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Micro-CT scanning and digital reconstructions have been used to compare the skulls of the Tasmanian tiger (thylacine) and wolf across their early development and into adulthood, establishing that not only did the thylacine resemble the wolf as adults, but also as newborns and juveniles.

"Remarkably, the Tasmanian tiger pups were more similar to wolf pups than to other closely related marsupials," Professor Andrew Pask from the University of Melbourne said.

The collaborative study with Flinders University and Museums Victoria complement earlier findings that thylacine and wolf have evolved similar instructions in their genome, which influence cranial stem cells during development.

While scientists have worked out that different animals evolve to look the same because they occupy similar places in the ecosystem, they have yet to explain how animals evolve to become convergent, particularly the forces driving their early development. The study provides significant new insights into how animals develop to look a certain way and then when in development these things happen.

Through collaborations with Australian museums and the Museum of the North in Alaska, USA, the team loaned thylacine and wolf skulls of different ages, stages and sizes, from newborns through to fully grown adults. They then applied micro-CT scanning to the skulls to generate digital models which could be compared to determine when during development similarities arose between the thylacine and wolf.

After reconstructing the early pouch development of the thylacine, lead author Dr Axel Newton focused on the question of when during development the Tasmanian tiger establish its dog-like skull shape.

"We know that the thylacine and wolf look similar as adults, but we don't know when they started to exhibit their remarkable similarities during development," he said.

Micro-CT scanning is a technique similar to a medical CAT scan, allowing researchers to generate high-resolution, digital reconstructions of complex shapes such as skulls and bones. From here they were able to establish that not only did the Tasmanian tiger resemble the wolf as adults but were very similar as newborns and juveniles.

Dr Vera Weisbecker, from Flinders University, said all marsupials - including the thylacine - are born with unusually well-developed jaws relative to the rest of the head.

"Scientists think that this reduces the potential of marsupials to evolve some extreme skull shapes. However, it clearly did not prevent the evolution of the thylacine's unusual wolf-like skull!"

The University of Melbourne's Dr Christy Hipsley, who specialises in CT, said the research shows how 3D imaging can reveal hidden diversity in nature.

"By comparing entire growth series from newborns to adults, we were able to visualise tiny differences in development that pinpoint when and where in the skull adaptations to carnivory arise on a cellular level. That is only made possible through museum loans of preserved specimens, in this case from as far away as Alaska."

Humans depend on their senses to perceive the world, themselves and each other. Despite senses being the only window to the outside world, people do rarely question how faithfully they represent the external physical reality. During the last 20 years, neuroscience research has revealed that the cerebral cortex constantly generates predictions on what will happen next, and that neurons in charge of sensory processing only encode the difference between our predictions and the actual reality.

A team of neuroscientists of TU Dresden headed by Prof Dr Katharina von Kriegstein presents new findings that show that not only the cerebral cortex, but the entire auditory pathway, represents sounds according to prior expectations.

For their study, the team used functional magnetic resonance imaging (fMRI) to measure brain responses of 19 participants while they were listening to sequences of sounds. The participants were instructed to find which of the sounds in the sequence deviated from the others. Then, the participants' expectations were manipulated so that they would expect the deviant sound in certain positions of the sequences. The neuroscientists examined the responses elicited by the deviant sounds in the two principal nuclei of the subcortical pathway responsible for auditory processing: the inferior colliculus and the medial geniculate body. Although participants recognised the deviant faster when it was placed on positions where they expected it, the subcortical nuclei encoded the sounds only when they were placed in unexpected positions.

These results can be best interpreted in the context of predictive coding, a general theory of sensory processing that describes perception as a process of hypothesis testing. Predictive coding assumes that the brain is constantly generating predictions about how the physical world will look, sound, feel, and smell like in the next instant, and that neurons in charge of processing our senses save resources by representing only the differences between these predictions and the actual physical world.

Dr Alejandro Tabas, first author of the publication, states on the findings: "Our subjective beliefs on the physical world have a decisive role on how we perceive reality. Decades of research in neuroscience had already shown that the cerebral cortex, the part of the brain that is most developed in humans and apes, scans the sensory world by testing these beliefs against the actual sensory information. We have now shown that this process also dominates the most primitive and evolutionary conserved parts of the brain. All that we perceive might be deeply contaminated by our subjective beliefs on the physical world."

These new results open up new ways for neuroscientists studying sensory processing in humans towards the subcortical pathways. Perhaps due to the axiomatic belief that subjectivity is inherently human, and the fact that the cerebral cortex is the major point of divergence between the human and other mammal's brains, little attention has been paid before to the role that subjective beliefs could have on subcortical sensory representations.

Given the importance that predictions have on daily life, impairments on how expectations are transmitted to the subcortical pathway could have profound repercussion in cognition. Developmental dyslexia, the most wide-spread learning disorder, has already been linked to altered responses in subcortical auditory pathway and to difficulties on exploiting stimulus regularities in auditory perception. The new results could provide with a unified explanation of why individuals with dyslexia have difficulties in the perception of speech, and provide clinical neuroscientists with a new set of hypotheses on the origin of other neural disorders related to sensory processing.

In a study published in Physical Review Letters, the team led by academician GUO Guangcan from University of Science and Technology of China (USTC) of the Chinese Academy of Sciences (CAS) made progress in high dimensional quantum teleportation. The researchers demonstrated the teleportation of high-dimensional states in a three-dimensional six-photon system.

To transmit unknown quantum states from one location to another, quantum teleportation is one of the key technologies to realize the long-distance transmission.

Compared with two-dimensional system, high-dimensional system quantum networks have the advantages of higher channel capacity and better security. In recent years more and more researchers of the quantum information field have been working on generating efficient generation of high-dimensional quantum teleportation to achieve efficient high-dimensional quantum networks.

As early as in 2016, the researchers from USTC experimentally showed that nonlocality can be produced from single-particle contextuality through two-particle correlations which do not violate any Bell inequality by themselves, and generated high-fidelity three-dimensional entanglement. In 2020, 32-dimensional quantum entanglement and efficient distribution of high-dimensional entanglement through 11 km fiber were respectively achieved to lay a solid foundation for scalable quantum networks.

In a linear optical system, auxiliary entanglement is the key to realizing high-dimensional quantum teleportation. The researchers exploited the spatial mode (path) to encode the three-dimensional states that has been demonstrated to extremely high-fidelity, and used an auxiliary entangled photon pair to perform the high-dimensional Bell state measurement (HDBSM), demonstrating the teleportation of a three-dimensional quantum state using the spatial mode of a single photon.

In this work, the fidelity of teleportation process matrix could reach 0.5967, which is seven standard deviations above the fidelity of 1/3, which proves the teleportation is both non-classical and genuine three dimensional.

This study paves the way to rebuild complex quantum systems remotely and to construct complex quantum networks. It will promote the research on high-dimensional quantum information tasks. Entanglement-assisted methods for HDBSM are feasible for other high-dimensional quantum information tasks.

Maize has a significantly higher productivity rate compared with many other crops. The particular leaf anatomy and special form of photosynthesis (referred to as 'C4') developed during its evolution allow maize to grow considerably faster than comparable plants. As a result, maize needs more efficient transport strategies to distribute the photoassimilates produced during photosynthesis throughout the plant.

Researchers at HHU have now discovered a phloem loading mechanism that has not been described before - the bundle sheath surrounding the vasculature as the place for the actual transport of compounds such as sugars or amino acids. The development of this mechanism could have been the decisive evolutionary step towards the higher transport rate that has made maize plants especially successful and useful. It is also likely linked to the more effective C4 photosynthesis used by maize compared with other plants, which only use C3 photosynthesis. The study was led by Dr. Ji Yun Kim and Prof. Dr. Wolf B. Frommer from the Institute of Molecular Physiology at HHU.

Plant leaves have different structures on the upper (adaxial) and lower (abaxial) sides, and each side performs different tasks. In maize, for example, sucrose transporters (SWEET) act in the `bundle sheath cells' (which frame the vascular bundle like a wreath) on the abaxial side of the leaf. In the model plant Arabidopsis thaliana, sugars released via SWEETs from phloem parenchyma cells are transported directly into the neighbouring companion cells via active transport. In maize, sugar is released in the direction of phloem by two large bundle sheath cells. The large surface of the bundle sheath cells compared to phloem parenchyma allows much higher transport rates. Compared to Arabidopsis, maize could transport sugar more effectively.

Doctoral student and first author Margaret Bezrutczyk from HHU emphasize: "The bundle sheath cells arranged in a wreath look the same at first glance. The single cell sequencing approach we used made it possible for the first time to distinguish between different types of bundle sheath cells in a maize leaf. With this technology, we expect that more cell types, especially those in the vascular bundles will be discovered in the future."

Institute Head Prof. Frommer emphasizes the significance of the finding, saying: "Maize plants are extremely productive due to their C4 photosynthesis. It is conceivable that the productivity of rice or other crops can be increased by transferring the loading mechanism from maize to these crops."

ANN ARBOR--A team of researchers has discovered an antibody that blocks the ability of the dengue virus to cause disease in mice. The findings open the potential for developing effective treatments and designing a vaccine for dengue and similar diseases.

Dengue virus, a member of a group of viruses called flaviviruses, causes 50 to 100 million cases of dengue disease each year, with no effective treatment or vaccine. Other members of this group include the viruses that cause Zika, yellow fever and West Nile fever.

In a new study scheduled to publish Jan. 8 in the journal Science, researchers from the University of California, Berkeley, and the University of Michigan revealed how an antibody called 2B7 neutralizes one specific protein made by the virus--a protein that is key to the dengue virus's ability to both replicate and cause disease.

The protein, called NS1 (short for "non-structural protein 1") circulates in the patient's blood and exacerbates disease by interacting directly with endothelial cells, the cells that form protective barriers around organs. By breaking apart the connections between endothelial cells, NS1 weakens this barrier, increasing permeability and contributing to increased vascular leak, which is the hallmark of severe dengue disease. This endothelial permeability may also enable the virus to more easily cross barriers to infect and damage target organs.

The authors and other researchers had previously demonstrated that this protein itself can cause leaks in the endothelial barrier, even in the absence of infectious viral particles. And in cases of dengue virus infection, the more NS1 found circulating in the host's blood, the more severe the infection is likely to be.

"We think of bacterial toxins, but this idea of a viral toxin is a new concept," said Eva Harris, a professor of infectious diseases and vaccinology at UC Berkeley's School of Public Health and one of the study's senior authors. "This is really an important protein in terms of creating new paradigms regarding how we think about viral proteins and their functions in disease."

In this latest study, the researchers identified specific regions of the protein that are responsible for damaging the endothelial cells: a so-called wing region that allows the protein to connect to the host cells, and another region that triggers destructive events within the endothelial cells.

By analyzing the precise way that the 2B7 antibody attaches to the protein, they found that the antibody is able to neutralize both of these regions--simply by getting in the protein's way. The antibody connects to NS1 in such a way that the wing regions cannot reach the endothelial cells, preventing the protein from latching onto (and thus interacting with and damaging) the endothelial cells.

"This collaborative approach gives us a lot of great insight into understanding the biology of this protein, its interactions with cells and its pathogenesis," said David Akey, a researcher at the U-M Life Sciences Institute and a lead author of the study. "It's an example of combining structure and function to open therapeutic avenues."

One reason no effective therapeutic has been found for dengue is that the disease can be caused by one of four different virus strains (dengue virus 1, 2, 3 or 4). Having antibodies against one strain of the virus can actually increase severity of a subsequent infection from another strain, a phenomenon called antibody-dependent enhancement.

By binding only to the NS1 protein and not to the virus particle itself, however, the 2B7 antibody does not lead to antibody-dependent enhancement of the infection.

"These findings tell us that we can really have an effect on the virus's pathogenesis by blocking these sites on just the circulating proteins," said Janet Smith, a professor at the U-M Life Sciences Institute and U-M Medical School. "It offers a strategy not only for a therapy to treat an infection, but also for a vaccine to prevent infection."

And because the NS1 protein is produced by many flaviviruses, the scientists believe the antibody that targets NS1 may be useful in treating or preventing multiple flaviviruses.

"We were able to show not only the mechanism of how the antibody protects the host cells, but also the actual mechanism of pathogenesis of this protein that is conserved across other flaviviruses," Harris said.

"I think the fact that this antibody is cross-reactive with other flavivirus NS1 proteins is one of the most exciting elements of this work," said Scott Biering, a postdoctoral researcher in Harris's lab and a lead author of the study. "This research is the proof of concept that you can target this one protein for multiple flaviviruses to protect against pathogenesis. It opens a lot of avenues not only for better understanding the mechanics of this virus, but also for developing effective therapeutics."

What The Study Did: Population data from Denmark were used to examine whether age at exposure to negative experiences in childhood and adolescence (parents' unemployment, incarceration, mental disorders, death and divorce, and the child's foster care experiences) was associated with outcomes in early adulthood.

Author: Signe Hald Andersen, Ph.D., of the Rockwool Foundation Research Unit in Copenhagen, Denmark, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2020.32769)

Editor's Note: The article includes funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

The coastline of Israel is one of the warmest areas in the Mediterranean Sea. Here, most marine species have been at the limits of their tolerance to high temperatures for a long time - and now they are already beyond those limits. Global warming has led to an increase in sea temperatures beyond those temperatures that Mediterranean species can sustain. Consequently, many of them are going locally extinct.

Paolo Albano's team quantified this local extinction for marine molluscs, an invertebrate group encompassing snails, clams and mussels. They thoroughly surveyed the Israeli coastline and reconstructed the historical species diversity using the accumulations of empty shells on the sea bottom.

Biodiversity loss in the last few decades

The shallow habitats at scuba diving depths are affected most. Here, the researchers were not able to find living individuals of up to 95 per cent of the species whose shells were found in the sediments. The study suggests that most of this loss has occurred recently, presumably in just the last few decades.

Additionally, most of the species still found alive cannot grow enough to reproduce, "a clear sign that the biodiversity collapse will further continue," says Albano. In contrast, the tropical species that enter from the Suez Canal thrive. The warm waters in the Eastern Mediterranean are very suitable habitats for them. Indeed, they occur in large populations and their individuals are fully fit to reproduce.

"For anyone accustomed to snorkel or dive in the Mediterranean," explains the researcher, "the underwater scenario in Israel is unrecognisable: The most common species are missing, while in contrast tropical species are everywhere".

The future perspectives for the Mediterranean are not good. The sea will continue to warm even if we would stop carbon dioxide emissions today. This is due to the inertia of the system, the long braking distance, so to speak.

It is thus likely that the biodiversity collapse will continue to spread. It may already be occurring in other eastern Mediterranean areas not surveyed yet, and it will expand to the West and intensify. Only intertidal organisms, which are to some extent pre-adapted to temperature extremes, and habitats in deeper water, where the temperature is markedly lower, will continue to persist - at least for some time.

"But the future is dim unless we immediately act to reduce our carbon emissions and to protect marine habitats from other pressures which contribute to biodiversity loss," says Paolo Albano, "The changes that already occurred in the warmest areas of the Mediterranean may not be reversible, but we would be able to save large parts of the rest of the basin."

Methodologically, the study was also interesting due to its interdisciplinary character: "These results came from the cooperation of scientists with very different backgrounds," says Martin Zuschin, Head of the Department of Palaeontology and co-author of the study - "In particular, the cooperation between ecologists and palaeontologists is providing unique new views on how humankind is impacting biodiversity".

DALLAS - Jan. 7, 2020 - A protein that wreaks havoc in the nerves and heart when it clumps together can prevent the formation of toxic protein clumps associated with Alzheimer's disease, a new study led by a UT Southwestern researcher shows. The findings, published recently in the Journal of Biological Chemistry, could lead to new treatments for this brain-ravaging condition, which currently has no truly effective therapies and no cure.

Researchers have long known that sticky plaques of a protein known as amyloid beta are a hallmark of Alzheimer's and are toxic to brain cells. As early as the mid-1990s, other proteins were discovered in these plaques as well.

One of these, a protein known as transthyretin (TTR), seemed to play a protective role, explains Lorena Saelices, Ph.D., assistant professor of biophysics and in the Center for Alzheimer's and Neurodegenerative Diseases at UTSW, a center that is part of the Peter O'Donnell Jr. Brain Institute. When mice modeled to have Alzheimer's disease were genetically altered to make more TTR, they were slower to develop an Alzheimer's-like condition; similarly, when they made less TTR, they developed the condition faster.

In healthy people and animals, Saelices adds, TTR helps transport thyroid hormone and the vitamin A derivative retinol to where they're needed in the body. For this job, TTR forms a tetramer - a shape akin to a clover with four identical leaflets. However, when it separates into molecules called monomers, these individual pieces can act like amyloid beta, forming sticky fibrils that join together into toxic clumps in the heart and nerves to cause the rare disease amyloidosis. In this condition, amyloid protein builds up in organs and interferes with their function.

Saelices wondered whether there might be a connection between TTR's separate roles in both preventing and causing amyloid-related diseases. "It seemed like such a coincidence that TTR had such opposing functions," she says. "How could it be both protective and damaging?"

To explore this question, she and her colleagues developed nine different TTR variants with differing propensities to separate into monomers that aggregate, forming sticky fibrils. Some did this quickly, over the course of hours, while others were slow. Still others were extremely stable and didn't dissociate into monomers at all.

When the researchers mixed these TTR variants with amyloid beta and placed them on neuronal cells, they found stark differences in how toxic the amyloid beta remained. The variants that separated into monomers and aggregated quickly into fibrils provided some protection from amyloid beta, but it was short-lived. Those that separated into monomers but took longer to aggregate provided significantly longer protection. And those that never separated provided no protection from amyloid beta at all.

Saelices and her colleagues suspected that part of TTR was binding to amyloid beta, preventing amyloid beta from forming its own aggregations. However, that important piece of TTR seemed to be hidden when this protein was in its tetramer form. Sure enough, computational studies showed a piece of this protein that was concealed when the leaflets were conjoined could stick to amyloid beta. However, this piece tended to stick to itself to quickly form clumps. After modifying this piece with chemical tags to halt self-association, the researchers created peptides that could prevent the formation of toxic amyloid beta clumps in solution and even break apart preformed amyloid beta plaques. The interaction of modified TTR peptides with amyloid beta resulted in the conversion to forms called amorphous aggregates that were easily broken up by enzymes. In addition, the modified peptides prevented amyloid "seeding," a process in which fibrils of amyloid beta extracted from Alzheimer's disease patients can template the formation of new fibrils.

Saelices and her colleagues are currently testing whether this modified TTR peptide can prevent or slow progression of Alzheimer's in mouse models. If they're successful, she says, this protein snippet could form the basis of a new treatment for this recalcitrant condition.

"By solving the mystery of TTR's dual roles," she says, "we may be able to offer hope to patients with Alzheimer's."

HOUSTON - (Jan. 7, 2021) - Proteogenomic analysis may offer new insight into matching cancer patients with an effective therapy for their particular cancer. A new study identifies three molecular subtypes in head and neck squamous cell carcinoma (HNSCC) that could be used to better determine appropriate treatment. The research led by Baylor College of Medicine, Johns Hopkins University and the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) is published in the journal Cancer Cell.

Researchers profiled proteins, phosphosites and signaling pathways in 108 human papillomavirus-negative HNSCC tumors in order to understand how genetic aberrations drive tumor behavior and response to therapies. Currently, there are a few FDA-approved therapies for HNSCC, including an epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) inhibitor and two PD-1 inhibitors, but response rates are moderate. In this study, researchers aimed to find out why certain patients respond to certain treatments to better match the patient to an appropriate course of treatment.

"We found three subtypes of head and neck squamous cell carcinoma, and each subtype may be good candidates for a different type of therapy - EGFR inhibitors, CDK inhibitors or immunotherapy," said Dr. Bing Zhang, lead contact of the study and professor in the Lester and Sue Smith Breast Center and the Department of Molecular and Human Genetics at Baylor. "We also identified candidate biomarkers that could be used to match patients to effective therapies or clinical trials."

Finding effective biomarkers

One important finding involved matching HNSCC patients to EGFR mAb inhibitors. Cetuximab, an EGFR mAb medication, was approved by the FDA in 2006 as the first targeted therapy for HNSCC, however the success rate for this treatment is low. Moreover, EGFR amplification or overexpression cannot predict response to EGFR mAbs. In this study, researchers found that EGFR ligands, instead of EGFR itself, act as the limiting factor for EGFR pathway activation. When ligand is low, the downstream pathway will not be triggered, even if EGFR protein is highly overexpressed.

"We proposed that the EGFR ligand should be used as a biomarker, rather than EGFR amplification or overexpression, to help select patients for the EGFR monoclonal antibody treatment," said Zhang, a member of the Dan L Duncan Comprehensive Cancer Center, a Cancer Prevention & Research Institute of Texas (CPRIT) Scholar and a McNair Scholar at Baylor. "Tumors with high EGFR amplification do not necessarily have high levels of EGFR ligands, which may underlie their lack of response to EGFR mAb therapy." The team confirmed this hypothesis by analyzing previously published data from patient-derived xenograft models and a clinical trial.

Additionally, tracking a key tumor suppressor known as Rb (retinoblastoma), the research team identified a striking finding that suggests that Rb phosphorylation status could potentially be a better indicator of a patient's response to CDK4/6 inhibitor therapy. The study showed that the many mutations in the genes regulating CDK4/6 activity were neither necessary nor sufficient for activation of CDK4/6. The team found that the CDK4 activity was best measured through Rb phosphorylation measurements, thus identifying a potential measure for patient selection in CDK inhibitor clinical trials.

Immunotherapy insights

The research team also found important insights into the effectiveness of immunotherapy. PD-1 inhibitors target the interaction between immune checkpoints PD-1 and PD-L1, but success rates of immunotherapy are low, even when PD-L1 expression is used for patient selection. The researchers examined tumors with high expression of PD-L1 and found that when a tumor overexpresses PD-L1, it also upregulates other immune checkpoints, thus allowing the tumor growth despite the use of PD-1 inhibitors. This observation suggests that PD-1 and PD-L1 activated tumors with hot immune environments may require multiple types of immunotherapy, which target different immune checkpoint proteins, to be effective.

Conversely, tumors with cold immune environments are not good targets for immunotherapy. Examination of how a tumor becomes immune-cold tumor showed that the problem stems from a flaw in its antigen presentation pathway where multiple key gene components of the antigen presentation pathway were deleted. As a result, although tumor antigens are being expressed, the immune system is not able to recognize them on the surface of the cell and therefore fail to activate the body's defense system against the tumor. These deletions have the potential to be effective targets for future therapies.

"This study extends our biological understanding of HPV-negative HNSCCs and generates therapeutic hypotheses that may serve as the basis for future studies and clinical trials toward molecularly-guided precision medicine treatment of this aggressive cancer type," said Dr. Daniel W. Chan, co-corresponding author of the study, professor of pathology and oncology, and director of the Center for Biomarker Discovery and Translation at the Johns Hopkins University School of Medicine.

One essential component of each eukaryotic cell is the cytoskeleton. Microtubules, tiny tubes consisting of a protein called tubulin, are part of this skeleton of cells. Cilia and flagella, which are antenna-like structures that protrude from most of the cells in our body, contain many microtubules. An example of flagell is the sperm tail, which is essential for male fertility and thus for sexual reproduction. The flagellum has to beat in a very precise and coordinated manner to allow progressive swimming of the sperm. Failure to do so can lead to male infertility. Researchers at the Institut Curie in Paris, the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, the center of advanced european studies and research (caesar) in Bonn together with the University of Bonn, the Institut Cochin in Paris and the Human Technopole in Milan now show that one particular enzymatic modification of the protein tubulin, called glycylation, is essential to keep sperm swimming in a straight line. These findings imply that a perturbation of this modification could underlie some forms of male infertility in humans.

Cells in our body make use of our DNA library to extract blueprints that contain the instructions to build structures and molecular machines called proteins. But the story does not end here: proteins can be modified by other proteins, called enzymes. That such modifications occur has been known for a long time, yet, surprisingly, their function is in many cases unknown. An excellent example of our lack of in-depth knowledge is the role of modifications of tubulin, the protein that forms microtubules. These are long filaments that are used to make scaffolds in cells. While microtubules are highly similar in all cells of our organism, they fulfil a wide variety of functions. One of the most specialized functions of microtubules is found in the sperm tail or flagellum. Sperm flagella are essential for male fertility and thus for sexual reproduction. They have to beat in a very precise and coordinated manner to allow progressive swimming of the spermatozoids, and failure to do so can lead to male infertility. To keep sperm swimming in a straight line, the modification of the protein tubulin by enzymes is essential. One modification is called glycylation, and was so far among the least-explored modifications of tubulin.

Scientists at the Institut Curie in Paris, the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden and the center of advanced european studies and research (caesar) in Bonn together with the University of Bonn, the Institut Cochin in Paris, and the Human Technopole in Milan took a closer look at glycylation. They found that in the absence of this tubulin modification, the way the flagella beat is perturbed, resulting in sperm that mostly swim in circles. The first author of the study, Sudarshan Gadadhar from the Institut Curie explains: "The core of the sperm flagellum is composed of microtubules, along with tens of thousands of tiny molecular motors, called dyneins, that make it possible to rhythmically bend these microtubules to produce waves for movement and steering. The activity of these dynein motor proteins must be tightly coordinated. In the absence of glycylation, they became uncoordinated, and as a result, we suddenly saw sperm swimming in circles."

To find this out, the authors of the study had created a mouse line that lacks the genetic blueprints for the enzymes that glycylate microtubules. "We observed functional defects on sperm from mice lacking glycylation, which resulted in a reduction of fertility. Since mice as a model system are known to have robust fertility, a similar defect in humans, could lead to male sterility" says Carsten Janke, CNRS (French National Centre for Scientific Research) researcher at the Institut Curie and one of the coordinators of the study.To find out why lack of glycylation led to perturbed sperm motility and male subfertility, the team used cryo-electron microscopy to visualize the molecular structure of the flagellum and of its molecular motors. Analysis of the mutant sperm flagella revealed that flagella were correctly built, but the mutation interfered with the coordinated activity of the axonemal dyneins - the motors that power the beating of the flagellum. This explains why the swimming of the sperm cells is perturbed.

Why is this discovery so important? The other coordinating authors, Gaia Pigino from MPI-CBG and the Human Technopole, and Luis Alvarez from the institute caesar, summarize: "This study, which shows how important glycylation is for the control of the dynein motors of the flagellum, is a prime example of how microtubule modifications directly affects the function of other proteins in cells. Our findings provide direct evidence that microtubules have an active role in regulating fundamental biological processes via a code of tubulin modifications. Further, this study points to a new mechanism underlying male infertility. Since sperm flagella are one of many types of cilia in our bodies, we expect similar tubulin modifications to be important in various cilia-related functions. Hence, our work opens a door to a deeper understanding of multiple diseases, such as developmental disorders, cancer, kidney diseases, or respiratory and vision disorders."

In the early decades of televised news, Americans turned to the stern faces of newsmen like Walter Cronkite, Tom Brokaw, and Dan Rather as trusted sources for news of the important events in America and around the world, delivered with gravitas and measured voices. The rise of comedy-news programs, helmed by the likes of Jon Stewart, Stephen Colbert, John Oliver, Trevor Noah, and Samantha Bee, raised concerns over the blending of entertainment and news. But could the merging of humor and news actually help inform the public?

In fact, new research suggests that humor may help keep people informed about politics. A study from the Annenberg School for Communication at the University of Pennsylvania and the School of Communication at Ohio State University found that, when compared to non-humorous news clips, viewers are not only more likely to share humorously presented news but are also more likely to remember the content from these segments.

"For democracy to work, it is really important for people to engage with news and politics and to be informed about public affairs," says senior author Emily Falk, Professor of Communication, Psychology, and Marketing at Annenberg. "We wanted to test whether humor might make news more socially relevant, and therefore motivate people to remember it and share it."

The researchers recruited young adults (18-34 years old) to watch a variety of news clips, which they designed to vary, so that some ended with jokes and others did not. In addition to collecting data on participants' brain activity using fMRI technology, the researchers administered a memory test to determine how much information participants retained from watching the clips. The researchers also asked participants to answer questions about how likely they would be to share the news clips with others.

Participants were more likely to remember information about politics and government policy when it was conveyed in a humorous rather than non-humorous manner and were more willing to share the information online. The findings also show that humorous news clips elicited greater activity in brain regions associated with thinking about what other people think and feel, which highlights the social nature of comedy.

"Our findings show that humor stimulates activity in brain regions associated with social engagement, improves memory for political facts, and increases the tendency to share political information with others," says lead author Jason Coronel, Assistant Professor of Communication at OSU. "This is significant because entertainment-based media has become an important source of political news, especially for young adults. Our results suggest that humor can increase knowledge about politics."

A study led by Columbia University Mailman School of Public Health researchers examines attitudes toward long-acting injectable (LAI) HIV therapies, among women with a history of injection--including medical purposes and substance use. The findings appear in the journal AIDS Patient Care and STDs.

Currently, most HIV therapies for treatment and prevention (pre-exposure prophylaxis, PrEP) necessitate daily pills, which pose barriers to adherence. Recently, however, LAI for HIV has emerged as an alternative with the potential to boost adherence, although little research has been done on how people with a history of injection feel about these new forms of injectable HIV therapy. There 258,000 women in the United States living with HIV.

The study involved interviews with 89 women across six different sites in the United States. Overall, participants highlighted how LAIs may improve adherence by freeing women of treatment fatigue and reminders associated with daily pill-taking, thus eliminating potential stigma, and facilitating confidentiality. Most women with a history of periodic injectable medication (such as birth control) would prefer LAI, but those with other frequent injections (such as for diabetes) who expressed a desire to limit the number and frequency of injections and clinic visits might not. Women with a history of injection drug use expressed mixed sentiments: some feared LAI might trigger a recurrence while others felt that familiarity with needles would predispose people who use injection drugs towards LAI.

The authors write that LAI HIV therapies would ideally coincide with existing LAI treatments (e.g., birth control) to minimize inconvenience and the need for multiple clinic visits, an approach currently used in some clinics that co-locate care for HIV and substance use.

"Future research needs to address injection-related concerns, and develop patient-centered approaches to help providers work with their patients to best identify which women could most benefit from LAI use," says first author Morgan Philbin, PhD, assistant professor of sociomedical sciences at Columbia Mailman School. "As LAI ART for HIV treatment and prevention is scaled-up, systems must be created for women and providers to collaborate in order to best identify which women might need additional support for LAI use and which might be better candidates for daily pills."

The researchers conducted in-depth interviews at six sites (New York, NY; Chicago, IL; San Francisco, CA; Atlanta, GA; Chapel Hill, NC; Washington, D.C.) as part of the Women's Interagency HIV Study, including women living with HIV and women at risk for HIV.

PHILADELPHIA - Medical school curriculums may misuse race and play a role in perpetuating physician bias, a team led by Penn Medicine researchers found in an analysis of curriculum from the preclinical phase of medical education. In a perspective piece published Tuesday in the New England Journal of Medicine, the researchers identified five key categories in which curriculum misrepresented race in class discussions, presentations, and assessments. The authors recommend that rather than oversimplifying conversations about how race affects diseases' prevalence, diagnosis, and treatment, medical school faculty must widen the lens to "impart an adequate and accurate understanding of the complexity of these relationships."

"In medical school, 20 years ago, we often learned that higher rates of hypertension in certain racial and ethnic groups, was due to genetic predisposition, personal behaviors, or unfortunate circumstances. Now we know this is not true. There are no characteristics innate to racial and ethnic groups, biological or otherwise, that adequately explains these differences. They stem, instead, from differential experiences in our society -- it's structural racism, not race," said the study's senior author Jaya Aysola, MD, MPH, assistant dean of Inclusion and Diversity in the Perelman School of Medicine and executive director at the Penn Medicine Center for Health Equity Advancement. "When we speak of dismantling structural racism, we must begin with medical education, where these sorts of race-based biases are still being reinforced in the classroom."

Though the researchers focused on lectures from a single medical school, the study authors from other institutions found similar misrepresentations of race in their preclinical medical curriculums. The five categories of biases that the research team identified were: semantics, prevalence of disparities without context, race-based diagnostic bias, pathologizing race, and race-based clinical guidelines.

For example, the study authors noted the use of "African American," is a socially and politically meaningful identity for many people, but not for all people of African descent. Moreover, they write, it is a poor proxy for genetic difference, since it lumps people from many different ancestral populations together. The researchers also found that educators regularly pathologized race, describing poor outcomes for minority patients, without referencing research on racism’s effects on health. Structural racism, such as policies that segregate neighborhoods by race, creates differential opportunities for education, employment, and optimal health. “Students are rarely exposed to such research or its implications,” the researchers write. The researchers also highlighted the teaching of guidelines that endorse the use of racial categories in the diagnosis and treatment of diseases. One course they analyzed, for instance, encouraged the use of race-adjusted glomerular filtration rate, or GFR, equations, which many experts now say limits care for Black patients and exacerbates health disparities.

"Race is not a biomedical term, and it is a poor proxy for ancestry. Yet, we continue to generate, impart, and assess medical knowledge with this imprecision. In doing so, we perpetuate biases and ignore the actual contributors to the race-based differences we see," Aysola said. "There are several aspects of the medical education apparatus that we have to fundamentally change in order to get to the ideal state where we're dismantling the structures that perpetuate racism."

The authors recommend that medical schools:

Standardize language to describe race and ethnicity, such as using a country of origin to discuss genetic predisposition to disease, rather than "Asian" or "African American."

Appropriately contextualize racial and ethnic differences in disease burden, including always considering the structural and social determinants of disease.

Generate and impart evidence-based medical knowledge when it comes to race, such as reforming board examinations to avoid testing students on race-based clinical guidelines and racial heuristics.

"We are not arguing that race is irrelevant, and our framework is not meant to trigger discussion of the advantages and disadvantages of using race in medicine," the authors write in closing. "Rather, we wish to provide evidence-based guidelines for defining and using race in generating and imparting medical knowledge."

As the planet continues to warm, the twin challenges of diminishing water supply and growing energy demand will intensify. But water and energy are inextricably linked. For instance, nearly a fifth of California's energy goes toward water-related activities, while more than a tenth of the state's electricity comes from hydropower. As society tries to adapt to one challenge, it needs to ensure it doesn't worsen the other.

To this end, researchers from UC Santa Barbara, Lawrence Berkeley National Laboratory and UC Berkeley have developed a framework to evaluate how different climate adaptations may impact this water-energy nexus. Their research appears in the open access journal Environmental Research Letters.

"Electricity and water systems are linked in many different ways," said coauthor Ranjit Deshmukh, an assistant professor in the environmental studies department. "Climate change is expected to stress these links so we presented a framework that maps these interdependencies and will enable us to understand and quantify its impacts on the energy-water nexus."

Although it's not the first study to look at these topics, it takes a more nuanced approach than the papers that have come before. "There have been many analyses on how climate change could affect the water and energy sectors separately, but those studies were not typically looking at interactions and feedbacks between the two," said lead author Julia Szinai of Berkeley Lab's Climate and Ecosystem Sciences Division. "Our paper develops a generalized framework that identifies how climate change affects these coupled water and electricity systems and potential adaptations to future gaps in supply and demand. By doing so we illustrate often overlooked tradeoffs and synergies in adapting to climate change."

The framework uses systems analysis to identify the biggest potential climate stressors on the water and energy sectors. It quantifies actions that will be needed to adapt to climate change, and examines the feedbacks that would result from these actions.

"For example, our framework shows how increased temperatures due to climate change will likely increase electricity demand for air conditioning and water demand for irrigation," Deshmukh explained. "Whereas snowpack loss in the Sierras and variable precipitation will affect the water supply, not just for urban and agricultural use, but also for hydropower generation and thermal power plant cooling."

California relies on snowpack in the Sierra Nevadas to slowly mete out water over the course of the year.

The team applied the framework they developed to California, which relies on the snowpack for a good deal of its water and expends significant amounts of energy to transport water from the north to the southern part of the state. They examined multiple adaptation strategies in the water sector and found that some are energy intensive while others can actually save both water and energy.

The researchers integrated data across a number of fragmented studies to estimate the overall range of possible water and energy futures for the state under various climate scenarios at the end of the century. Their analysis found that two factors will likely dominate climate change's direct impacts on California's electricity sector: higher air conditioning loads and decreased hydropower availability.

"One of the most important points of the paper is that adapting our water system to climate change can either significantly exacerbate electricity grid stress, or on the flip side, it could help to alleviate it," said co-author and Berkeley Lab climate scientist Andrew Jones. "If we focus on adapting the water system by using big transfers of water across basins, or by using energy-intensive desalination, that's just going to make the electricity problem much more difficult. If, on the other hand, we adapt the water system by conserving water, it's actually a win-win situation because you're also reducing the energy required for water."

Currently, a staggering 19% of California's electricity consumption goes toward water-related applications, such as treating, transporting, pumping and heating. Additionally, about 15% of in-state electricity generation comes from hydropower.

The state has already seen some impacts of climate change on its water-energy systems. Extended droughts exacerbated by climate change have led to spikes in electricity consumption for groundwater pumping, and corresponding hydropower deficits have required replacement by dirtier fossil fuels.

The team is certain that the climate crisis will have a huge impact on the state's future water supplies. That said, the effect is wildly uncertain. In the worst case, available water supplies could decrease 25%; however, they could increase 46%.

"There are significant uncertainties in the climate model projections for precipitation," said Deshmukh. "But irrespective of those uncertainties, the adaptation measures offer significant co-benefits." Conserving water would save energy as well as money for consumers, and allow for greater flow in the state's natural streams and rivers.

When the team applied their framework to the worst-case scenario, they found that choosing the most energy-intensive adaptation strategies in the water sector could result in an energy imbalance as large as that caused directly by climate change.

"I think this is the first study to show that water sector adaptation can have as large of an impact on the electricity sector as the direct effect of climate change itself," said Jones.

"This study has highlighted the benefit of coordinated adaptation planning between the two sectors," added lead author Szinai, "so we're now linking a more detailed water resources management model and an electricity planning model that can demonstrate resilient pathways for building out electricity infrastructure in the Western U.S. when climate change impacts are included from the water sector."

Deshmukh is currently leading a team to explore the connections between energy, water and the climate by quantifying the impacts of climate change on hydropower dams and thermal power plants in 12 countries across southern Africa. He hopes to identify optimal investments in electricity infrastructure.

"California has a choice in how it wants to adapt its water sector to the impacts of climate change," Deshmukh stated. "The state can either pursue energy intensive climate adaptation measures such as desalination or develop a portfolio of measures that maximize water conservation potential. Planners and policymakers in the water and energy sectors need to coordinate their actions and plans for adapting to climate change."

Tapping into an ancient evolutionary survival mechanism, cancer cells enter into a sluggish, slow-dividing state to survive the harsh environment created by chemotherapy or other targeted agents.

In research published January 7, 2020 in Cell, Princess Margaret Scientist Dr. Catherine O'Brien and team discovered that when under threat, all cancer cells - rather than just a subset - have the ability to transition into this protective state, where the cells "rest" until the threat, or chemotherapy, is removed.

It is the first study to identify that cancer cells hijack an evolutionary conserved program to survive chemotherapy. Furthermore, the researchers show that novel therapeutic strategies aimed at specifically targeting cancer cells in this slow-dividing state can prevent cancer regrowth.

"The tumour is acting like a whole organism, able to go into a slow-dividing state, conserving energy to help it survive," says Dr. O'Brien, who is also an Associate Professor in the Department of Surgery at the University of Toronto.

"There are examples of animals entering into a reversible and slow-dividing state to withstand harsh environments.

"It appears that cancer cells have craftily co-opted this same state for their survival benefit."

Dr. Aaron Schimmer, Director of the Research Institute and Senior Scientist at Princess Margaret Cancer Centre, notes that this research shows that cancer cells hibernate, like "bears in winter."

He adds: "We never actually knew that cancer cells were like hibernating bears. This study also tells us how to target these sleeping bears so they don't hibernate and wake up to come back later, unexpectedly.

"I think this will turn out to be an important cause of drug resistance, and will explain something we did not have a good understanding of previously."

Using human colorectal cancer cells, the researchers treated them with chemotherapy in a petri dish in the laboratory.

This induced a slow-dividing state across all the cancer cells in which they stopped expanding, requiring little nutrition to survive. As long as the chemotherapy remained in the dish, the cancer cells remained in this state.

In order to enter this low-energy state, the cancer cells have co-opted an embryonic survival program used by more than 100 species of mammals to keep their embryos safe inside their bodies in times of extreme environmental conditions, such as high or low temperatures or lack of food.

In this state, there is minimal cell division, greatly reduced metabolism, and embryo development is put on hold. When the environment improves, the embryo is able to continue normal development, with no adverse effects on the pregnancy.

Dr. O'Brien, who is a surgeon specializing in gastrointestinal cancer, explains that cancer cells under attack by the harsh chemotherapy environment are able to adopt the embryonic survival strategy.

"The cancer cells are able to hijack this evolutionarily conserved survival strategy, even as it seems to be lost to humans," she says, adding that all of the cancer cells enter this state in a co-ordinated manner, in order to survive.

Remembering a talk three years ago on cellular mechanisms driving this survival strategy in mouse embryos, Dr. O'Brien had an "Aha!" insight.

"Something clicked for me when I heard that talk," she said. "Could the cancer cells be hijacking this survival mechanism to survive chemotherapy?"

So Dr. O'Brien contacted the Toronto Mt. Sinai Hospital researcher Dr. Ramalho-Santos who had given the original talk at Princess Margaret.

She compared the gene expression profile of the cancer cells in the chemotherapy-induced, slow-dividing state to the paused mouse embryos in Dr. Ramalho-Santos' lab, and found that they were strikingly similar.

Similar to embryos, cancer cells in the slow-dividing state require activation of the cellular process called autophagy, meaning "self-devouring". This is a process in which the cell "devours" or destroys its own proteins or other cellular components to survive in the absence of other nutrients.

Dr. O'Brien tested a small molecule that inhibits autophagy, and found that the cancer cells did not survive. The chemotherapy killed the cancer cells without this protective mechanism.

"This gives us a unique therapeutic opportunity," says Dr. O'Brien. "We need to target cancer cells while they are in this slow-cycling, vulnerable state before they acquire the genetic mutations that drive drug-resistance.

"It is a new way to think about resistance to chemotherapy and how to overcome it."