Earth

Overview

The research team of Professor Toshihiko Eki of the Department of Applied Chemistry and Life Science (and Research Center for Agrotechnology and Biotechnology), Toyohashi University of Technology used a next-generation sequencer to develop a highly efficient method to analyze soil nematodes by using the 18S ribosomal RNA gene regions as DNA barcodes. They successfully used this method to reveal characteristics of nematode communities that inhabit fields, copses, and home gardens. In the future, the target will be expanded to cover all soil-dwelling organisms in agricultural soils, etc., to allow investigations into a soil's environment and bio-diversity. This is expected to contribute to advanced agriculture.

Details

Similar to when the UN declared 2015 to be the International Year of Soils, there have recently been many efforts worldwide to raise awareness of the importance of the soil that covers our Earth and its conservation. Diverse groups of organisms such as bacteria, fungi, protists, and small soil animals inhabit the soil, and together they form the soil ecosystem. Nematodes are a representative soil animal; they are a few millimeters long and have a shape resembling a worm. They play an important role in the cycling of soil materials. Many soil nematodes are bacteria feeders, but they have a wide variety of feeding habits, such as feeding on fungi, plant parasitism, or being omnivorous. In particular, plant parasitic nematodes often cause devastating damage to crops. Therefore, the classification and identification of nematodes is also important from an agricultural standpoint. However, nematodes are diverse, and there are over 30,000 species. Additionally, because nematodes resemble one another, morphological identification of nematodes is difficult for anyone but experts.

The research team focused on "DNA barcoding" to identify the species based on their unique nucleotide sequences of a barcode gene, and they established a method using a next-generation sequencer that can decode huge numbers of nucleotide sequences. They used this to analyze nematode communities from different soil environments. Initially, four DNA barcode regions were set for the 18S ribosomal RNA genes shared by eukaryotes. The soil nematodes used for analysis were isolated from an uncultivated field, a copse, and a home garden growing zucchini. The PCR was used to amplify the four gene fragments from the DNA of the nematodes and determine the nucleotide sequences. Additionally, the nematode-derived sequence variants (SVs) representing independent nematode species were identified, and after taxonomical classification and analysis of the SVs, it was revealed that plant parasitizing nematodes were abundant in the copse soil and bacteria feeders were abundant in the soil from the home garden. It was also determined that predatory nematodes and omnivorous nematodes were abundant in the uncultivated field, in addition to bacteria feeders.

This DNA barcoding method using a next-generation sequencer is widely used for the analysis of intestinal microbiota, etc., but analyses of eukaryotes such as nematodes are still in the research stage. This research provides an example of its usefulness for the taxonomic profiling of soil nematodes.

Development Background

Research team leader Toshihiko Eki stated, "Through genetic research, I have been working with nematodes (mainly C. elegans) for around 20 years. As a member of our university's Research Center for Agrotechnology and Biotechnology, I came up with this theme while considering research that we could perform that is related to agriculture. As a test, we isolated nematodes from the university's soybean field and unmanaged flowerbed and analyzed the DNA barcode for each nematode. Bacteria feeders were abundant in the soybean field, and that was used for comparison with the flowerbed, where weed-parasitizing nematodes and their predator nematodes were abundant. This discovery was the start of our research (Morise et al., PLoS ONE, 2012). If that method using one-by-one DNA sequencing was the first generation, the current method using the next-generation sequencer is the second generation, and we were able to clarify characteristics of nematode communities representing the three ecologically different soil environments according to expectations."

Future Outlook

Currently, the research team is developing the third-generation DNA barcoding method which involves purifying DNA directly from the soil and analyzing the organisms in the whole soil instead of isolating and analyzing any particular soil-dwelling organisms. They are currently analyzing the soil biota of cabbage fields, etc. They are aiming to precisely analyze how communities of soil-dwelling organisms including microbes change with crop growth, clarify the effects that cultivated plants have on these organisms, and investigate biota closely related to plant diseases. If this research moves forward, crops can be cultivated and managed logically based on biological data in agricultural soils, and it can contribute to advancing smart agriculture in Japan, such as in the prominent Higashi-Mikawa agriculture region and beyond.

Ludwig-Maximilians-Universitaet (LMU) in Munich researchers have shown how RNA-binding proteins modulate synaptic responses that mediate the transmission of nerve cell impulses.

Cells in the central nervous system possess a high degree of flexibility, which enables them to adapt to fluctuating demands and respond to changing patterns of neuronal activity. This is achieved by modulating the connections between nerve cells, which are mediated by structures called synapses that determine how neighboring neurons respond to stimulation. These adjustments in turn require the intracellular transport of mRNAs. Consequently, the required proteins can be synthesized close to the synapses themselves. Specific mRNA-binding proteins play a vital role in this process. A research team led by LMU biochemist Michael Kiebler has now characterized two such proteins in detail. The study demonstrates that they modulate different aspects of synaptic transmission. Thereby, they are complementing each other in order to maintain balanced neuronal activity.

The RNA-binding proteins in question, named Staufen and Pumilio respectively, are known to have essential functions in the central nervous system. Both are involved in the regulation of synaptic transmission, and they share a common set of target RNAs. They can even be found in the same RNA granules - heterogeneous particles made up of mRNAs and proteins that guide them to their final destinations. "The functional interactions between the two RNA-binding proteins, and the nature of the signaling pathways that they regulate in nerve cells had remained unknown up to now", says Rico Schieweck, lead author of the new report.

Using cultured nerve cells, Kiebler's research group has now shown that Staufen and Pumilio control the activity of synapses in quite distinct ways. Staufen primarily controls mRNA levels and thereby the amount of proteins they encode. Pumilio, on the other hand, regulates directly the process of mRNA translation, and controls how much protein is synthesized per mRNA molecule. In fact, it plays a dual role in synaptic transmission itself. "We demonstrated that Pumilio is a hitherto unrecognized coordinator of inhibitory synapses, and therefore regulates the excitability of neuronal synapses," Schieweck explains. If the gene for Pumilio is deleted, synapses become hyperactive, and the overall level of neuronal activity increases. Based on their results, Kiebler and his colleagues propose that Pumilio and Staufen can be regarded as yin and yang factors, which together control the expression of synaptic proteins. Thanks to their differential and highly selective effects on a variety of processes, they sensitively tune the activity of individual synapses.

Disruption of the neuronal equilibrium is a hallmark of neurological and neuropsychiatric disorders, such as epilepsy and autism. The researchers believe that their findings will contribute to a better understanding of these conditions, because they provide insight into the mechanisms that enable different RNA-binding proteins to alter the functional characteristics of synapses.

Skoltech researchers and their colleagues from Russia and the UK investigated the safety and efficacy of new chemistry in antisense oligonucleotides used to treat spinal muscular atrophy (SMA), a debilitating genetic disease. Their results may lead to the development of drugs with less toxicity and fewer injections needed thanks to prolonged action. The paper was published in the journal Nucleic Acid Therapeutics.

Antisense oligonucleotides are single stranded chemically modified fragments of DNA that target pre-messenger RNA, short bits of genetic information a ribosome reads to make a protein. Depending on how a particular antisense oligonucleotide works, the target mRNA can either be destroyed or undergo subtle changes in how it's spliced, i.e. how exons, the coding regions, are excluded or included in the final mRNA.

Antisense oligonucleotides are good at targeting so-called monogenic disorders, where the cause of the disease stems from one particular gene/protein. A common example of such disease is spinal muscular atrophy (SMA); people with this disease lose a functional protein encoded by gene SMN1, and even though the human genome contains a nearly identical copy, SMN2, the mRNAs transcribed from this gene lack just one necessary exon, which leads to a poorly functioning protein.

To help the cells successfully use SMN2 instead of SMN1, an antisense oligonucleotide can interfere with splicing of the precursor to mature mRNA that includes a particular exon. That is how nusinersen, the clinically approved antisense oligonucleotide against SMA marketed as Spinraza®, works.

Timofei Zatsepin, Associate Professor at the Skoltech Center of Life Sciences, CLS Senior Research Scientist Olga Sergeeva and their colleagues studied alternatives to phosphorothioate groups in splice switching oligonucleotides. Previously, Dr. Stetsenko from Novosibirsk state university had developed oligonucleotides with methanesulfonyl (mesyl, μ) or 1-butanesulfonyl (busyl, β) phosphoramidate groups.

"Phosphorothioate is the key chemical modification of nucleic acids developed by Prof. Fritz Eckstein in late 1960s that is present in almost all oligonucleotide drugs approved so far. It improves stability, pharmacodynamics, and pharmacokinetics of oligonucleotides, but demonstrates significant toxicity that limits applications of oligonucleotide drugs. During the last 30 years, many alternatives were developed, but we do believe that mesyl phosphoramidates are superior to other phosphate mimics in therapeutic oligonucleotides," Zatsepin said.

The new compounds are a bit unusual as their structure is quite confusing when one sees the formula for the first time. "You expect that such a bulk group should strongly interfere with all intracellular interactions. However, our colleagues from Novosibirsk, led by Dr. Dmitry Stetsenko, previously demonstrated that μ-oligonucleotides are much less toxic than PS oligonucleotides, while duplexes of μ-oligonucleotides with DNA are good substrates of RNAse H - a key enzyme for mRNA degradation via antisense mechanism," Zatsepin noted.

The researchers were inspired by these results and looked, among other things, for splice switching oligonucleotides with potentially prolonged action. Nusinersen is administered several times a year via an injection into the spinal canal, so fewer injections would improve the quality of life for patients with SMA.

The team was able to test the activity of novel antisense oligonucleotides in vitro in SMA patient-derived fibroblasts and in vivo in a neonatal mouse model of SMA. "In our study we found that μ-oligonucleotides were active in vitro, while in vivo the efficacy was lower in comparison to nusinersen at the same dose. As μ-oligos are more stable and less toxic in vivo than PS oligos, we propose that μ-oligos used in higher doses can provide the same efficacy together with more prolonged action - this study is under development now," Zatsepin explained.

During summer 2020, the Yangtze River basin experienced persistent, record-breaking meiyu rainfall. Likewise, the region suffered from severe flooding and water damage as accumulated rainfall broke records dating back to 1954. Regions outside the meiyu rain belt received significant summer rainfall as well, including Beijing, located in northeastern China.

Typically, an above average meiyu rainfall season follows a strong El Niño during the previous winter. However, summer 2020 followed a neutral El Niño-Southern Oscillation (ENSO) event. Therefore, scientists are working to explore the many dynamic components of this outlying season, and why some predictability signals, like the phase of ENSO, did not verify well for summer 2020 rainfall forecasts across the Yangtze River basin.

As part of the Climate Science for Service Partnership (CSSP) China project, a group of scientists from Institute of Atmospheric Physics, Chinese Academy of Sciences and the UK Met Office Hadley Centre collaborated, finding clues as to why the 2020 summer meiyu season was so unique. They just published their research, data, discussion, and conclusions in Advances in Atmospheric Sciences.

Despite the poor ENSO signal, archived model data and observations agree that the Met Office GloSea5 operational forecast system provided an accurate above average summer 2020 rainfall projection. Researchers attribute the reliable forecast to a good reproduction of the notably anomalous western North Pacific subtropical high (WNPSH) pressure system. The model uses local and tropical Indian Ocean sea surface temperature (SST) data to predict the size and placement of the WNPSH throughout the summer season.

"These results support that the anomalous WNPSH change and associated local air-sea interactions could exist without the impact of ENSO", said Dr. Chaofan Li, the lead author of the study.

Collaborators also explored which extratropical dynamics may have driven extreme heavy rainfall. They found that the East Asian westerly jet (EAJ) was significantly accelerated in observed data, but not nearly as intense in model simulations. While this scenario may favor more meiyu rainfall, accurately predicting the placement and speed of the EAJ through the summer season is more difficult. That said, the EAJ likely boosted seasonal Yangtze River rainfall against weaker model projections, hindering precision forecasting and disaster mitigation.

"Unfortunately, the forecast Yangtze River rainfall anomaly was weaker compared to that observed," added Dr. Li, "But the forecast members are useful to identify predictability and dynamical causes for this exceptional rainfall".

A recent proof-of-concept study finds that a low-cost training program can reduce hazardous driving in older adults. Researchers hope the finding will lead to the training becoming more widely available.

"On-road training and simulator training programs have been successful at reducing car accidents involving older drivers - with benefits lasting for years after the training," says Jing Yuan, first author of the study and a Ph.D. student at North Carolina State University. "However, many older adults are unlikely to have access to these training programs or technologies."

"We developed a training program, called Drive Aware, that would be accessible to anyone who has a computer," says Jing Feng, corresponding author of the study and a professor of psychology at NC State. "Specifically, Drive Aware is a cognitive training program for older adults to help them accurately detect road hazards. The goal of our recent study was to determine the extent to which Drive Aware influences driving behaviors when trainees actually get behind the wheel."

To test Drive Aware, the researchers enlisted 27 adults, ages 65 and older. All of the study participants took a baseline driving test in a driving simulator. Nine of the study participants were then placed in the "active training" group. The active training group received two interactive Drive Aware training sessions, about a week apart. Nine other study participants were placed in a "passive training" group. This group watched video of other people receiving the Drive Aware training sessions. This took place twice, with sessions about a week apart. The remaining nine study participants served as the control group and received no training. All 27 study participants then took a second driving test in the driving simulator.

The researchers found that study participants who were part of the active training group had 25% fewer "unsafe incidents" after the training. Unsafe incidents included accidents with other vehicles, pedestrians, running off the road, etc. There was no statistically significant change in the number of unsafe incidents for study participants in the passive training group or the control group.

"In short, we found that older adults were less likely to have an accident in the driving simulator after receiving the Drive Aware training," Yuan says.

"This testing was done with a fairly modest number of study participants," Feng says. "If we can secure the funding, we'd like to scale up our testing to more clearly establish how effective this training is at reducing accidents among older drivers. If the results are as good as they look right now, we'd want to find ways to share the training program as broadly as possible. Not many people can afford one-on-one on-the-road training, or training that involves high-end driving simulators. But we think a lot of people would be able to access Drive Aware, and it has the potential to save a lot of lives."

Scientists have discovered how plants manage to live alongside each other in places that are dark and shady.

Moderate shade or even the threat of shade - detected by phytochrome photoreceptors - causes plants to elongate to try to outgrow the competition.

But in the deep gloom of a dense forest or a cramped crop canopy where resources and photosynthesis are limited, this strategy doesn't work. In these conditions it would be a waste of energy and detrimental to survival to elongate stems because seedlings would never be able to over-grow larger neighbours.

So how do plants prevent elongated growth under deep shade conditions? The secret lies in their internal clocks, says the research collaboration from the John Innes Centre and the University of Bristol.

They have discovered that when plants detect deep shade, this changes the expression of genes in certain parts of the circadian clock - the internal daily timer found in plants and other organisms. These clock components perform an additional role in suppressing stem elongation, blocking the over-topping of neighbours that would normally happen in moderate shade.

The work identifies a previously unknown role for the circadian clock in regulating plant development, and the findings have implications for both natural plant populations and crops, say the researchers.

The study is relevant to natural plant populations because the researchers identify a new process that controls the development of plants growing under conditions such as those found in temperate woodlands in summer and tropical rainforests.

Crops are often grown in dense stands which means that the plants shade each other; so the findings identify processes that might be manipulated to allow crops to be grown more densely or to control their height.

Professor Antony Dodd of the John Innes Centre said, "The biological clock of plants is a key regulator of their development and fitness. This work sheds new light on a new role for circadian rhythms in adapting plants to competition with other plants in their environments."

Professor Kerry Franklin of the University of Bristol said, "The majority of plant shade avoidance research focuses on early neighbour detection and moderate shading. This work reveals new insights into how plants adapt to very deep shade, where resources are severely limited."

The study provides evidence for the robustness and stability of the circadian clock in stressful environments, information that may be useful in developing new generations of crops in a challenging climate.

Phytochrome A elevates plant circadian-clock components to suppress shade avoidance in deep-canopy shade appears in PNAS.

Knowing the weight of a commodity provides an objective way to value goods in the marketplace. But did a self-regulating market even exist in the Bronze Age? And what can weight systems tell us about this? A team of researchers from the University of Göttingen researched this by investigating the dissemination of weight systems throughout Western Eurasia. Their new simulation indicates that the interaction of merchants, even without substantial intervention from governments or institutions, is likely to explain the spread of Bronze Age technology to weigh goods. The results were published in Proceedings of the National Academy of Sciences (PNAS).

To determine how different units of weight emerged in different regions, researchers compared all the weight systems in use between Western Europe and the Indus Valley from 3,000-1,000 BC. Analysis of 2,274 balance weights from 127 sites revealed that, with the exception of those from the Indus Valley, new and very similar units of weight appeared in a gradual spread west of Mesopotamia. To find out if the gradual formation of these systems could be due to propagation of error from a single weight system, the researchers modelled the creation of 100 new units. Taking into account factors such as measurement error, the simulation supported a single origin between Mesopotamia and Europe. It also showed that the Indus Valley probably developed an independent weight system. The research demonstrated that if information flow in Eurasia trade was free enough to support a common weight system, it was likely to be sufficient to react to local price fluctuations.

The weight systems that emerged between Mesopotamia and Europe were very similar. This meant that a single merchant could travel, for instance, from Mesopotamia to the Aegean and from there to Central Europe and never need to change their own set of weights. The merchant could trade with foreign partners while simply relying on approximating the weights. There was no international authority that could have regulated the accuracy of weight systems over such a wide territory and long time span. In Europe, beyond the Aegean, centralised authorities did not even exist at this time. The researchers conclude that the emergence of accurate weight systems must have been the outcome of a global network regulating itself from the bottom-up.

"With the results of our statistical analysis and experimental tests, it is now possible to prove the long-held hypothesis that free entrepreneurship was already a primary driver of the world economy even as early as the Bronze Age," explains Professor Lorenz Rahmstorf from the Institute for Prehistory and Early History, University of Göttingen. Merchants could interact freely, establish profitable partnerships, and take advantage of the opportunities offered by long-distance trade. "The idea of a self-regulating market existing some 4,000 years ago puts a new perspective on the global economy of the modern era," says Dr Nicola Ialongo, University of Göttingen. He adds, "Try to imagine all the international institutions that currently regulate our modern world economy: is global trade possible thanks to these institutions, or in spite of them?"

Los Angeles, Calif. - The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, today announced that findings from a sub-study of REPRIEVE (A5332/A5332s, an international clinical trial studying heart disease prevention in people living with HIV) have been published in the Journal of the American Medical Association Network Open (JAMA Network Open). The study found that approximately half of study participants, who were considered by traditional measures to be at low-to-moderate risk of future heart disease, had atherosclerotic plaque in their coronary arteries.

While it is well-known that people living with HIV are at increased risk of cardiovascular events, including heart attacks and strokes, little is understood about the prevalence and extent of atherosclerosis in heart blood vessels and associated biological factors. The Mechanistic sub-study of REPRIEVE was designed to specifically identify factors that contribute to cardiovascular disease among people living with HIV.

"This sub-study of REPRIEVE is seeking to better understand why people living with HIV develop heart disease, even when their HIV is well controlled and they don't have many traditional risk factors," said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles. "REPRIEVE is the largest study of cardiovascular disease among people living with HIV and this is an important early report that sets the stage for future important findings."

Today's publication describes baseline data on 755 participants between the ages of 40 and 75 years old, who were enrolled at 31 sites across the United States. The sub-study used coronary CT angiography to assess the amount of plaque in participants' coronary arteries and then correlated those findings with blood samples that measured inflammation and immune activation.

Nearly half the participants (49 percent) had plaque in their coronary arteries, though the plaques were mostly seen in just a few areas of the coronary arteries. The presence of plaque was associated with a higher burden of risk factors, but also with higher levels of inflammation independent of traditional risk scores. In almost all individuals (97 percent), the plaque was mild and did not cause a narrowing of more than 50 percent of the coronary artery. While significant narrowing was rare, about one-quarter of participants (23 percent) had plaque with features that could potentially cause problems in the future (also known as vulnerable plaque).

In the general population, epidemiologic studies have shown that future cardiovascular disease increases with higher ASCVD PCE (atherosclerotic cardiovascular disease pooled cohort equation) risk scores, an index of traditional risk. REPRIEVE recruited participants with low to moderate ASCVD risk and a low average 10-year risk score of 4.5 percent. The clinical significance of mild or even significant plaque in asymptomatic people with low cardiovascular risk is unknown, as is the effectiveness of statin therapy to prevent cardiovascular disease in this population. REPRIEVE will address these important questions by following these participants to determine if the plaque reported in the Mechanistic sub-study of REPRIEVE is clinically significant (whether it is related to future cardiovascular events), whether statin therapy can reduce plaque and markers of inflammation, and if statin therapy can reduce the incidence of heart attacks and strokes.

"Heart disease is a major cause of illness and death among people living with HIV, including those with well-controlled HIV disease receiving antiretroviral treatment," said Steven Grinspoon, M.D., Massachusetts General Hospital. "Until now, our understanding of coronary artery disease among people living with HIV has been very limited. These findings significantly expand our knowledge and provide important insights that will lay the foundation to ultimately help us better support the health and well-being of people living with HIV."

PHILADELPHIA -- (June 29, 2021) -- New biomarkers that predict HIV remission after antiretroviral therapy (ART) interruption are critical for the development of new therapeutic strategies that can achieve infection control without ART, a condition defined as functional cure. These biomarkers can also provide critical clues into the biological mechanisms that control HIV replication after stopping therapy, and can help design novel strategies to cure HIV. Scientists at The Wistar Institute have identified metabolic and glycomic signatures in the blood of a rare population of HIV-infected individuals who can naturally sustain viral suppression after ART cessation, known as post-treatment controllers. These findings were published in Nature Communications and may provide new, non-invasive biomarkers to predict both the likelihood and duration of HIV remission after treatment interruption.

Cure-directed clinical trials are designed to test new therapeutic interventions to eradicate HIV infection. These trials require study participants to undergo analytical treatment interruption (ATI) to allow researchers to evaluate their strategies in the absence of the confounding effect of ART. HIV remains undetectable during ART, yet in the vast majority of cases viral loads go up within a few days or weeks after stopping ART and need to be carefully monitored. Currently, there are no simple, non-invasive methods available to monitor viral rebound after ATI. Therefore, biomarkers are urgently needed to improve the safety of ATI by predicting how long a patient can be off ART, and will be critical to understanding the mechanisms of post-ART viral control.

"We analyzed one of the largest sets of samples ever studied from post-treatment controllers, who don't experience viral rebound after ART interruption," said Mohamed Abdel-Mohsen, Ph.D., assistant professor in The Wistar Institute Vaccine & Immunotherapy Center, who led the study. "This condition is extremely rare and provides very important insights into what a functional HIV cure looks like. Analyzing the blood of these individuals, we identified promising biomarker signatures that may fast-track future HIV cure trials and treatments. These biomarkers also provide us with insights on how post-treatment controllers restrain infection and how we can design novel HIV curative strategies to recapitulate this promising phenotype in the millions of HIV-infected individuals worldwide."

The study was conducted using blood samples available from two cohorts of patients who participated in previous clinical trials: a group of 24 HIV-infected individuals who underwent an open-ended ATI without concurrent immunoregulatory agents (the Philadelphia cohort) and one group of 74 individuals from six AIDS Clinical Trial Group (ACTG) clinical studies that evaluated different vaccines and immunotherapies. Importantly, this cohort included all 27 participants from these studies that were identified as post-treatment controllers and 47 non-controllers from the same studies.

Researchers analyzed blood samples collected shortly before ATI for the presence and quantity of certain small molecules produced as a result of cellular metabolism, called metabolites, and proteins that have sugar molecules attached to them, called glycoproteins. Metabolites and glycoproteins are secreted or leaked from various tissues and enter the circulation, therefore their abundance and chemical characteristics can reflect the overall status of multiple organs, making them excellent candidates for biomarker discovery.

The team first performed metabolomic analyses on the Philadelphia cohort samples and identified a select set of metabolites linked to inflammation whose pre-ATI levels are associated with time to viral rebound. These observations were confirmed in virus reactivation assays in vitro.

They then extended the metabolomic analysis to the larger cohort, also including glycomic studies to measure the levels of sugar-bound proteins. Since this cohort includes post-treatment controllers and non-controllers, Abdel Mohsen and colleagues were able to confirm their observations by comparing the two groups.

Using machine learning algorithms, they then combined the identified biomarkers to create two models for prediction of the likelihood and timing of viral rebound, with 95% and 74% accuracy, respectively.

"A growing body of research applies metabolomics and glycomics methods for the unbiased discovery of biomarkers associated with clinical conditions," said Leila Giron, Ph.D., postdoctoral fellow in the Abdel-Mohsen lab and first author on the study. "We are among the first to apply this strategy in the context of ATI to analyze two carefully selected and well characterized groups of individuals, including a rare population of post-treatment controllers."

Overall, this study identified potential biomarkers associated with control of HIV after ART and has the potential to contribute significantly to both HIV cure research and discovery of novel biological mechanisms underlying viral control in people living with HIV.

This press release is in support of a presentation by Dr Gulam Bahadur presented online at the 37th Annual Meeting of ESHRE.

29 June 2020: Studies indicate that the optimal and safe number of oocytes needed for achieving an ongoing pregnancy is between six and 15. However, the use of egg freezing, frozen embryo replacement (FER) cycles and aggressive stimulation regimes has increased this number in order to boost success rates in older women and in poor responders who produce fewer eggs. What is not known is the impact of numbers of eggs retrieved and of over-stimulation practices on the health of patients, and on their emotional and financial well-being.

Now, a retrospective observational study suggests that IVF clinics in the UK may be retrieving "far too many oocytes" and that most of them "may never be used and are probably discarded". Details of the analysis are presented today online at the virtual Annual Meeting of ESHRE by Dr Gulam Bahadur from North Middlesex University Hospital, London, who said the results may well reflect global practices too.

The findings based on number of eggs extracted versus IVF cycles show that a total of more than 1.625 million eggs in the UK were retrieved from 147,274 women between 2015 and 2018. Although an average of 11 eggs was collected per patient, 16% of cycles were associated with 16-49 oocytes retrieved (per cycle) and 58 women each had over 50 eggs collected in a single egg retrieval procedure.

"Our observations suggests that the high oocyte number per retrieval procedure needs re-evaluation," says Bahadur. "In particular, this needs to focus on the side effects, including ovarian hyperstimulation syndrome and procedure-related complications, and on the fate of unused frozen oocytes and the costs associated with freezing them.

"Patients should be advised that it's better to collect fewer eggs leading to good quality embryos which may go to term and result in a healthy baby."

This report is based on all UK IVF clinics and relates to non-donor fertility treatment carried out between 2015 and 2018 during which 172,341 fresh oocyte retrieval cycles took place. All outcomes and patterns remained uniform over the four years.

The study showed that a sizable number (n = 10,148) of cycles did not yield any oocytes.

More than half (53%) of all IVF cycles were in the desired egg yield range of 6-15. In addition, a quarter of cycles (n = 42,574) yielded 1-5 eggs; 14% (n = 23,794) produced 16-25; and a minority (2% or 3,970) resulted in 26-49 oocytes. The authors point out that multiple birth rates increase significantly from 6-15 oocytes onwards, which presents a risk to patients and babies such as birth complications and low birth weight.

A total of 931,265 embryos resulted from all eggs retrieved - a fertilisation rate of 57%. Of the embryos created, more than one in five (22% or 209,080) were transferred into the uterus, while a slightly higher proportion (24% or 219, 563) were frozen.

The fate of the unfertilised oocytes (43%) is unknown, but they are likely to have been discarded, as is normal practice. The authors say that most of the embryos not transferred (54%) will likely be discarded after patients have paid for several years of maintaining them in storage.

"This comes with a financial and emotional cost," says Bahadur. "Patients build an attachment with this frozen material and there's insufficient counselling to support them. They should be given more information about the implications of freezing eggs and embryos."

The tiny mouse embryo has a heart that beats. Its muscles, blood vessels, gut and nervous system are beginning to develop. But this embryo is unusual: It was made in a lab, out of mouse embryonic stem cells, and represents the most sophisticated in vitro (in a dish) model of a mammal ever so created.

This new model, developed at the University of Virginia School of Medicine by Christine and Bernard Thisse, is a major step forward in scientists' efforts to mimic the natural development of a mammal by using stem cells. Its existence is a wonder that will help scientists understand mammalian development, battle diseases, create new drugs and, eventually, grow tissues and organs for people in need of transplants.

"We found a way to instruct aggregates of stem cells to initiate embryonic development. In response to this controlled instruction, the aggregates develop into embryo-like entities in a process that recapitulate the embryonic steps one-by-one," explained Christine Thisse, PhD, of UVA's Department of Cell Biology. "What is amazing is that we can get the variety of tissues that are present in an authentic mouse embryo."

Bernard Thisse, PhD, who is also part of the Department of Cell Biology, noted the significance of the advance: "Human organs are made of multiple cell types that originate from different parts of the growing embryo," he said. "The gut, for example, is made from cells that form an hollow tube. Models of this tube in a dish have been made and are called gut organoids. However, this tube is not enough to make a functional gut because this organ contains other components, such as smooth muscles, blood vessels and nerves that control the function of the gut and which are made from cells of a different origins. The only way to have all the variety of cells necessary to the formation of functional organs is to develop systems in which all precursor cells are present. The embryo-like entities we have engineered using stem cells are providing just this."

The Potential of Stem Cells

Stem cells are special cells that can turn into other cell types with specific functions. For example, stem cells turn into our hearts, our brain, our bones, our nerves. So scientists have been eager to harness the potential of stem cells, to put them to work to advance medical research and benefit human patients. But building sophisticated models with multiple cell types has proved incredibly challenging. It is far easier to direct the formation of a single cell type in a dish than to conduct the orchestra needed to have an organism develop as in nature.

The Thisses' new model is notable for its sophistication. It is the first in vitro model of a mammalian embryo with so many tissues to be built from stem cells, the researchers report. Most importantly, those structures are organized as they should be, around the notochord (the precursor of the vertebral column), a defining trait of vertebrate animals. In the Thisses' model, different cells types are woven together elegantly and correctly - a huge achievement.

To accomplish this, the Thisses and their collaborators had to overcome some of the greatest challenges in the stem cell field. Prior models failed to develop properly, or weren't organized correctly, or were plagued by other problems. Using their expertise in developmental biology and building on their previous work using cells from fish embryos (published in the journal Science in 2014), the Thisses solved these problems. The result is the beginnings of a mouse in a dish with properly organized cells and tissues. With the Thisses' model, the notochord is present and accounted for; the digestive tract starts to develop; the heart beats; and, for the first time in vitro, a nervous system develops with the formation of a neural tube.

"This in vitro mouse model shows that we are able to induce cells to execute complex developmental programs in the right succession of steps. Having all the variety of tissues made allows us to hope that the scientific community will be able to build organs with a proper vascularization, innervation and interactions with other tissues," Christine Thisse said. "This is essential to be able one day to produce functional human replacement organs in a dish. This would overcome the shortage of organ for transplants."

The Thisses' new model isn't a complete mouse yet and can't develop into one. Key parts are still missing, such as the anterior part of the brain. For now, the development of the embryoids stops at a time corresponding to middle period of gestation of a mouse embryo. The researchers' real accomplishment is developing an effective approach to creating sophisticated, embryonic-like structures, mimicking the development of a mouse embryo. This advances their field substantially, and it gives scientists more tailored control over stem cells than they have ever known.

"The embryoids we are currently producing lack the anterior brain domains," Bernard Thisse said. "However, with the techniques we have developed, we should be able, at some point, to manipulate molecular signals that control embryo formation, and this should lead generating embryo-like entities containing all tissues and organs including the anterior brain."

"The knowledge we acquired along all our career of developmental biologists served as a starting point for this study in the stem cell field," Christine Thisse said. "This was a big jump for us, but it shows that if you have a solid idea, it can be used to cross barriers and can be developed for other purposes. I say that for students: Nothing is definitive, there is room for knowing more and for solving problems."

"Watching an embryo develop is a marvelous thing to behold," she added. "I am lucky my work led me to contribute to the knowledge of how invertebrate and vertebrate embryos develop, and that using these principles, we were able to produce embryo formation in a dish using stem cells as building bricks."

Findings Published

The Thisses and their collaborators have published their findings in the scientific journal Nature Communications. The research team consisted of Peng-Fei Xu, Ricardo Moraes Borges, Jonathan Fillatre, Maraysa de Oliveira-Melo, Tao Cheng, Bernard Thisse and Christine Thisse.

The research was supported by the March of Dimes (grant 1-FY15-298), the Jefferson Trust (FAAJ3199) and the University of Virginia. Maraysa de Oliveira-Melo was supported by CNPq-Brazil (200535/2014-5).

As smoky air becomes more common during Washington's wildfire season, many wildlife enthusiasts wonder: What happens to the birds?

Few studies have looked at wildfire smoke impacts on animals, let alone birds. And as Washington and the larger West Coast continue to experience more massive wildfires and smoke-filled air, understanding how birds are affected by smoke -- and how air pollution may influence our ability to detect birds -- are important factors for bird conservation.

Researchers from the University of Washington now provide a first look at the probability of observing common birds as air pollution worsens during wildfire seasons. They found that smoke affected the ability to detect more than a third of the bird species studied in Washington state over a four-year period. Sometimes smoke made it harder to observe birds, while other species were actually easier to detect when smoke was present. The results were published June 29 in the journal Ornithological Applications.

"We want to know how wildfire smoke affects birds and other wildlife, and this study is a great place to start," said lead author Olivia Sanderfoot, a doctoral candidate in the UW School of Environmental and Forest Sciences. "Smoke clearly has an impact on detection of wildlife, and that hasn't been adequately explored in the literature to date. Now we know that smoke pollution specifically affects our observations of birds and our ability to detect them."

The researchers combined data from eBird, an online citizen-science program managed by the Cornell Lab of Ornithology, with publicly available data from an extensive network of air quality monitors across Washington state. They were able to analyze how fine particulate matter, known as PM2.5 and a marker of smoke pollution, affected the probability of observing 71 common bird species during the wildfire seasons of 2015 to 2018. Higher concentrations of smoke affected the chances of observing 37%, or 26, of the bird species included in the study.

Sixteen of the bird species were harder to observe with more wildfire smoke, the study found. These include turkey vultures, Canada geese, two gull species, bald eagles and several other birds of prey. Many of these birds are observed circling high above the ground, so it's not surprising that people would have a harder time detecting them on smoky days, the authors said. However, 10 additional species were easier to observe when smoke concentrations were higher. These include three types of warblers, cedar waxwing, spotted towhee and California quail.

The reasons for this aren't clear and are outside of the scope of this study, but the authors lay out some hypotheses for future exploration. It could be that reduced visibility due to smoke pushes some birds lower to the ground where they can be more easily seen and heard. Or, as smoke prompts birds of prey to relocate, that could alleviate pressure on some songbirds and cause them to be more active -- and thus more detectable by people.

"These behavioral changes are all hypotheticals, and we very much hope that researchers follow up on them because we have a lot to learn about how smoke affects wildlife," Sanderfoot said.

Conservation and management efforts rely on the ability to observe animals in the wild, and it's no different for birds. Air pollution clearly plays a role in detecting animals, and this paper makes the case that it should be considered alongside other factors like time of day, temperature and precipitation that all can influence observations of animals.

"If we see or hear birds more or less frequently because of smoke, that also impacts bigger inferences we make in terms of how certain bird populations are doing," said senior author Beth Gardner, an associate professor in the School of Environmental and Forest Sciences. "We want to get that part right, so we first need to understand the effect of air pollution on how we're seeing birds in the wild."

The researchers chose a four-year study period that included some summers where wildfire smoke was heavy in parts of the state, and other summers where smoke was negligible. All of the species included in the study had to have had at least 750 observations recorded for the first year (2015), and all observations used were within about 20 miles (32 kilometers) of an air quality monitor in Washington.

Data from the catastrophic 2020 wildfire season was not part of this analysis, although air quality during that period was worse than in any of the years in the study. As extreme wildfire seasons like 2020 become more common, it's important to consider the influence of events like these in future studies, the researchers said.

The Structural Bioinformatics and Network Biology laboratory, led by ICREA Researcher Dr. Patrick Aloy, has completed the bioactivity information for a million molecules using deep machine-learning computational models. It has also disclosed a tool to predict the biological activity of any molecule, even when no experimental data are available.

This new methodology is based on the Chemical Checker, the largest database of bioactivity profiles for pseudo pharmaceuticals to date, developed by the same laboratory and published in 2020. The Chemical Checker collects information from 25 spaces of bioactivity for each molecule. These spaces are linked to the chemical structure of the molecule, the targets with which it interacts or the changes it induces at the clinical or cellular level. However, this highly detailed information about the mechanism of action is incomplete for most molecules, implying that for a particular one there may be information for one or two spaces of bioactivity but not for all 25.

With this new development, researchers integrate all the experimental information available with deep machine learning methods, so that all the activity profiles, from chemistry to clinical level, for all molecules can be completed.

"The new tool also allows us to forecast the bioactivity spaces of new molecules, and this is crucial in the drug discovery process as we can select the most suitable candidates and discard those that, for one reason or another, would not work," explains Dr. Aloy.

The software library is freely accessible to the scientific community at bioactivitysignatures.org and it will be regularly updated by the researchers as more biological activity data become available. With each update of experimental data in the Chemical Checker, artificial neural networks will also be revised to refine the estimates.

Predictions and reliability

The bioactivity data predicted by the model have a greater or lesser degree of reliability depending on various factors, including the volume of experimental data available and the characteristics of the molecule.

In addition to predicting aspects of activity at the biological level, the system developed by Dr. Aloy's team provides a measure of the degree of reliability of the prediction for each molecule. "All models are wrong, but some are useful! A measure of confidence allows us to better interpret the results and highlight which spaces of bioactivity of a molecule are accurate and in which ones an error rate can be contemplated," explains Dr. Martino Bertoni, first author of the work.

Testing the system with the IRB Barcelona compound library

To validate the tool, the researchers have searched the library of compounds at IRB Barcelona for those that could be good drug candidates to modulate the activity of a cancer-related transcription factor (SNAIL1), whose activity is almost impossible to modulate due to the direct binding of drugs (it is considered an 'undruggable' target). Of a first set of 17,000 compounds, deep machine learning models predicted characteristics (in their dynamics, interaction with target cells and proteins, etc.) for 131 that fit the target.

The ability of these compounds to degrade SNAIL1 has been confirmed experimentally and it has been observed that, for a high percentage, this degradation capacity is consistent with what the models had predicted, thus validating the system.

This work has been possible thanks to the funding from the Government of Catalonia, the Spanish Ministry of Science and Innovation, the European Research Council, the European Commission, the State Research Agency and the ERDF.

Scientists at the University of Southampton have found that a marine invasive species - a sea squirt that lives on rocky shores - could spread along 3,500 kilometres of South American coastline if climate change or human activities alter sea conditions.

The researchers - working with colleagues at Pontificia Universidad Católica de Chile; Flinders University, Australia; University of Johannesburg and Rhodes University, South Africa - analysed the creature's DNA and used predictive modelling to identify regions it could move to and thrive in.1 Findings are published in the journal PNAS.

The team took a multidisciplinary approach to predict the potential distribution of a species that is currently restricted. Studying species with small distributions provides a unique opportunity to understand how some eventually become widespread.

Pyura praeputialis is an invertebrate that dominates the ecology of the regions it lives in and has the capacity to alter, fundamentally, coastal habitats. By outcompeting and overgrowing native fauna, invasive species such as this can cause impacts to biodiversity and even important economic activities.

The team sequenced the DNA of 190 samples from 13 sites along South America and Australia. They discovered that the species found in South America originated from a single region off Sydney, Australia - possibly transported to Antofagasta Bay in Chile on the hulls of wooden trading boats over 100 years ago. The population has remained trapped in the bay ever since, contained within its body of relatively warm water, which is 2-3 degrees higher than the surrounding sea.

However, this latest study suggests that just a slight change in currents, sea temperature and/or shipping routes may lead to an unchallenged expansion of the species to encompass a vast portion of coast, including northern Chile, Peru and much of Ecuador.

Lead researcher, research fellow Jamie Hudson comments: "Understanding why some species are widespread, whereas others have narrow ranges is a fundamental question in biological studies. Our work shows the importance that combining genomic data from DNA and habitat modelling can have in helping predict potential changes in the distribution of species and their impacts.

"The unusual conditions of Antofagasta Bay provided us with ideal conditions to study a species which has had its distribution restricted by local conditions. We found high genomic diversity in both native and introduced populations, indicating high adaptive potential in Chile."

The researchers concluded that further monitoring of Pyura praeputialis in the region is strongly recommended and that, more generally, future studies should consider both habitat suitability and genomic data to assess holistically the spread potential of invasive species.

A new approach to molecular drug design has yielded a highly promising bladder cancer drug, which induced rapid shedding of tumour cells and resulted in a significant reduction in tumour size when used in clinical trials.

These potent effects were seen in patients with non-muscle invasive bladder cancer (NMIBC) and the treatment was shown to be safe, as no drug-related side effects were observed.

The exciting research involved a collaborative group of scientists from Trinity College Dublin, Charles University and Motol Hospital (Prague), Lund University, and startup company Hamlet Pharma. The study has just been published in leading journal Nature Communications.

Bladder cancer - a global killer

Bladder cancer is the fifth most common malignancy in Europe (and the fourth most common in the US). It is associated with the highest life-time treatment costs per patient of all cancers, and more than 80% of patients recur after complete surgical removal of the first tumour.

Over the past three decades, few drugs have been approved for non-muscle-invasive disease and - compounding the problem - access to these drugs is limited by insufficient supply, including BCG immuno-therapy and common chemotherapeutics such as Mitomycin and Epirubicin.

The new approach

The new approach involved designing a drug candidate using the "intrinsically disordered proteins" (IDP) concept, which relates to the recent understanding that a large segment of proteins in the body do not have a fixed 3D structure (they each typically instead take shape in a variety of ways/structures that change depending on a range of factors).

This contrasts with the more common drug design direction taken, which is based on the "lock and key" concept. This relates to the idea that proteins have fixed, well-organised 3D structures, allowing drugs to be designed to target very specific regions.

The new approach involved the use of an IDP complex known as HAMLET - a component of human milk - which, when partially unfolded, possesses tremendous cancer-killing abilities.

Dr Ken H Mok, Associate Professor in Trinity's School of Biochemistry and Immunology and the Trinity Biomedical Sciences Institute led the structural element of the work. He said:

"Targeted cancer therapies have made significant advances in recent years but the lack of tumour specificity remains a significant concern. Few current therapies kill cancer cells without harming healthy tissues, and severe side effects have become accepted as a necessary price to pay for survival or cure. This research is therefore extremely exciting as the clinical trials show great impact in reducing tumour size in people with this form of bladder cancer without any side-effects.

"From a scientific perspective - and with a nod to the great potential for other therapeutic discoveries - it is also extremely exciting to have contributed to an entirely new approach to molecular drug design. Intrinsically disordered proteins compose over 50% of the human proteome and their malleability to adapt towards binding a variety of surfaces may, in some cases such as this, result in a gain of function. One motif may have a 'targetable weakness' that others don't have.

"This concept may help people understand why drugs designed using "lock and key" principles often fail in clinical trials if they encounter different structural forms of the protein they were made to attack. Once the blueprints change, a promising drug may not have the desired impact.

"In a way, we are witnessing an analogous rapid variation in protein structure during this COVID-19 pandemic, albeit through the sampling of mutation space. Although not an intrinsically disordered protein, the spike protein (S-protein) of the virus is continuously varying its thermodynamic stability or allowing it to be processed more readily by our cells - in other words, it is practising a kind of conformational fluidity."