Culture

The arthropods have been among the most successful animals on Earth since the Cambrian Period, about 520 million years ago. They are the most familiar and ubiquitous, and constitute nearly 80 percent of all animal species today, far more than any other animals.

But how did arthropods evolve and what did their ancestors look like? These have been a major conundrum in animal evolution puzzling generations of scientists for more than a century.

Now researchers from the Nanjing Institute of Geology and Palaeontology of the Chinese Academy of Sciences (NIGPAS) have discovered a shrimp-like fossil with five eyes, which has provided important insights into the early evolutionary history of arthropods. The study was published in Nature on Nov. 4.

The fossil species, Kylinxia, was collected from the Chengjiang fauna in southwest China's Yunnan Province. The fauna documents the most complete early animal fossils in the Cambrian time.

Prof. HUANG Diying, corresponding author for the study from NIGPAS, said, "Kylinxia is a very rare chimeric species. It combines morphological features from different animals, which is analogous to 'kylin,' a chimeric creature in traditional Chinese mythology."

"Owing to very special taphonomic conditions, the Kylinxia fossils exhibit exquisite anatomical structures. For example, nervous tissue, eyes and digestive system - these are soft body parts we usually cannot see in conventional fossils," said Prof. ZHAO Fangchen, co-corresponding author of the study.

Kylinxia shows distinctive features of true arthropods, such as a hardened cuticle, a segmented trunk and jointed legs. However, it also integrates the morphological characteristics present in very ancestral forms, including the bizarre five eyes of Opabinia, known as the Cambrian "weird wonder," as well as the iconic raptorial appendages of Anomalocaris, the giant apex predator in the Cambrian ocean.

Among the Chengjiang fauna, Anomalocaris is a top predator that can reach two meters in body length, and has been regarded as an ancestral form of arthropod. But huge morphological differences exist between Anomalocaris and true arthropods. There is a great evolutionary gap between the two that can hardly be bridged. This gap has become a crucial "missing link" in the origin of arthropods.

The research team conducted detailed anatomical examinations of the fossils of Kylinxia. They demonstrated that the first appendages in Anomalocaris and true arthropods were homologous. The phylogenetic analyses suggested that there was affinity between the front appendages of Kylinxia, small predatory appendages in front of the mouth of Chelicerata (a group that includes spiders and scorpions) and the antennae of Mandibulata (a subdivision of arthropods including insects such as ants and bees).

"Our results indicate that the evolutionary placement of Kylinxia is right between Anomalocaris and the true arthropods. Therefore, our finding reached the evolutionary root of the true arthropods," said Prof. ZHU Maoyan, a co-author of the study.

"Kylinxia represents a crucial transitional fossil predicted by Darwin's evolutionary theory. It bridges the evolutionary gap from Anomalocaris to true arthropods and forms a key "missing link" in the origin of arthropods, contributing strong fossil evidence for the evolutionary theory of life," said Dr. ZENG Han, first author of the study.

New York University researchers have created a "developmental atlas" of gene expression in neurons, using gene sequencing and machine learning to categorize more than 250,000 neurons in the brains of fruit flies. Their study, published in Nature, finds that neurons exhibit the most molecular diversity during development and reveals a previously unknown type of neurons only present before flies hatch.

"Diversity of the different cell types that make up our brains can only be fully understood in light of their developmental history," said NYU Biology Professor Claude Desplan, the study's senior author.

Brains are composed of thousands of different types of neurons. Despite sharing the same genetic information, neurons achieve this diversity by turning on different sets of genes in each neuron type and at each point in their development.

To understand the diversity of brain cells, researchers have long studied fruit flies, whose brains, although much simpler than those of humans, can be used as a model system. Researchers previously identified the roughly 60,000 cells and 200 neuronal types that make up fruit flies' optic lobes, the areas of the brain that process visual information, including color vision and detection of objects and motion.

In their new study in Nature, researchers in Desplan's lab sought to thoroughly characterize the diversity of neurons in the optic lobe and build a "developmental atlas" of gene expression, comparing cells in the brains of adult flies and exploring differences during development.

The researchers created their "atlas" by taking advantage of a form of a recently invented technique known as single-cell mRNA sequencing, which allowed them to capture and sequence mRNA from more than 250,000 single cells. Using a combination of machine learning approaches, they assigned each of these cells to a specific cell type throughout development.

"Our datasets almost completely account for the known neuronal diversity of the optic lobes and can serve as a paradigm to understand brain development across species," said Neset Özel, a postdoctoral associate at NYU and one of the study's lead authors. "The 'atlas' constitutes an enormous resource for the research community: we can now simply look up whether a particular gene is active or not in any cell type of our choice and at any point during its development."

While building their "developmental atlas," the researchers made several discoveries. First, they found a completely new type of neurons in fruit flies, which is present only on the surface of the optic lobe during development but is removed through programmed cell death right before the flies hatch.

"While we do not yet understand the functions of these previously unknown neurons, neurons with very similar properties--called Cajal-Retzius cells--also exist in mammalian brains, and they are critical for proper brain development," said Felix Simon, a biology doctoral student at NYU and the other lead author of the study.

In addition, the researchers found that neurons exhibit the highest levels of molecular diversity during development compared to adult neurons, allowing cells during development to form connections with specific partner cells--and avoid the wrong ones. As a result, neurons can gain distinct features and functions solely due to their developmental history, even though their physiological properties in adult brains might be identical.

"This has large implications for the studies of neurodevelopmental disorders. Disruptions to neural circuit function could occur entirely due to defects in certain genetic programs that are only transiently active during development and would be impossible to understand by simply looking at the end result," explained Özel.

Finally, the study revealed that neurons that look identical in form can express different sets of genes in the upper versus lower part of the brain. These differences can give flies the ability to perform different calculations on the visual information they receive--for instance, the sky versus the ground.

A new study suggests that it is possible to design drugs that can target a type of shape-shifting protein involved in Alzheimer's disease, which was previously thought to be undruggable.

A team of researchers, led by the University of Cambridge, have identified a new mechanism of targeting amyloid-beta, a protein fragment that clumps together and kills healthy brain cells in people with Alzheimer's disease.

Working with colleagues from Imperial College London, Institut Pasteur, and the University of Florence, the researchers found that it is possible for a drug-like molecule to target amyloid-beta in its disordered state, reducing its ability to form the toxic clusters which are the hallmark of Alzheimer's disease. The results, reported in the journal Science Advances, could form the basis of a new avenue for the development of potential treatments for the disease.

"Amyloid-beta is a disordered protein, a type of target that is elusive for standard therapeutic approaches," said Professor Michele Vendruscolo from Cambridge's Centre for Misfolding Diseases, who led the research. "It is constantly changing shape, so traditional drug discovery techniques don't work on it. By revealing a new drug-binding mechanism, we have extended traditional drug discovery approaches based on the optimisation of the binding affinity to include disordered proteins."

Most drugs work by binding proteins through what is often described as a lock-and-key mechanism, where a drug fits into a protein's grooves like a key in a lock. However, since they are often changing shape, disordered proteins such as amyloid-beta don't have stable 'locks' for drugs to bind to, which is why they are considered 'undruggable.'

The approach developed by the researchers is based on the so-called disordered binding mechanism that they discovered, where small molecules form a disordered complex with the protein target, so that it is like the protein and the drug are 'dancing' with one another.

The researchers characterised this new mechanism using a combination of biophysical experiments, mathematical modelling, in vivo experiments and computation.

First, they tested the aggregation of amyloid-beta in the presence of the compound in in vitro assays. Data from these experiments allowed the researchers to build a mathematical model of how the drug was able to inhibit the aggregation of amyloid-beta at the microscopic level.

The team also used high-performance computing methods to study the binding interaction at the atomic level. These intensive calculations allowed the researchers to 'see' how the binding was occurring at the atomic level, which is otherwise almost impossible to observe experimentally. Further tests were then carried out in nematode worms, which are often used as a model organism to study Alzheimer's disease.

"In contrast to the traditional lock-and-key binding mechanism, in which a drug tightly interacts with its target in a specific conformation, we found that both the small molecule and the disordered protein remained extremely dynamic, and that the small molecule interacted with many parts of the protein," said Gabriella Heller, Schmidt Science Fellow and the study's first author.

"This way of stabilising native states of proteins is a powerful drug discovery strategy, which has so far been extremely challenging for disordered proteins," said Vendruscolo.

Amyloid beta, the protein which the team targeted, is closely associated with Alzheimer's disease as it is the primary component of senile plaques, which are characteristically found in the brains of the people affected by the disease.

While this research is still preliminary in terms of clinical translation, it demonstrates that targeting the formation of these plaques by preventing the aggregation of amyloid-beta is a major therapeutic strategy. To date the mainstream approach has been to develop antibodies to bind to the aggregates, promoting their removal and interfering with their self-assembly.

"Disordered proteins are also involved in a wide range of diseases including cancer and cardiovascular disease. We hope that we can extend this understanding to also target disordered proteins involved in other diseases," said Heller.

Exposure to high temperatures in pregnancy is associated with an increase in adverse pregnancy outcomes, especially preterm birth and stillbirth, and among women in lower socioeconomic groups, finds a study published by The BMJ today.

Although the effects may appear small in size, the researchers say the findings "could have a major impact on public health as exposure to high temperatures is common and escalating." Moreover, conditions such as preterm birth often have lifelong implications for affected newborns.

Increases in global temperatures raise concerns about heat impacts on health, especially in vulnerable groups such as the elderly, those living in poverty, and the chronically ill.

Previous evidence reviews have found associations between exposure to high temperatures and pregnancy outcomes, but have included few studies and have not assessed differences across population groups and by type of heat exposure.

So an international team of researchers set out to assess whether exposure to high temperatures in pregnancy is associated with increased risk for preterm birth, low birth weight and stillbirth.

They analysed the results of 70 studies, set in 27 countries, seven of which were low and middle income countries, that reported associations between high temperatures and preterm birth, birth weight and stillbirths.

Differences in study design and quality of evidence were taken into account.

WHO estimates that 15 million babies are born preterm each year, the leading cause of death among children under 5. The average rate of preterm birth in the studies was 5.6%, much lower than the global average of about 10%.

Of the 47 studies that assessed preterm births, 40 reported that preterm births were more common at higher than lower temperatures. Further analysis showed that the odds of a preterm birth rose, on average, by 5% per 1°C increase in temperature and by 16% during heat waves than on non-heatwave days.

Nearly 2 million stillbirths occur each year worldwide. The average stillbirth rate was 6.2 per 1000 births in the eight included studies, about half the rates documented in many lower-income countries.

All eight studies detected an increase in stillbirths at higher temperatures, with stillbirths increasing by 5% per 1°C rise in temperature. In most cases, associations between temperature and stillbirth were most pronounced in the last week or month of pregnancy.

Low birth weight, associated with a range of short and long-term consequences, occurred on average in 3% of infants in the included studies. Of the 28 studies that assessed birth weight, 18 found an increased risk at higher temperatures, but generally the impacts of temperature on weight were small, with most studies reporting only minor changes.

However, the researchers point out that, "even apparently minor decrements in birth weight could have a major impact on public health as exposure to high temperatures is common and escalating."

Finally, associations between temperature and outcomes were largest among women in lower socioeconomic groups, suggesting that pregnant women in low and middle income countries may be at particular risk from heat exposure, they add.

This review was based on observational studies, of which about a third were of low quality, so no firm conclusions can be drawn about cause and effect. The researchers also point to limitations, such as differences in temperature measures between studies, and the possibility that other factors, such as air pollution, may have had an effect on pregnancy outcomes.

Nevertheless, they say the review included more studies than previous reviews, allowing for comparisons of three outcomes and a more comprehensive assessment of heat sensitivity in pregnancy.

As such, they say the review "highlights the need to identify interventions targeting heat related conditions in pregnant women, especially in women at the age extremes and in lower socioeconomic groups, and to determine their effectiveness."

They argue that pregnant women "merit a place alongside the groups typically considered as at high risk for heat related conditions."

"Given increases in the frequency and intensity of heatwaves, the number of pregnant women exposed to these conditions worldwide, and the significant individual and societal burdens associated with preterm birth and stillbirth, research and policy initiatives to deal with these connections are a high priority," they conclude.

Some claim that machine learning technology has the potential to transform healthcare systems, but a study published by The BMJ finds that machine learning models have similar performance to traditional statistical models and share similar uncertainty in making risk predictions for individual patients.

The NHS has invested £250m ($323m; €275m) to embed machine learning in healthcare, but researchers say the level of consistency (stability) within and between models should be assessed before they are used to make treatment decisions for individual patients.

Risk prediction models are widely used in clinical practice. They use statistical techniques alongside information about people, such as their age and ethnicity, to identify those at high risk of developing an illness and make decisions about their care.

Previous research has found that a traditional risk prediction model such as QRISK3 has very good model performance at the population level, but has considerable uncertainty on individual risk prediction.

Some studies claim that machine learning models can outperform traditional models, while others argue that they cannot provide explainable reasons behind their predictions, potentially leading to inappropriate actions.

What's more, machine learning models often ignore censoring - when patients are lost (either by error or by being unreachable) during a study and the model assumes they are disease free, leading to biased predictions.

To explore these issues further, researchers in the UK, China and the Netherlands set out to assess the consistency of machine learning and statistical techniques in predicting individual level and population level risks of cardiovascular disease and the effects of censoring on risk predictions.

They assessed 19 different prediction techniques (12 machine learning models and seven statistical models) using data from 3.6 million patients registered at 391 general practices in England between 1998 and 2018.

Data from general practices, hospital admission and mortality records were used to test each model's performance against actual events.

All 19 models yielded similar population level performance. However, cardiovascular disease risk predictions for the same patients varied substantially between models, especially in patients with higher risks.

For example, a patient with a cardiovascular disease risk of 9.5-10.5% predicted by the traditional QRISK3 model had a risk of 2.9-9.2% and 2.4-7.2% predicted by other models.

Models that ignored censoring (including commonly used machine learning models) substantially underestimated risk of cardiovascular disease.

Of the 223,815 patients with a cardiovascular disease risk above 7.5% with QRISK3 (a model that does consider censoring), 57.8% would be reclassified below 7.5% when using another type of model, explain the researchers.

The researchers acknowledge some limitations in comparing the different models, such as the fact that more predictors could have been considered. However, they point out that their results remained similar after more detailed analyses, suggesting that they withstand scrutiny.

"A variety of models predicted risks for the same patients very differently despite similar model performances," they write. "Consequently, different treatment decisions could be made by arbitrarily selecting another modelling technique."

As such, they suggest these models "should not be directly applied to the prediction of long term risks without considering censoring" and that the level of consistency within and between models "should be routinely assessed before they are used to inform clinical decision making."

November 4, 2020 (ATLANTA) - As wildlife populations decline around the globe, understanding the natural and human-induced factors that influence their growth is critical for determining the risk of population declines and developing effective conservation strategies.

In a new study by the Dian Fossey Gorilla Fund and University of California Davis, "Violent encounters between social units hinder the growth of a high-density mountain gorilla population," in the journal Science Advances, scientists used five decades of data to examine the role of social behavior in explaining fluctuations in the growth rate of a subpopulation of mountain gorillas monitored by the Fossey Fund.

The researchers found a dramatic slowing of the population growth rate as a result of social factors, namely increases in infant mortality resulting from violent encounters between groups living at higher density and with more overlap in their home ranges.

"This is one of the few studies to demonstrate the considerable impact that social behavior can have on whether or not a population grows," says Dr. Winnie Eckardt, co-lead author of the study and research manager at the Fossey Fund.

Roughly 600 of the estimated 1,063 remaining mountain gorillas live in the Virunga massif, a small forest spanning the countries of Rwanda, Uganda and the Democratic Republic of the Congo.

While small, the population has grown significantly since the early 1980s, when there were estimated to be just 250 individuals. Conservation measures implemented since then in this 430-square-kilometer forest led to a remarkable recovery of the Virunga mountain gorilla population. Repeated censuses during the 1980s and early 2000s, however, found the population growth to be uneven, with the subpopulation monitored by the Fossey Fund experiencing a faster growth rate than the rest of the population.

By 2006, this study population was composed of three large stable groups, each with multiple silverbacks. While the average gorilla group numbers 10 individuals, these groups ranged from 25 to a record 65 gorillas and included up to eight silverbacks.

When the young silverbacks in these groups started challenging the older group leaders, the resulting social instability led to a series of group fissions and formations. As a result, an area previously shared by just three groups was now occupied by up to 11 smaller groups, with fewer silverbacks per group.

Expansion of these groups into new areas was limited by the presence of agricultural fields immediately next to the park and the presence of other gorilla groups. The threefold increase in group density resulted in higher overlap in home ranges between groups and more frequent intergroup interactions. Such interactions are often violent, as males hoping to attract females target other males and their infants. As a result, infant mortality increased by 57%, contributing to slowing the annual population growth rate from 5.05% to 2.37%.

"Before 2007, we would talk about intergroup encounters for months because they were so rare," recalls Eckardt. "After that, they began to happen with such frequency that we could hardly keep up with documenting them."

One implication of the findings is that in socially living species, the density of groups rather than the density of individuals may play a larger role in regulating population growth. "Scientists often talk about how many individuals an environment can hold, also known as carrying capacity," say co-author Jean Paul Hirwa, the Fossey Fund's gorilla program manager. "But what these data clearly show is that for social species, this number can depend on how the animals chose to organize themselves. For example, 100 gorillas living in three groups, as we saw in the 2000s, likely require less space than 100 gorillas living in 10 groups."

"The Virunga gorilla population has been increasing for almost 40 years, but its habitat has not. As the gorilla density reaches unusually high value, scientists fear that between-group aggression and stress will significantly affect the welfare of the animals," says Dr. Damien Caillaud, a co-lead author of the study and associate professor of anthropology at UC Davis.

The study also shows the challenges for the broader Virunga mountain gorilla population. Other mountain gorilla subpopulations within the region now look similar to the study groups in the 2000s, with high growth rates, large sizes and multiple males. Should they undergo a similar set of social changes, this could result a further slowing of the overall growth of the population.

"This study highlights the value of long-term data to understanding the ever-changing population dynamics of a species, which is ultimately linked to its conservation," says Dr. Tara Stoinski, co-author and CEO of the Fossey Fund. "Mountain gorillas are an incredible conservation success story, but their population is very small--just over 1,000 individuals. Our hope is that improving our understanding of what factors are influencing the population's growth will aid in developing effective conservation strategies."

PHILADELPHIA - Multiple sclerosis (MS) is an autoimmune disorder that develops as the body's immune system attacks the central nervous system. Specifically, it attacks the protective layer surrounding nerve cells, called the myelin sheath. Current MS therapies aim to counter this inflammatory response by suppressing the immune system, which can lead to serious side effects like a higher risk of infection, and even cancer. Jefferson researchers have found a way to prevent immune cells from attacking myelin and halt disease progression, while leaving the rest of the immune system intact, in mouse models of MS. The study was published in Science Translational Medicine on November 4th.

"There are many possible immune-activating antigens in the myelin sheath, but the biggest hurdle is that we don't know which component of myelin is triggering the immune response in MS patients," says senior author Abdolmohamad Rostami, MD, PhD, Professor and Chairman of the Department of Neurology at Sidney Kimmel Medical College - Thomas Jefferson University and Vickie and Jack Farber Institute for Neuroscience - Jefferson Health. "Previous studies have used single myelin antigens or combinations of antigens to prevent auto-immunity in animal models, but in humans they have had limited success."

For answers, the researchers turned to cells called oligodendrocytes. These cells wrap their cell membrane around nerve cells to produce the myelin sheath. Tiny sacs called extracellular vesicles (EVs) can be harvested from cultured oligodendrocytes. The researchers found that these EVs contain almost all the relevant myelin antigens. With all of the antigens present, there'd be a higher chance that these vesicles could halt the autoimmune attack on myelin.

"The neat thing about these EVs is that they give us an opportunity to treat the disease in an antigen-specific way, without having to know the exact identity of the target antigen," explains Dr. Rostami. "It covers all the bases."

The researchers were able to safely inject the EVs intravenously in three different mouse models of MS representing early and late stages of the disease. When administered before disease developed, the EVs had a prophylactic effect, preventing the onset of symptoms like decrease in mobility and paralysis. When given after disease onset, EVs significantly reduced severity of disease in all three models, to the point that the animals could walk again.

"The antigens involved in the auto-immune response can differ between MS patients, and even change over time in an individual patient," explains Dr. Rostami. "The fact that our approach was effective in different experimental models shows this could act as a universal therapy."

Importantly, the researchers found that the experimental therapy only affected immune cells that were attacking the myelin layer. The rest of the immune system was intact and not weakened at all.

"This is a huge advantage of our antigen-specific method over current therapies, which are like a sledgehammer to the immune system," says Dr. Rostami, "and what makes it so novel."

Translating the approach to the clinical setting, the team found that they were able to isolate the vesicles from human-derived oligodendrocytes. These human vesicles, like those from mice, also contained multiple myelin antigens, and therefore could have the same therapeutic effect in patients.

Dr. Rostami and his team are now working on getting the intravenous EVs approach patented, which could be a revolutionary step for MS treatment.

"This study was made possible by a talented group of scientists, especially Giacomo Casella, a postdoctoral fellow in our laboratory, and Bogoljub Ciric, and Guang-Xin Zhang, faculty members here at Jefferson," says Dr. Rostami.

What The Study Did: Researchers investigated whether loosening of state firearm restrictions in Missouri were associated with changes in rates of suicide by firearms among young people ages 14 to 24.

Authors: Apurva Bhatt, M.D., of the University of Missouri-Kansas City/Center for Behavioral Medicine in Kansas City, 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.2020.24303)

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.

What The Study Did: Rates and characteristics of needle stick and other sharps injuries among resident physicians and other staff at a large health care center were examined in this study.

Authors: John G. Zampella, M.D., of the New York University Grossman School of Medicine in New York, 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/jamasurg.2020.4112)

Editor's Note: The article includes conflicts of interest 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.

More than 250 million people suffer from COPD, a progressive inflammatory lung disease. On the list of the most frequent causes of death worldwide, COPD ranks third behind heart attacks and stroke. The primary cause of COPD is exposure to cigarette smoke. Ninety percent of COPD patients are or have been chronic smokers. Other risk factors include exposure to air pollution. Despite intensive research efforts, there is no cure for COPD. Resulting fibrosis and lung epithelial cell death are key features of COPD, preventing patients from breathing effectively. Current therapies focus on relieving symptoms (mainly breathlessness and cough with phlegm) and reducing the progression of the disease and its comorbidities (mainly muscle wasting). In severe cases, patients are in need of lung transplantation.

Focus on tissue regeneration

"One of the biggest issues in COPD is that the lung cannot regenerate itself", says Dr. Ali Önder Yildirim, Director at the Institute of Lung Biology and Disease at Helmholtz Zentrum München and lead of the new study. "Therefore, a treatment that cures the disease needs to focus on lung tissue regeneration and blocking of lung epithelial cell death."

In 2009, the research group of Univ. Prof. Mathias Heikenwälder at DKFZ prevented liver tissue from chronic inflammation and fibrosis. They had achieved this by blocking the lymphotoxin beta receptor signaling pathway within the liver, which is responsible for the activation and organization of immune cells as well as for chronic liver inflammation leading to fibrosis. "This is why we have long suspected that the blocking of lymphotoxin beta receptor could also play a role in regenerative processes in other organs," explains Heikenwälder.

The development of diseases in the liver and the lung show many similarities. In COPD, immune cells form newly organized structures in the lung, so called tertiary follicles, which are known to play an important role in the disease progression. The formation of these follicles requires the activation of the lymphotoxin beta receptor in the lung - the same receptor which was targeted in Heikenwälder's study in the liver. "We wanted to investigate on the role of this receptor and its signaling in COPD and whether we might be able to use it in a therapeutic setting", says Yildirim. The researchers therefore blocked the signaling of the lymphotoxin beta receptor in lungs of mice which had developed smoke-induced COPD typical immune cell follicles, fibrosis and lung epithelial cell death.

Full restoration of lung tissue in mice

The result: Blocking of lymphotoxin beta receptor signaling in mice lung tissue disrupted the formation of the immune cell follicles, prevented lung epithelial cell death and, surprisingly, at the same time triggered lung tissue regeneration. "The lung in those mice regenerated despite the continuous exposure to chronic cigarette smoke. We observed a full restoration of lung tissue", says Dr. Thomas M. Conlon, part of Yildirim's group at Helmholtz Zentrum München. "Moreover, as the mice lungs healed, co-morbidities such as muscle wasting also improved."

The researchers found that the regeneration of compromised lung epithelial cells is induced by so-called Wnt signaling which is automatically activated through the blocking of lymphotoxin beta receptor signaling in those cells. "Wnt signaling is an essential pathway for lung development. In COPD, it gets switched off preventing lung tissue from being able to repair and regenerate" says Heikenwälder. In previous experiments, re-activation of Wnt signaling in mice has been proven to induce lung repair.

Novel therapeutic approach

"This could become a novel therapeutic approach for COPD. Our idea is to develop lymphotoxin beta receptor blockers for COPD which reduce lung epithelial cell death and lung inflammation. The automatic activation of Wnt signaling could then induce lung tissue regeneration", says Yildirim.

In first preclinical experiments, the group showed that the lymphotoxin beta receptor signaling in human lung tissue is identical to the signaling in mice. This offers great potential for implementing lung regenerative medicine approaches in the clinic. To achieve this ultimate goal, the researchers aim to test this novel therapeutic approach published in Nature journal in human clinical trials over the coming years.

Two population screen and treat programmes commonly prescribed to prevent older people falling have no impact on reducing fractures, researchers from the University of Warwick and University of Exeter have concluded.

As part of the largest clinical trial of its kind in the UK, funded by the National Institute for Health Research, the team examined two approaches to preventing falls in older people to find out if they also resulted in fewer fractures. Their results, published today (4 November) in the New England Journal of Medicine, showed that these programmes are not effective, when using a population screening approach, in reducing fractures in older people.

Up to one in 20 older people with a history of falling sustains a fracture annually, with some being admitted to hospital or needing to move to a care home. One in three people with a hip fracture dies within one year. Hip fractures alone cost the UK over £2 billion per year. Strategies to prevent fall-related fractures are desperately needed.

The study examined two screen and treat programmes: multi-factorial fall prevention (MFFP), and exercise for people at increased falls risk. People living in the community were screened for falls risk and invited to attend the programmes. Both interventions are widely used in health services internationally, and prescribed regularly for older people.

Multi-factorial fall prevention involved a one-hour assessment with a trained health professional for eight risk factors for falls. Following this, participants would either be given specific advice, see their GP for a detailed medication review, or be referred for physiotherapy-led exercise. The exercise programme ran for six months during which they were seen by a physiotherapist and exercised at home.

The trial recruited 9803 people aged 70 and older - with the eldest being 101 years old - and who were living in the community (i.e. not in a care home). They were asked to complete a short questionnaire to determine their individual risk of experiencing a fall and those with a higher risk of falls were provided with a falls prevention advice booklet, then randomly assigned to take part in either the 6-month exercise programme, the multi-factorial fall prevention programme, or no further intervention beyond the advice booklet. By taking a population-based screening approach, rather than targeted approach focusing solely on those already being treated for falls, the researchers could build a realistic picture of the broader impact of these programmes on all older people.

The researchers then used data from NHS Digital, combined with general practice records and reports from the participants themselves, to determine how many times they went to hospital or attended Accident and Emergency with a fracture over the course of 18 months. When they compared fracture rates from both screen and treat programmes to those who had only received the advice booklet, they found no reduction in fracture rates between them.

Lead author Professor Sallie Lamb of the University of Exeter, who began the research while working at the University of Warwick, said: "Whilst this is a disappointing result, it shows that we must continue to invest in research and development to reduce fractures in older people. We need to think about the broader causes of fractures, and also understand more about what happens to cause falls."

Co-author Professor Martin Underwood from Warwick Clinical Trials Unit at the University of Warwick said: "Exercise programmes and multifactorial fall prevention are commonly advised for older people at risk of falling based on evidence that they reduce falls, but until now the evidence hasn't shown that they reduce fractures. We have shown beyond reasonable doubt that these interventions are ineffective at reducing fractures."

Co-author Professor Julie Bruce from Warwick Clinical Trials Unit at the University of Warwick said: "We saw benefits to the general health of people doing exercise and a short-term reduction in the number of falls after exercise. People completing the 6-month exercise programme became stronger and their balance improved but that did not translate into a reduction in fractures in the long term. The take home message is that we would encourage older people to do physical activity and keep mobile because of the health benefits."

They belong to the bark beetle family, and they are the only animals in nature, along with leaf-cutter ants and some termites, that practice agriculture: ambrosia beetles. These insects, which are about two millimetres in size, carry fungal spores into their nests and sow them in specially created tunnels in the wood. They then care for the growing fungal cultures that serve as food for them.

Like farmers, the beetles also have to defend their fungal cultures against pests, such as other fungi that threaten to overgrow the gardens. Individually living beetles could hardly manage this work. This is why ambrosia beetles have developed sophisticated social systems over the course of evolution, similar to those of bees and other social insects. "This is unique in beetles," says Würzburg biologist Peter Biedermann.

Biedermann is fascinated by ambrosia beetles. He studied them at the Biocentre of Julius-Maximilians-Universität (JMU) Würzburg in Bavaria, Germany. "Because they have been practicing this type of sustainable agriculture for 60 million years, I am interested in how they combat harmful fungi. Perhaps we can learn from the beetles for our own agriculture".

Fascinating social system discovered in second beetle species

Ambrosia beetles are spread all over the world. In the case of the Fruit-tree pinhole borer (Xyleborinus saxesenii) native to Europe and invasive worldwide, Biedermann described an extraordinarily highly developed social system already in 2011 (publication Biedermann & Taborsky, PNAS). He has now found a similar social system in the sugercane shot-hole borer Xyleborus affinis, which lives in the tropics of the Americas. No other beetles with this peculiarity are known so far.

Biedermann presents his new findings on the social system of the American beetle in the magazine Frontiers in Ecology & Evolution: After a beetle mother has established a new nest with fungal gardens and the first offspring develops, many young beetles stay with their mother for the time being. They help her to care for the fungi and to raise the offspring.

Female workers can reproduce

This is comparable to the workers of the bees. "In contrast to the sterile bee workers, however, the female beetle workers are capable of reproduction: depending on their life situation, they decide whether they will eventually establish their own nest, whether they will lay eggs in the birth nest themselves or whether they will exclusively help the mother," says the biologist.

This social system is termed cooperative brood care, which is very rare in nature and is a preliminary stage to the eusocial system of social insects with their sterile workers and a fertile queen. These beetles could help science to understand the evolution of sociality.
Abundance of "weed fungi" determines activity

In his study, Biedermann has also discovered new information about the sugercane shot-hole borers farming activities. The beetles adjust their fungal care behaviour according to whether there are many or few "weed fungi" growing in the nest. Furthermore, it was shown that beetle daughters who do not reproduce themselves help with the work in the nest, but otherwise show less social behaviour than their egg-laying sisters.

Peter Biedermann recently took over the professorship for forest entomology and forest protection at the University of Freiburg in Germany. His next step there will be to investigate whether ambrosia beetles can distinguish between weedy and food fungi on the basis of their odour and how the beetles selectively weed or chemically control the fungal weeds.

Bethesda, Maryland (Nov. 4, 2020) - Early identification and removal of cancerous colorectal polyps is critical to preventing the progression of colorectal cancer and improving survival rates. The U.S. Multisociety Task Force on Colorectal Cancer has released new guidance for endoscopists on how to assess colorectal lesions for features associated with cancer, discuss how these factors guide management, and outline when to advise surgery after malignant polyp removal.

Key recommendations from the U.S. Multisociety Task Force on Colorectal Cancer, which is comprised of leading experts representing the American College of Gastroenterology (ACG), the American Gastroenterological Association (AGA) and the American Society for Gastrointestinal Endoscopy (ASGE), include:

Management of malignant polyps must begin with a thorough and knowledgeable endoscopic assessment designed to identify features of deep submucosal invasion.

In nonpedunculated lesions with features of deep submucosal invasion, endoscopic biopsy and tattooing should be followed by surgical resection.

Nonpedunculated lesions with high risk of superficial submucosal invasion should be considered for en bloc resection and proper specimen handling.

When pathology reports cancer in a lesion that was completely resected endoscopically, the decision to recommend surgery is based on polyp shape, whether there was en bloc resection and adequate histologic assessment, the presence or absence of unfavorable histologic features, the patient's risk for surgical mortality and morbidity, and patient preferences.

Predicting the outcomes of actions in order to make good decisions is a critical role of brain function. This process is thought to work through two fundamentally different mechanisms called "model-free" and "model-based" learning. Though fundamental for flexible and adaptive behaviour, the neurobiology of model-based learning remains poorly understood.

Now, in a study published in the scientific journal Neuron, scientists pin down a brain area crucial for this type of learning and demonstrate how its activity encodes multiple aspects of the decision-making process.

Disentangling cognitive schemes

"Model-free and the model-based learning are distinct, but complementary", says lead author Thomas Akam, a researcher at Oxford University, who worked together on this study with Rui Costa, investigator at the Champalimaud Centre for the Unknown and now Director and CEO of Columbia's Zuckerman Institute, and Peter Dayan, Director of the Max Planck Institute for Biological Cybernetics in Tübingen

Whereas the model-based approach relies on understanding the underlying structure of the problem and creating a plan, for instance figuring out the best route to get to a new restaurant, the model-free approach allows you to act quickly with less mental effort in familiar situations.

"The model-free approach simply consists of opting for actions that gave a good result in the past. So in this example, after multiple visits to the restaurant, making the trip would become completely habitual, freeing your mind to focus on other things", Costa adds.

According to the authors, we switch between these modes of acting all the time without even realising. For instance, if you find a closed road on your habitual route to the restaurant, you may quickly transition to the model-based approach to come up with an alternative.

"The two approaches often operate in parallel, which creates a challenge in studying the neural basis of the model-based decision making", says Akam.

To isolate the contribution of these two cognitive schemes, the researchers developed a novel experimental task.

A custom-made puzzle

"We adapted a task that was originally developed for humans so that we could study brain mechanisms in mice", says Akam.

Mice would initiate a trial by poking their noses into one of two central ports, located one above the other. This would light up one of two side ports where the mice could collect a water reward (one located to the left and the other to the right of the central ports).

To do the task well, the mice had to figure out two key variables. The first was which side-port was more likely to offer a reward. And the second was which of the central ports activated the more rewarding side port. Once the mice learned the task, they would opt for the action sequence that offered the best outcome.

Though this task may seem artificial, Akam points out that it captures certain important features of real-world decision-making. "Just like in real life, the subject has to perform extended sequences of actions, with uncertain consequences, in order to obtain desired outcomes", he explains.

To promote flexible learning strategies, every now and then, one of two changes would happen. "One manipulation was to switch the mapping between the central and the side ports. The other was to change which of the side ports had a higher probability of giving reward", Akam explains.

How was this experimental approach useful for disentangling the different cognitive schemes? "In principle, the task can be solved by either model-free or model-based learning; mice could simply learn the model-free prediction 'top is good', or they could learn a model of the task 'top leads to left, left to reward ", Akam says. "However, these different strategies would generate different patterns of choices. By looking at the subjects' behaviour we were able to assess the contribution of either approach."

When the team analysed the results - about 230,000 individual decisions - they learned that the mice were using both approaches in parallel. "This confirmed that the task was suitable for studying the neural basis of these mechanisms", Costa says. "We then moved on to the next step - investigating the neural basis of this behaviour."

A neural map of model-based learning

The team focussed on a brain region called anterior cingulate cortex (ACC)."Previous studies established that ACC is involved in action selection and provided some evidence that it could be involved in model-based predictions," Dr. Costa explained. "But no one had checked the activity of individual ACC neurons in a task designed to differentiate between these different types of learning"

Remarkably,the researchers discovered that the activity of the neurons created a map that represented various aspects of the behaviour of the mice. "By looking at the pattern of activity across the population we could decode very accurately where in the trial the subject was. For instance, if it was about to choose the bottom port, or was moving from the top to the right port, or receiving a reward on the left", Akam recounts.

In addition to representing the animal's current location in the task, ACC neurons also encoded which state was likely to come next. "This provided direct evidence that ACC is involved in making model-based predictions of the specific consequences of actions, not just whether they are good or bad", says Costa.

Moreover, ACC neurons also represented whether the outcome of actions was expected or surprising, potentially providing a mechanism for updating predictions when they turn out to be wrong.

Finally, to test whether the ACC was needed for model-based decision-making, the team silenced ACC neurons in individual trials while the animals were deciding what option to choose. As a result, "mice failed to correctly update their strategy, suggesting that silencing ACC prevents the animals from using model-based predictions. Consistent with this interpretation, ACC silencing had a stronger effect on subjects who relied more on a model-based strategy", Akam explains.

"These results were very exciting," Costa points out. "These data identify the anterior cingulate cortex as a key brain region in model-based decision-making, more specifically in predicting what will happen in the world if we choose to do a particular action versus another."

Next steps

According to the authors, a big challenge in contemporary neuroscience is understanding how the brain controls complex behaviours like planning and sequential decision making. "Our study is one of the first to demonstrate that it is possible to study these aspects of decision-making in mice", says Akam.

"These results will allow us and others to use the powerful tools for monitoring and manipulating brain activity available in this species to build mechanistic understanding of flexible decision making", he concludes.

In a small study of adults with major depression, Johns Hopkins Medicine researchers report that two doses of the psychedelic substance psilocybin, given with supportive psychotherapy, produced rapid and large reductions in depressive symptoms, with most participants showing improvement and half of study participants achieving remission through the four-week follow-up.

A compound found in so-called magic mushrooms, psilocybin produces visual and auditory hallucinations and profound changes in consciousness over a few hours after ingestion. In 2016, Johns Hopkins Medicine researchers first reported that treatment with psilocybin under psychologically supported conditions significantly relieved existential anxiety and depression in people with a life-threatening cancer diagnosis.

Now, the findings from the new study, published Nov. 4 in JAMA Psychiatry, suggest that psilocybin may be effective in the much wider population of patients who suffer from major depression than previously appreciated.

"The magnitude of the effect we saw was about four times larger than what clinical trials have shown for traditional antidepressants on the market," says Alan Davis, Ph.D., adjunct assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. "Because most other depression treatments take weeks or months to work and may have undesirable effects, this could be a game changer if these findings hold up in future 'gold-standard' placebo-controlled clinical trials." The published findings cover only a four-week follow-up in 24 participants, all of whom underwent two five-hour psilocybin sessions under the direction of the researchers.

"Because there are several types of major depressive disorders that may result in variation in how people respond to treatment, I was surprised that most of our study participants found the psilocybin treatment to be effective," says Roland Griffiths, Ph.D., the Oliver Lee McCabe III Professor in the Neuropsychopharmacology of Consciousness at the Johns Hopkins University School of Medicine and director of the Johns Hopkins Center for Psychedelic and Consciousness Research. He says the major depression treated in the new study may have been different than the "reactive" form of depression in patients they studied in the 2016 cancer trial. Griffiths says his team was encouraged by public health officials to explore psilocybin's effects in the broader population of those with major depressive disorder because of the much larger potential public health impact.

For the new study, the researchers recruited 24 people with a long-term documented history of depression, most of whom experienced persisting symptoms for approximately two years before enrolling in the study. The average age of participants was 39; 16 were women; and 22 identified themselves as white, one person identified as Asian and one person identified as African American. Participants had to taper off any antidepressants prior to the study with the help of their personal physician to ensure safe exposure to this experimental treatment.

Thirteen participants received the psilocybin treatment immediately after recruitment and after preparation sessions, and 11 participants received the same preparation and treatment after an eight-week delay.

Treatment consisted of two psilocybin doses given by two clinical monitors who provided guidance and reassurance. The doses were given two weeks apart between August 2017 and April 2019 at the Johns Hopkins Bayview Medical Center Behavioral Biology Research Building. Each treatment session lasted approximately five hours, with the participant lying on a couch wearing eyeshades and headphones that played music, in the presence of the monitors.

All participants were given the GRID-Hamilton Depression Rating Scale - a standard depression assessment tool - upon enrollment, and at one and four weeks following completion of their treatment. On the scale, a score of 24 or more indicates severe depression, 17-23 moderate depression, 8-16 mild depression and 7 or less no depression. At enrollment, participants had an average depression scale rating of 23, but one week and four weeks after treatment, they had an average depression scale score of 8. After treatment, most participants showed a substantial decrease in their symptoms, and almost half were in remission from depression at the follow-up. Participants in the delayed group didn't show decreases in their symptoms before receiving the psilocybin treatment.

For the entire group of 24 participants, 67% showed a more than 50% reduction in depression symptoms at the one-week follow-up and 71% at the four-week follow-up. Overall, four weeks post-treatment, 54% of participants were considered in remission - meaning they no longer qualified as being depressed.

"I believe this study to be a critically important proof of concept for the medical approval of psilocybin for treatment of depression, a condition I have personally struggled with for decades," says entrepreneur and philanthropist Tim Ferriss, who supported the funding campaign for this study. "How do we explain the incredible magnitude and durability of effects? Treatment research with moderate to high doses of psychedelics may uncover entirely new paradigms for understanding and improving mood and mind. This is a taste of things to come from Johns Hopkins."

The researchers say they will follow the participants for a year after the study to see how long the antidepressant effects of the psilocybin treatment last, and will report their findings in a later publication.

Griffiths, whose research with psilocybin, begun in the early 2000s, was initially viewed by some with skepticism and concern, says he is gratified by Johns Hopkins' support and heartened by the dozens of startups and research labs that have followed suit with their own research. He says numerous companies are now actively working to develop marketable forms of psilocybin and related psychedelic substances.

According to the National Institute of Mental Health, more than 17 million people in the U.S. and 300 million people worldwide have experienced major depression.