Culture

A new study adds another layer to the remarkable evolutionary transition of life from water to land on Earth.

The international study of the prehistoric 'relic' tetrapods, including salamander and lobe-finned lungfish and coelacanths, adds another perspective to the evolution of other four-legged land animals, including related animals such as frogs and reptiles which live in both terrestrial and aqueous environments.

Using micro-CT and MRI scans to make 3D models of small animal heads, palaeontology researchers from the University of Edinburgh, University of Calgary and Flinders University shone a light on how the eating habits and brains of the some of the first land-based lifeforms prepared them for life on dry land.

The study published in the journal Royal Society Open Science, Flinders University researcher Dr Alice Clement says the transition from water to land by the earliest tetrapods (backboned animals with four legs rather than fins) in the Devonian Period (359-419 million years ago) is seen as one of the greatest steps in evolution. But she says little is known about the changes in brain morphology over this transition.

"Coelacanth and lungfish are the only lobe-finned fish alive today, but their relatives were the lineage of fish that first left the water to colonise land," Dr Clement says.

"Soft tissue, such as brains and muscles, doesn't survive in fossil records so we studied the brains of living animals, and the internal space of the skull or 'endocast' to figure out what brains of fossils animals must have looked like.

"Our main finding is that salamanders and lungfish have brains quite similar in size and shape to each other, while the coelacanth is a real outlier with a tiny brain."

University of Edinburgh researcher Dr Tom Challands says the high-tech scanning of braincase and jaw structure in six sarcopterygians shows a correlation between how tight or loose the brain fills the skull.

"For the first time, we have been able to demonstrate the interplay between how the jaw muscles affect how the brain sits inside the brain cavity," says first author Dr Tom Challands, from University of Edinburgh's Grant Institute of Earth Sciences.

"As animals made their way out of water and on to land, their food sources changed and the brain had to adapt to a completely new way of living - different sensory processing, different control for movement, balance, and so on," he says.

"Each of these plays against each other and our work basically shows the effect of masticatory (eating) changes are balanced with maintaining a skull that can support and protect the brain."

He says some of the features of these earliest land animals is reflected in other modern animals.

"Moreover we see similarities between the fish and land animals, suggesting that some muscle-brain-skull arrangements were already primed for living on land."

Researchers at the University of Tokyo have identified how the architecture of the cell nucleus can change gene activity in plants. This discovery reveals fundamental knowledge about genome regulation and points towards future methods for potentially manipulating the expression of many genes simultaneously.

The long strands of DNA and the protein machinery needed to turn gene expression on or off are contained, floating within the nuclei of cells. The nucleus is essentially a sack made of a flexible, double-membrane envelope that is supported by an inner, fine-mesh frame of proteins called the nuclear lamina.

"DNA does not drift aimlessly within the nucleus. We expect that there is nonrandom spatial positioning of genes around the nuclear lamina," said Professor Sachihiro Matsunaga who led the research project from the University of Tokyo Graduate School of Frontier Sciences, recently published in Nature Communications.

Gene regulation is often studied at the one-dimensional level of reading the DNA sequence. Additional layers of gene regulation exist in 3D by changing the shape of the DNA strand. Examples include the epigenetic code that dictates how tightly to wind up the strands of DNA and the phenomenon of "kissing genes," where distant segments of the DNA strand fold together and change the activity of the genes that touch each other.

These new results provide evidence for another 3D method of gene regulation involving not just the architecture of the genome, but the architecture of its container, the nucleus.

The scientific community has long known that the shape and size of the nucleus can fluctuate dramatically during a cell's life and that these changes can even be timed as an "internal clock" to determine the age of a cell. However, these discoveries have been made using animal cells. Plants do not possess any genes evolutionarily related to the genes responsible for the nuclear lamina in animals.

"Textbooks usually have a few sentences about animal lamina, but nothing at all to say about plant lamina," said Matsunaga.

Prior work in 2013 by some members of the research team identified a group of four proteins known as CROWDED NUCLEI (CRWN) as the most likely components of the plant nuclear lamina.

To confirm the presence of CRWN proteins in the lamina, researchers first attached fluorescent tags onto the proteins and isolated nuclei out of root cells from young thale cress plants, the roadside weed commonly used in research labs. Then they measured the proteins' location in ultrahigh-resolution microscopy images.

These extremely zoomed-in images show weblike patterns formed by the CRWN proteins around the shell of the nucleus.

Healthy plant cells have an oval-shaped nucleus, looking like a large egg in the center of the cell. Plants genetically altered to lack CRWN proteins have nuclei that are smaller and rounder than normal, likely creating a more crowded environment for the DNA inside.

Researchers then screened the genetically altered plants to see if any other genes had different activity levels when crwn genes were inhibited. Multiple genes known to be involved in responding to copper were less active, indicating that somehow the nuclear lamina is connected to copper tolerance.

Plants that lack CRWN proteins grow shorter than healthy plants even in normal soil. Thale cress with inactive crwn genes planted in soil with high copper levels grew even smaller with a significantly weaker appearance, further evidence that the nuclear lamina has a role in plants' response to environmental stress.

Researchers also visualized the physical location of copper tolerance genes within the nucleus of both normal and high copper levels. In healthy plants in the high copper condition, the copper tolerance genes clustered together and moved even closer to the periphery of the nucleus. The copper tolerance genes appeared to spread out and drift around the nuclei in plants with inactive crwn genes.

"If the plant nucleus has distinct regions for active transcription of DNA, it is likely that those regions will be near the nuclear lamina. This is important and interesting because it is opposite to animal cells, which we know have active regions in the center of nuclei while the periphery is inactive," said Matsunaga.

Most gene editing technologies to increase or decrease gene activity work directly at the one-dimensional level of altering the DNA sequence of the individual gene. Understanding how the nuclear lamina affects gene expression could reveal future methods for altering the activity of many genes at the same time by resculpting the genome and nuclear lamina.

Thanks to modern medicine, humans tend to live much longer than before. Unfortunately, this also opens a wider window to develop chronic diseases with late onset, such as neurodegenerative diseases. Despite considerable research being devoted toward developing a cure for diseases like amyotrophic lateral sclerosis, there are currently no effective treatments.

Most of these neurological diseases have one thing in common: an accumulation of abnormal proteins around neurons. Researchers agree that these improperly fabricated proteins become progressively more toxic by interacting with healthy proteins, disrupting their functions. This picture, however, may be incomplete.

In a recent study published in the Journal of Cell Biology, scientists from Daegu Gyeongbuk Institute of Science and Technology, Korea, have discovered the mechanism of action by which abnormal proteins actually unleash the inherent, but normally latent, toxicity of a natural protein in neurons, causing defects in dendrites (branched parts of a neuron that connect to the next neuron). Therefore, their results provide some clarity as to what actually goes on in diseased neurons. Though the researchers focused on Machado-Joseph disease (MJD), the implications of their results are relevant to other diseases as well.

First, they screened existing data to find candidate genes that were abnormally expressed in MJD patients and mice models. Then, based on the results and using MJD flies as animal models, they identified a problematic transcription factor--a protein that controls and regulates the transcription from DNA of other proteins--called NF-κB. Though this transcription factor is essential for the proper functioning and development of dendrites, the researchers found that something went awry with it when abnormal MJD proteins were around.

Through multiple subsequent experiments, they elucidated a long chain of inhibitory/promoting interactions between native proteins that, at a certain point, clashes with the accumulated abnormal proteins and cascades into a "deregulation" of NF-κB. In turn, this improper regulation unlocks the latent toxicity of NF-κB.

Professor Sung Bae Lee, who led the study, remarks: "Our results open-up a new avenue toward finding cures for neurodegenerative diseases by creating inhibition-based drugs that target improperly regulated latent toxic factors." Such new potential treatments would directly target the early stages of neuron damage, stopping neurological disorders right on their tracks.

This study lights a beacon of hope for many countries that are struggling to deal with the problems of an aging society. "Korea will become a super-aged society in the near future and establishing an appropriate social system to care for and treat people with neurodegenerative diseases is turning into an urgent social issue," comments Professor Lee. This might be the first step in a completely new road toward treating these chronic age-related diseases.

A new study in health care workers led by the Barcelona Institute for Global Health (ISGlobal), an institution supported by "la Caixa" Foundation and the Hospital Clínic of Barcelona, shows that IgA and IgM antibodies to SARS-CoV-2 decay quickly, while IgG antibody levels are maintained for at least three months after infection. The longer follow-up of this cohort will provide much-needed information on the duration of different types of antibodies to SARS-CoV-2, the virus that causes COVID-19, as well as their role in protecting from disease and reinfection.

Since the start of the COVID-19 pandemic, there have been two burning questions: how many people have really been infected, and whether infected people are protected from future reinfections or disease. ISGlobal researchers Carlota Dobaño and Alberto García-Basteiro joined forces to help answer these questions with the SEROCOV1 study, which intends to follow-up a cohort of over 550 health care workers at the Hospital Clínic of Barcelona.

The team showed that, at the peak of the COVID-19 pandemic in Spain, the prevalence of SARS-CoV-2 infection among health care workers was 11.2% (9.2% had antibodies and 2% had active infection detected by PCR). This was slightly higher than the antibody prevalence among the general population in Barcelona (7%), estimated by a national seroprevalence study performed shortly after.

In this new study, researchers from ISGlobal and Hospital Clínic present data after 3 months of follow-up of the same cohort of health care workers. As in the first study, an immune assay based on the Luminex technology developed by Dobaño's team was used to measure three main types of antibodies (IgM, IgG and IgA) directed against the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein, which allows it to infect human cells.

The results show that, one month after the initial seroprevalence assessment conducted at the beginning of April 2020, the percentage of participants with evidence of previous or current infection had increased to 15% and that around 60% of the new infections detected were asymptomatic. "In one month, we found 25 new infections among the participants, which is quite high, considering that the peak of the pandemic had passed and the population had been confined for more than one month," says García-Basteiro, who is also a medical doctor at the International Health Service of Hospital Clínic.

Of the 82 seropositive participants detected at month 1, 66 were followed up for an additional two months. By month three, most (78%) had no longer detectable levels of IgM, some (24.5%) had no longer detectable IgA, but the majority (97%) maintained detectable levels of IgG. In fact, IgG levels in some of the participants increased as compared to the first analysis. Symptomatic cases had higher levels of IgA but no differences in the speed at which antibodies declined were observed between asymptomatic and symptomatic infections. Overall, IgG1 levels were higher, although high IgG2 levels correlated with a longer duration of symptoms.

"Our findings confirm that IgM and IgA antibodies rapidly decline within the first month or two after infection, which should be kept in mind when performing seroprevalence studies or interpreting serological results" says Gemma Moncunill, first author of the study. "While the duration of detectable IgG antibodies following infection is still unknown, our results show that they remain relatively stable for at least three months," she adds. The SEROCOV1 team (which includes researchers from several ISGlobal's programs and from the departments of Occupational Health, Preventive Medicine and International Health at Hospital Clínic) plans to follow-up this cohort for a longer time, in order to assess the evolution of the seroprevalence in this high risk group, the duration of detectable antibodies, including several isotypes and subclasses to several antigens, and their role in protecting from disease and reinfection.

An extremely powerful assay to measure SARS-CoV-2 antibodies

In fact, Dobaño's team has recently developed and published a multiplex assay for simultaneously measuring IgM, IgA and IgG to a panel of eight different viral fragments (antigens) from SARS-CoV-2 spike (S), nucleoprotein (N) and membrane (M) proteins. The assays show a specificity of 100% and a sensitivity of over 95%, and have been optimized to minimize processing time. By combining multiple markers, these assays can detect a wider range of low-level antibody responses in the population. "In addition to better assessing SARS-CoV-2 immunity in the population, these assays can be of great value for evaluating markers of protection when testing COVID-19 vaccines," says Dobaño.

There is an idea within the coronavirus research field that there is some kind of T cell abnormality in critically ill COVID-19 patients, but specific details have not yet been clarified. To shed light on the problem, a research collaboration based in Kumamoto University (Japan) has performed a genetic analysis of T cells from lung tissue of COVID-19 patients. Their work revealed abnormalities in T cells that resulted in overactivation that may cause severe pneumonia. The researchers believe that their findings will lead to new ways of avoiding severe pneumonia caused by coronavirus infections.

COVID-19 continues to have an enormous impact on daily lives. Why some people become severely ill while the majority of those infected are asymptomatic or very mildly ill is still a major unanswered question. Risk factors for severe disease include old age, diabetes, obesity, and hypertension. We also know that critically ill patients experience an increase in inflammation factors (inflammatory cytokines) and immune system overreaction, whereas the number of T cells, the "command centers" for immune cells, is significantly reduced in the blood. However, the medical implications of these findings are still unclear.

T cells regulate the activity of the immune system by recognizing specific viruses. They also play important roles in virus elimination and the acquisition of immunity. In this study, researchers focused on T cells to determine the causes of severe pneumonia in COVID-19. CD4+ T cells (helper T cells) work to eliminate viruses from the body by promoting the maturation and activation of cytotoxic T cells, which attack virus-infected cells, and B cells, which produce antibodies. On the other hand, when some CD4+ T cells become highly activated, they express the transcription factor FoxP3 and become regulatory T cells which then act as brakes to inhibit T cell responses. This research analyzed genetic data from bronchoalveolar lavage fluids from lungs of patients with COVID-19 from Wuhan, China to characterize the activity and genetic characteristics of the CD4+ T cells present.

Using state-of-the-art bioinformatics techniques, they found that while T cells were markedly activated in the lungs of patients with severe pneumonia, the induction of FoxP3 was inhibited and the T cell braking function stopped working. While T-cell activities are usually balanced between accelerating and braking, one of the most important brakes was not functioning in severe COVID-19 which may have led to severe pneumonia.

"This study has clarified the association between severe pneumonia and T cell abnormalities. We expect that these findings will lead to a better understanding of the mechanisms of severe pneumonia in patients with COVID-19," said study leader, Associate Professor Masahiro Ono. "A more detailed understanding of the pathogenesis based on this research may contribute to the development of drugs to prevent the development of severe COVID-19 and to diagnose the risk of severe disease."

SINGAPORE, 20 November 2020 - Sometimes, too much of a good thing can turn out to be bad. This is certainly the case for the excessive cell growth found in cancer. But when cancers try to grow too fast, this excessive speed can cause a type of cellular ageing that actually results in arrested growth. Scientists at Duke-NUS Medical School have now discovered that a well-known signalling pathway helps cancers grow by blocking the pro-growth signals from a second major cancer pathway.

Inhibiting Wnt signalling with ETC-159 reactivates the hyperactive RAS-MAPK pathway, causing cells to led undergo senescence.Many cancers are driven by activating mutations in the RAS-MAPK signalling pathway which triggers a cascade of proteins that directs cells to grow, divide and migrate. Mutations in proteins involved in this cascade can turn on genes that make this process go into overdrive, causing cells to grow out of control and aggressively invade other parts of the body. However, too much RAS-MAPK signalling causes cancer cells to prematurely age, and eventually stop growing -- a process called cellular senescence.

Publishing in Cancer Research, the Duke-NUS research team found that another important and well-known biochemical pathway, the 'Wnt' (pronounced 'wint') signalling pathway, allows some cancers to grow by dampening RAS-MAPK signalling.

The team made the discovery while investigating how Wnt proteins regulate pancreatic cancers. Scientists have long observed that genetic mutations causing Wnt proteins to be hyperactive drive many common cancers. The long-held thinking had been that this is because Wnt signalling causes cells to grow too fast. The new findings suggest this idea needs re-evaluation.

By making RAS-MAPK signalling "not too hot and not too cold", Wnt signalling enables cancers to grow steadily instead of heading towards the premature ageing that can be caused by excessive RAS-MAPK signalling. These findings support a growing awareness that cancers need a "just-right" level of RAS-MAPK signalling. Disrupting modulating signals like Wnt can cause cancers to stop growing by forcing them to undergo cellular senescence, similar to just getting old.

Assistant Professor Babita Madan, from Duke-NUS Cancer and Stem Cell Biology (CSCB) Programme, a senior co-author of the study, explained, "Using an experimental drug, ETC-159 , to stop Wnts in multiple models of human pancreatic and colorectal cancer, we found that, unexpectedly, Wnt signalling turns off as many genes as it turns on."

Digging deeper, the team made the connection between Wnt signalling and the diminished activity of the RAS-MAPK pathway. Inhibiting Wnt signalling with ETC-159 and other anti-cancer drugs actually activated RAS-MAPK signalling, while inhibiting cancer growth at the same time.

"This makes sense; while activating mutations in the RAS-MAPK pathway are common in cancer, in isolation, they cause cells to stop growing by causing senescence, a form of ageing-induced arrested cell growth," said Professor David Virshup, Director of the CSCB Programme, and also a senior co-author of the study. (Prof Virshup's seminal research on Wnts led to the development of ETC-159.) "By reining in RAS-MAPK signalling, Wnt signalling achieves Goldilocks' goal of getting it not too hot, not too cold, but just right."

One implication of this research is that it opens up additional ways to attack cancers. The traditional way is to kill cancer cells, however this new study shows that stopping cancer cell growth can be achieved by inducing senescence.

"Cancer is the second leading cause of death globally, responsible for an estimated one in six deaths. In Singapore, cancer cases have been rising over the years, and the number of people living with cancer will continue to increase ," noted Professor Patrick Casey, Senior Vice Dean for Research at Duke-NUS. "Studies like these exemplify the importance of robust fundamental science research to guide new approaches and strategies that have the potential to make a major impact on disease."

Glyphosate is the most commonly used broad-spectrum herbicide. Researchers from the University of Turku in Finland have developed a new bioinformatics tool to predict if a microbe, e.g. a human gut bacterium, is sensitive to glyphosate.

"Glyphosate targets an enzyme called EPSPS in the shikimate pathway. This enzyme is crucial to synthesizing three essential amino acids. Based on the structure of the EPSPS enzyme, we are able to classify 80-90% of microbial species into sensitive or resistant to glyphosate," says Docent Pere Puigbò, developer of the new bioinformatics tool.

Based on the analyses using the new bioinformatics tool, 54% of the human core gut bacterial species are potentially sensitive to glyphosate.

"This groundbreaking study provides tools for further studies to determine the actual impact of glyphosate on human and animal gut microbiota and thus to their health," explains Docent Marjo Helander.

Glyphosate is thought to be safe to use because shikimate pathway is found only in plants, fungi and bacteria. However, glyphosate may have a strong impact on bacterial species in the human microbiome, and several recent studies have shown that perturbations in the human gut microbiome are connected to many diseases. Therefore, the widespread use of glyphosate may have a strong effect on gut microbiomes as well as on human health.

The dominance of this herbicide in the pesticide market is mainly attributed to the use of transgenic crops, such as soy, corn and canola, which are often grown as glyphosate-resistant varieties outside Europe. In Europe, glyphosate is commonly used to desiccate cereal, bean and seed crops before harvest. It is also used to eradicate weeds prior to sowing in no-till cropping systems.

The risk to come across glyphosate residue in food that has been grown in Finland is small, because desiccation of the cereal fields by glyphosate is not allowed in Finland.

A rich and diverse microbial community is living in soil, on plant surfaces, and in animal guts. It is possible that even low glyphosate residue may indirectly affect pest and pathogen occurrence in these communities.

"In addition to bioinformatics, we need experimental research to study the effects of glyphosate on microbial communities in variable environments," Helander adds.

The work of Leonardo Da Vinci is an invaluable heritage of the 15th century. From engineering to anatomy, the master paved the way for many scientific disciplines. But what else could the drawings of Da Vinci teach us? Could molecular studies reveal interesting data from the past? These questions led an interdisciplinary team of researchers, curators and bioinformaticians, from both the University of Natural Resources and Life Science and the University of Applied Science of Wien in Austria, as well as the Central Institute for the Pathology of Archives and Books (ICPAL) in Italy, to collaborate and study the microbiome of seven different drawings of Leonardo Da Vinci. 

The molecular study of art pieces has already proved to be a valuable approach, and Dr Piñar, first author of the study, is not at her first try. In 2019, her team was able to investigate the storage conditions and even the possible geographical origin of three statues requisitioned from smugglers through the study of their microbiome and, earlier this year, the microbiome of ancient parchments allowed to elucidate the animal origin of the skins used for their manufacture 1,000 years ago. In the study presented here, the Austrian team is using an innovative genomic approach called Nanopore, considered as third-generation sequencing, to reveal for the first time the complete microbiome composition of several of Da Vinci's drawings. The study is published today in Frontiers in Microbiology.

Overall, the results show a surprising dominance of bacteria over fungi. Until now, fungi were thought to be a dominant community in paper-supported art and tended to be the main focus of microbial analysis due to their biodeterioration potential. Here, a high proportion of these bacteria are either typical of the human microbiome, certainly introduced by intensive handling of the drawings during restoration works, or correspond to insects microbiomes, which could have been introduced, a long time ago, through flies and their excrements. 

A second interesting observation is the presence of a lot of human DNA. Unfortunately, we cannot assume that this DNA comes from the master himself but it might rather have been introduced by the restoration workers over the years. Finally, for both bacterial and fungal communities, correlation with the geographical location of the drawings can be observed. 

Altogether, the insects, the restoration workers, and the geographic localization seem to all have left a trace invisible to the eye on the drawings. While it is difficult to say if any of these contaminants originate from the time when Leonardo Da Vinci was sketching its drawings, Dr Piñar highlights the importance that tracking these data could have: "The sensitivity of the Nanopore sequencing method offers a great tool for the monitoring of objects of art. It allows the assessment of the microbiomes and the visualization of its variations due to detrimental situations. This can be used as a bio-archive of the objects' history, providing a kind of fingerprint for current and future comparisons." Thus, scientists could develop new methods to not only conserve the visual appearance of art but also to document the invisible journey of our artistic and cultural heritage.

Philadelphia, November 20, 2020--Researchers at Children's Hospital of Philadelphia (CHOP) have resolved a severe lymphatic disorder in a girl with Noonan Syndrome that had led to upper gastrointestinal bleeding, fluid collection around the lungs, and numerous surgeries that had been unable to resolve her symptoms. By identifying a genetic mutation along a pathway related to lymphatic vessel development and function, the research team was able to target the pathway using an existing drug they had used in a previous case to remodel a patient's lymphatic system.

The case study, which was published today in Pediatrics, describes a resolution of the patient's symptoms within three months while on the medication.

"This study is quite significant," said first author Yoav Dori, MD, PhD, Director of the Jill and Mark Fishman Center for Lymphatic Disorders at CHOP. "Inhibiting this pathway seems to have sweeping, widespread effects on the lymphatic system. How this process occurs is not fully understood, but is remarkable in its speed and breadth. This gives us a lot of hope for treating other patients with genetic mutations along this same pathway in the future."

The patient described in the paper, Maria, first came to CHOP when she was 14, after experiencing severe anemia due to upper gastrointestinal bleeding, as well as other symptoms including fluid build-up in the cavity around her lungs, chronic fatigue, delayed puberty, and difficulty gaining weight. Maria had been born with Noonan Syndrome, a genetic disorder that prevents normal development in various parts of the body and often results in short stature, heart defects and other physical problems, including an abnormal lymphatic system. Despite aggressive medical therapy elsewhere, Maria continued to bleed internally, and she underwent multiple blood transfusions to try to stabilize her health.

Within two days of transferring to CHOP, the lymphatics team, led by Dori, determined Maria had many lymphatic irregularities, which were leading to internal bleeding and lung problems, so they scheduled Maria's first intervention, a lymphatic embolization procedure that would seal the leaky vessels in her gut.

However, within two months of the procedure, Maria's gastrointestinal bleeding recurred. Over the following 8 months, she underwent two additional procedures, as well as a cauterization procedure to close off some of the blood vessels in her gut, but the benefits of each procedure lasted only about three months before the bleeding and her symptoms returned.

Based on whole exome sequencing done at CHOP's Center for Applied Genomics, the research team learned that Maria had a genetic mutation in the SOS1 gene, which operates along the RAS-MAPK pathway. This pathway involves mitogen-activated protein kinase (MEK), and Maria's mutation caused an overproduction of MEK, which resulted in the uncontrolled proliferation of her lymphatic vessels.

The research team had previously used a MEK inhibitor in another patient with a severe lymphatic disorder with great success. That patient had a mutation in the ARAF gene, which is also on the RAS-MAPK pathway. Within months of beginning treatment with trametinib, a MEK inhibitor, the patient saw a resolution of his symptoms and a complete remodeling of his lymphatic system.

Given that SOS1 operates on the same pathway as ARAF, Jean Belasco, MD, an oncologist in CHOP's Cancer Center who co-led the study, applied for compassionate use of the drug in Maria's case, given the lack of other treatment options.

"The success of trametinib in another patient with a mutation on the RAS-MAPK pathway encouraged us to try this approach, since other procedures and therapies continued to be unsuccessful," Belasco said. "Although we are in the early days of this type of personalized medicine, the hope is that by looking at patients' mutations, we can find more drugs and better care for patients with genetic diseases."

Within three months of starting the drug, Maria's vital signs stabilized. The bleeding stopped, her electrolyte, hemoglobin, and albumin levels returned to normal, and she began to gain weight. Maria's mother noticed that Maria wasn't going through periods of exhaustion anymore, and her pallor improved.

"She looks better than she's ever looked," her mother said. "She looks like a normal teenager. It's like night and day. She's also a lot happier. I think she knew deep down she was dying. The medicine gave her hope."

Hakon Hakonarson, Director of the Center for Applied Genomics and co-author of the paper, said that although Maria's SOS1 mutation is distinctly different than the ARAF mutation seen in the other patient, the drug was equally effective because it targets and blocks the function of MEK. He likened the scenario to a pathway where 15 events need to occur for a cell to function. Maria's SOS1 mutation might occur at step nine, whereas the ARAF mutation might occur at step three, but both genes are on a chain that ultimately passes through a tunnel that leads to phosphorylation and overactivity of MEK. Since both mutations were so-called gain of function mutations, MEK - and thus lymphatic activity - was overexpressed in both patients. The MEK inhibitor put the brakes on a system in overdrive.

"Remarkable advances in genetics have allowed us to uncover these mutations and cluster them into selective pathways and determine effective therapies based on genetic mutations with very high precision," said Hakonarson. "No one could have guessed that this drug would have worked for Maria without knowing the underlying genetics. This discovery is extremely important because Noonan Syndrome has the biggest patient population with alterations in MEK signaling. Not all Noonan patients will have mutations that respond to this therapy, but a very good number of them will."

He added that the treatment could also benefit patients with other genetic defects, though he noted the ongoing use of the drug treats the symptoms caused by these mutations, but does not fix the gene or cure the underlying condition.

"MEK inhibition has the potential to have significant effects on other organ systems affected by RAS-MAPK gene defects, such as the heart, eyes, skin and the coagulation system," Hakonarson said.

Hakonarson is also part of CHOP's Comprehensive Vascular Anomalies Program (CVAP), a CHOP Frontier Program that uses state-of-the-art genomics and personalized research strategies to determine the causes of complex vascular conditions and identify targeted therapies. The program works closely with the Lymphatic Imaging and Interventions Frontier Program, which is led by Dori. CHOP's Frontier Programs conduct cutting-edge research that translates into advanced clinical care. The CVAP, in particular, draws on the extensive clinical and genomic research capacity within the Cancer Center and Center for Applied Genomics.

Even with the success of the breakthrough treatment pioneered by these programs, it is not entirely clear why MEK inhibitors not only resolve patients' symptoms but also completely remodel their lymphatic systems. Hakonarson said one possibility is that when mutated genes cause uncontrolled growth of the lymphatic system, the body's vessels leak fluid everywhere in the body. When you shut down the unregulated growth, other homeostatic mechanisms that are balancing the system come into effect, so the overreactive cells that were growing out of control die and are replaced by normal cells that gradually build up the lymphatic system.

Whatever the mechanism, Maria's mother said her daughter had no hesitation at being the first patient with Noonan Syndrome to try this treatment to resolve a lymphatic issue.

"Maria saw the value from the beginning," she said. "She saw the value for herself, but she was also thinking of other Noonan kids, some of whom have passed away from lymphatic issues. She was willing and eager."

A new synthetic probe offers a safe and straightforward approach for visualizing chromosome tips in living cells. The probe was designed by scientists at the Institute for Integrated Cell-Material Science (iCeMS) and colleagues at Kyoto University, and could advance research into aging and a wide range of diseases, including cancers. The details were published in the Journal of the American Chemical Society.

"Chromosome ends are constantly at risk of degradation and fusion, so they are protected by structures called telomeres, which are made of long repeating DNA sequences and bound proteins," says iCeMS chemical biologist Hiroshi Sugiyama, who led the study. "If telomeres malfunction, they are unable to maintain chromosome stability, which can lead to diseases such as cancer. Also, telomeres normally shorten with each cell division until they reach their limit, causing cell death."

Visualizing telomeres, especially their physical arrangements in real-time, is important for understanding their relevance to disease and aging. Several visualization approaches already exist, but they have disadvantages. For example, some can only observe telomeres in preserved, or 'fixed', cells. Others are time-consuming or involve harsh treatments that denature DNA.

Sugiyama and his colleagues overcame these issues by using a synthetic pyrrole-imidazole polyamide (PIP) probe that can precisely deliver a fluorescent compound to telomeres on the tips of chromosomes.

"PIPs are a class of small molecules made from pyrrole and imidazole molecules that can be pre-programmed to bind to a selected DNA sequence," explains Yutaro Tsubono, the first author of this study.

The team designed a PIP that targets the DNA repeating sequence found in telomeres. A fluorescent compound, called silicon-rhodamine, was attached to the PIP. The probe, called SiR-TTet59B, binds to telomeres in living cells. When the low-intensity near-infrared light is shone on the cells, the silicon-rhodamine fluoresces, showing the telomeres in action.

"Our study on this programmable, near-infrared probe creates opportunities to use these molecules in biological and medical applications," says iCeMS bioengineer Ganesh Pandian Namasivayam.

The team used their probe to observe telomere dynamics during different phases of cell division and to gauge telomere length by measuring the fluorescence intensity. Being able to visualize telomere length was both surprising and exciting, says Namasivayam, as it can be developed to create an efficient and robust approach for detecting severe telomere shortening in diseases, such as age-related retinal degeneration, with low energy light.

Since PIPs can be designed to target any DNA sequence in the genome by changing their arrangement, the scientists anticipate the approach can be adapted to make near-infrared fluorescent probes for visualizing other important DNA sequences related to disease.

Researchers analyzing snow and stream samples from the National Geographic and Rolex Perpetual Planet Everest Expedition have found evidence of microplastic pollution on Mount Everest. While the highest concentrations of microplastics were around Base Camp where hikers and trekkers spend the most time, the team also found microplastics as high up as 8,440 meters above sea level, just below the summit. The findings appear November 20 in the journal One Earth.

"Mount Everest has been described as 'the world's highest junkyard,'" says first author Imogen Napper (@Imogennapper), a National Geographic Explorer and scientist based at the University of Plymouth who is described by her colleagues as a "plastic detective." "Microplastics haven't been studied on the mountain before, but they're generally just as persistent and typically more difficult to remove than larger items of debris."

Microplastics--tiny particles of plastic that come from the slow breakdown of larger litter--pose a huge ecological threat because they are easily consumed by animals and are so small that they are difficult to clean up. Microplastics are common in the ocean, but are not as carefully studied on land, especially remote mountaintops.

"I didn't know what to expect in terms of results, but it really surprised me to find microplastics in every single snow sample I analyzed. Mount Everest is somewhere I have always considered remote and pristine. To know we are polluting near the top of the tallest mountain is a real eye-opener."

While some members of the research team climbed the mountain collecting samples during the Everest expedition in the spring of 2019, much of the work was done in a lab many miles away, where Napper and her team analyzed the samples. "The closest I got to Mount Everest was in my lab at University of Plymouth in the UK," Napper jokes. She wanted to determine not only whether there was plastic on the mountain, but what type of plastic was there. This is an important step in figuring out where the pollution originated.

"The samples showed significant quantities of polyester, acrylic, nylon, and polypropylene fibers," says Napper. "Those materials are increasingly being used to make the high-performance outdoor clothing climbers use as well as tents and climbing ropes, so we highly suspect that these types of items are the major source of pollution rather than things like food and drink containers."

While this study clearly demonstrated the presence of microplastics on Mount Everest, the best way to clean this pollution remains to be seen.

"Currently, environmental efforts tend to focus on reducing, reusing, and recycling larger items of waste. This is important, but we also need to start focusing on deeper technological solutions that focus on microplastics, like changing fabric design and incorporating natural fibers instead of plastic when possible," she says.

The researchers also hope that their work will help clarify the extent to which plastic pollution jeopardizes all environments, not just the ocean.

"These are the highest microplastics discovered so far," says Napper. "While it sounds exciting, it means that microplastics have been discovered from the depths of the ocean all the way to the highest mountain on Earth. With microplastics so ubiquitous in our environment, it's time to focus on informing appropriate environmental solutions. We need to protect and care for our planet."

More evidence has emerged that food labelling can encourage manufacturers to improve product nutrition, but University of Melbourne experts say the star labelling system must be compulsory to make a big difference.

A team from the University of Melbourne, the University of Auckland, and the George Institute for Global Health analysed product nutrition labels in Sydney and Auckland supermarkets to see if the Health Star Rating system (HSR) made a difference to how the food industry formulates food.

Nutritional information is mandatory on the back of packaged Australian and New Zealand foods but HSR labels, which have appeared on the front since 2014 and rate a food from 0.5 (least healthy) to five (most healthy) stars, are voluntary.

The most comprehensive study of food industry response to the HSR system, published in PLOS Medicine, has confirmed that HSR labelling causes some products to become healthier.

The Australia and New Zealand Ministerial Forum on Food Regulation introduced the voluntary front-of-pack HSR and a published HSR calculator decides how many stars a food gets. HSR labels aim to improve diets by encouraging consumers to choose healthier products and prompting manufacturers to reformulate their products to be healthier.

This study looked at the reformulation effects of HSR labels. Researchers analysed nutrition and labelling information on packaged products in four major New Zealand supermarkets annually from 2013, and Sydney supermarkets Aldi, Coles, IGA, and Woolworths from 2014.

They tracked the nutrition information of 58,905 unique packaged food products to see if HSR labelling led to nutrient composition changes. Using the HSR calculator, they also scored unlabelled products to allow control comparisons.

Products that elected to display the HSR on-pack were 6.5 and 10.7 per cent more likely to increase their HSR score by 0.5 stars than those that didn't display the stars in Australia and New Zealand respectively.

New Zealand products with HSR showed a four per cent decline in salt content, while Australian products fell by 1.4 per cent. The HSR was associated with a 2.3 per cent decrease in sugar content in New Zealand and a statistically insignificant 1.1 per cent decline in Australia.

The healthiest products that would have scored four to five stars showed little healthier reformulation - most reformulation occurred in less healthy products with HSR labels.

In Australia, an average product with HSR that scored 0.5 to 1.5 stars lost 14kJ of energy per 100g (1.3 per cent), compared to a product that scored four to five stars which saw almost no changes in energy. Similar patterns were observed for almost all nutrients studied in both countries.

Lead author and University of Melbourne Research Fellow Dr Laxman Bablani said while the improvements sounded small, even modest changes could lead to big health impacts at a population level.

"If the labels were compulsory the impact could be much greater, as HSR adoption by the unhealthiest products was less than half that of the healthiest products," Dr Bablani said.

In 2019, around 15 per cent of products that scored two stars had HSR labels in both countries, compared to more than 35 per cent of those that scored four stars and above. Examples of positive reformulation included:

A popular flavoured cracker now has six per cent less fat and roughly 10 per cent less sodium per 100g than before it adopted HSR labels in 2016. This took it from 1.5 to two stars.

Several instant soup varieties cut sodium and energy to increase their rating from three to 3.5 stars in the year they were labelled.

A major supermarket branded barbeque sauce cut sugar by 4.5g per 100g (9.6 per cent) in 2017 when it adopted HSR labels.

University of Auckland Professor Cliona Ni Mhurchu said the HSR could have a much bigger impact if more unhealthy products adopted it.

"Our study suggests that the total effect of HSR on supporting healthier population diets could be markedly increased if it was adopted by many more products," Professor Ni Mhurchu said.

"In short, it suggests that making the HSR mandatory would generate substantially greater public health benefits than the current voluntary system."

Senior author and University of Melbourne Professor Tony Blakely agreed compulsory HSR labels could improve unhealthy foods.

"There is little incentive for manufacturers to label unhealthy foods voluntarily," Professor Blakely said.

"If it was compulsory, the quality of packaged food would improve, and consumers may possibly make better choices about healthy and unhealthy foods."

A plant used in traditional Chinese medicine has evolved to become less visible to humans, new research shows.

Scientists found that Fritillaria delavayi plants, which live on rocky slopes of China's Hengduan mountains, match their backgrounds most closely in areas where they are heavily harvested.

This suggests humans are "driving" evolution of this species into new colour forms because better-camouflaged plants have a higher chance of survival.

The study was carried out by the Kunming Institute of Botany (Chinese Academy of Sciences) and the University of Exeter.

"It's remarkable to see how humans can have such a direct and dramatic impact on the colouration of wild organisms, not just on their survival but on their evolution itself," said Professor Martin Stevens, of the Centre for Ecology and Conservation on Exeter's Penryn Campus in Cornwall.

"Many plants seem to use camouflage to hide from herbivores that may eat them - but here we see camouflage evolving in response to human collectors.

"It's possible that humans have driven evolution of defensive strategies in other plant species, but surprisingly little research has examined this."

In the new study, the researchers measured how closely plants from different populations matched their mountain environment and how easy they were to collect, and spoke to local people to estimate how much harvesting took place in each location.

They found that the level of camouflage in the plants was correlated with harvesting levels.

In a computer experiment, more-camouflaged plants also took longer to be detected by people.

Fritillaria delavayi is a perennial herb that has leaves - varying in colour from grey to brown to green - at a young age, and produces a single flower per year after the fifth year.

The bulb of the fritillary species has been used in Chinese medicine for more than 2,000 years, and high prices in recent years have led to increased harvesting.

"Like other camouflaged plants we have studied, we thought the evolution of camouflage of this fritillary had been driven by herbivores, but we didn't find such animals," said Dr Yang Niu, of the Kunming Institute of Botany. "Then we realised humans could be the reason."

Professor Hang Sun, of the Kunming Institute of Botany, added: "Commercial harvesting is a much stronger selection pressure than many pressures in nature.
"The current biodiversity status on the earth is shaped by both nature and by ourselves."

An international research team led by UCSF scientists has shown, for the first time, that gut immune cells travel to the brain during multiple sclerosis (MS) flare-ups in patients. These gut cells seem to be playing a protective role, helping drive MS symptoms back into remission.

Scientists know that in MS, other types of immune cells go haywire and attack myelin, crucial insulation material that helps nerve cells communicate with one another quickly and reliably. The resulting damage leads to periodic MS attacks that can leave patients struggling with vision loss, memory problems, pain and other symptoms. These "relapse" symptoms often subside on their own after days or weeks, but medical experts still don't have a good understanding of what flips the switch from flare-up to remission and back again.

The new findings, published November 20, 2020 in Science Immunology, suggest that an unexpected new player might help bring flare-ups under control: immune cells from the gut that express a type of antibody called IgA. In the gut, these cells serve as a critical first line of defense against foreign invaders and, scientists think, help keep the teeming bacteria of our gut microbiome from growing out of control. Recently, a UCSF-led international research team made the surprising discovery that, in animal models of MS, these gut immune cells leave the digestive system and travel to the brain where they appear to help cut inflammation.

"It was a very new idea," said Sergio Baranzini, PhD, a professor of neurology and member of the UCSF Weill Institute for Neurosciences, lead author on the new study. "Nobody thought to look for this type of immune cell."

Now the team, including scientists in Canada, Germany, Sweden and Switzerland, has gone a step further, finding traces of the IgA antibody in the cerebrospinal fluid of MS patients during flare-ups, but not when episodes are in remission. They also found signs of IgA-producing immune cells in donated postmortem brain tissue that had been damaged during MS attacks. The findings confirm for the first time that gut immune cells are involved in MS relapses in humans.

"Only at the time of an attack was there an increase in these cells and the antibodies they produce," Baranzini said. "That really caught our attention."

In the hopes of determining what these gut immune cells were doing in the brain, the team then looked to see what kinds of molecules the IgA antibody reacted to. Recent research has provided evidence that an unhealthy gut microbiome plays a role in MS, when certain potentially damaging species of bacteria proliferate. While the team found that IgA did not bind to myelin protein, it did bind to some of these harmful bacteria species, suggesting that, unlike other immune cells, which are known to cause damage in MS, IgA-expressing immune cells play a protective role, possibly chasing these harmful bacteria to the brain and mounting a defense against them there.

"This opens up a whole new line of research," said Anne-Katrin Pröbstel, MD, a former UCSF postdoctoral researcher, now at the University of Basel in Switzerland and first author on the paper. "I think it has huge potential for therapeutics."

Collaborations within the UCSF Benioff Center for Microbiome Medicine allowed researchers to work with the various bacteria thought to be hallmarks of the MS microbiome, and the work relied heavily on data and biological samples collected through the multidisciplinary UCSF EPIC Study, which has followed hundreds of MS patients over 16 years.

"I think UCSF is one of the only places where we could have done this, because of the access to patient samples that allow us to look at bacteria in the gut, immune cells from the blood, immune cells from the spinal fluid and brain tissue," said Pröbstel. "It's really a unique resource."

Aconvolutional neural network is a type of artificial neural network in which the neurons are organized into receptive fields in a very similar way to neurons in the visual cortex of a biological brain. Today, convolutional neural networks (CNNs) are found in a variety of autonomous systems (for example, face detection and recognition, autonomous vehicles, etc.). This type of network is highly effective in many artificial vision tasks, such as in image segmentation and classification, along with many other applications.

Convolutional networks were inspired by the behaviour of the human visual system, particularly its basic structure formed by the concatenation of compound modules comprising a linear operation followed by a non-linear operation. A study published in the advanced online edition of the journal Vision Research examines the phenomenon of visual illusions in convolutional networks compared to their effect on human vision. A study by Alexander Gómez Vila, Adrian Martín, Javier Vázquez-Corral and Marcelo Bertalmío, members of the Department of Information and Communication Technologies (DTIC) with the participation of the researcher Jesús Malo of the University of Valencia.

"Because of this connection of CNNs with our visual system, in this paper we wanted to see if convolutional networks suffer from similar problems to our visual system. Hence, we focused on visual illusions. Visual illusions are images that our brain perceives differently from how they actually are", explains Gómez Vila, first author of the study.

In their study, the authors trained CNNs for simple tasks also performed by human vision, such as denoising and deblurring. What they observed is that these CNNs trained under these experimental conditions are also "deceived" by brightness and colour visual illusions in the same way that visual illusions deceive humans.

Furthermore, as Gómez Villa explains, "for our work we also analyse when such illusions cause responses in the network that are not as physically expected, but neither do they match with human perception", that is to say, cases in which CNNs obtain a different optical illusion than the illusion that humans would perceive.

The results of this study are consistent with the long-standing hypothesis that considers low-level visual illusions as a by-product of the optimization to natural environments (that a human sees in their everyday). Meanwhile, these results highlight the limitations and differences between the human visual system and CNNs artificial neural networks.