic malignancies.

 just to illustrate how complex gasdermins are in health and disease, another gasdermin protein, gasdermin A, along with gasdermin D, additionally have been implicated in autoimmune diseases and certain cancers. Yet, as reported in intricate detail in the Case Western study, gasdermin proteins are noteworthy for their pore-forming capabilities, particularly under the influence of chemotherapy.

 offers fresh insight into pyroptotic pathways by uncovering multiple routes to cancer-cell death—a contrarian stance to prevailing scientific wisdom. Even though a high abundance of gasdermin E had a dominant effect, the conversion to pyroptosis in human myeloid cells could be independently mediated via the transmembrane protein pannexin-1, a channel also known as PANX1. This occurred either through the induction of an alternate pyroptotic pathway dependent on gasdermin D or independent entirely of gasdermins.

In blood and bone marrow biopsies from 15 leukemia patients, the relative abundance of gasdermin E, gasdermin D, and PANX1 predicted which pathway would mediate pyroptotic cell death in response to chemotherapy exposure.

The take home message from the study is multifocal: Cancer cells don't simply die just because they've been exposed to chemo. They die through a programmed mechanism that can proceed through any one of several signaling pathways. 

They also have soundly demonstrated that pyroptosis during chemotherapy doesn't rely solely on gasdermin E. Studying human myeloid cells exposed to chemo, the scientists found that pyroptosis can also proceed through PANX1. And even in the face of dogma-challenging research, there may be other pore-forming pathways that have yet to be found.

 Bowen Zhou et al, Gasdermins and pannexin-1 mediate pathways of chemotherapy-induced cell lysis in hematopoietic malignancies, Science Signaling (2022). DOI: 10.1126/scisignal.abl6781

Part 2

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