Culture

Several organisms possess "ion channels" (gateways that selectively allow charged particles called ions to enter the cells and are integral for cell function) called "channelrhodopsins," that can be switched on and off with the help of light. Different channelrhodopsins respond to different wavelengths in the light spectrum. These channels can be expressed in foreign organisms (animals even in human) by means of genetic engineering, which in turn finds applications in optogenetics, or the application of light to modulate cellular and gene functions. So far, the shortest wavelength that a channelrhodopsin responds to was blue.

However, recently, a group of scientists from the Nagoya Institute of Technology, Japan, and Jawaharlal Nehru University, India, have identified a channelrhodopsin that responds to an even shorter indigo blue wavelength of light. In their study published in Nature's Communications Biology, the group of researchers, led by Professor Hideki Kandori and Associate Professor Satoshi P. Tsunoda, identified a novel channelrhodopsin, which they named KnChR, from a species of terrestrial alga called Klebsormidium nitens. "We chose this alga, because it is known to be responsive to light, but its photoreceptor domain has not been established," reports Prof. Kandori. Unlike other discovered channelrhodopsins, KnChR was found to respond to indigo blue light (see Figure 1).

It is known that KnChR is made up of a seven-cell membrane spanning region, which forms the pore that allows the entry and exit of different ions. This region is followed by a protein moiety including a peptidoglycan binding domain. In order to investigate the properties of KnChR, the researchers performed extensive genetic and electrophysiological experiments.

What was perhaps the most exciting result was that they could identify the role of the "cytoplasmic domain." All known channelrhodopsins have a large "cytoplasmic domain," or region that is located in the internal area of the cell. As Prof. Kandori explains, "All currently known channelrhodopsins comprise a large cytoplasmic domain, whose function is elusive. We found that the cytoplasmic domain of KnChR modulates the ion channel properties."

Accordingly, the results of the experiments showed that changing the lengths of the cytoplasmic domain caused the changes in ion channel closure. Particularly, the shortening of the domain resulted in increased channel 'open time' by more than ten-fold. In addition, the researchers also identified two arginine amino acid residues, namely R287 and R291, in the same region, which played an important role in the properties of generated light currents. They found that KnChR exhibited maximal sensitivity at 430 nm and 460 nm, making it the 'bluest' channelrhodopsin (see Figure 2).

Overall, the researchers have faith in the KnChR being helpful in biological systems requiring specific excitation parameters. When asked about the implications of these findings, Prof. Tsunoda, who is the corresponding author of the study suggests, "KnChR would expand the optogenetics tool kit, especially for dual light applications when short-wavelength excitation is required." What this means is that the light-operated property of KnChR can be applied in targeted manipulation of an organism's biological functions, in a research setting. A few examples would include manipulation of neuronal and myocyte activities.

Indeed, we can hope that the scope of this discovery would expand beyond the laboratory into real-world applications. These real-world applications could include cure for Alzheimer's disease and heart diseases, light therapy for recovery from depression, and visual restoration.

Monash University researchers have uncovered for the first time the reason mutations in a particular gene lead to mitochondrial disease.

The finding, published in PNAS journal and led by Professor Mike Ryan from Monash University's Biomedicine Discovery Institute, shows that a gene responsible for causing loss of vision and hearing, TMEM126A, makes a protein that helps build an important energy generator in mitochondria. So, if this gene is defective, it reduces mitochondrial function and impares energy production, uncovering why mutations lead to the disease.

Mitochondria are critical structures within living cells that play a central role in energy conversion and their job is to process oxygen and take in the sugars and proteins from the food we eat to produce the energy our bodies need to function properly. Mitochondria produce 90 per cent of the energy our body needs to function.

Mitochondrial disease is an inherited, chronic illness that can present at birth or develop later in life and occurs when mitochondria fail to produce enough energy for the body to function properly. The cells of the optic nerve and the inner ear are particularly sensitive to mitochondrial defects due to the high energy requirements to transfer information to the brain, but Mitochondrial diseases can affect almost any part of the body.

Using a combination of cutting-edge technologies, the study found that loss of TMEM126A results in an isolated complex I deficiency - a common form of mitochondrial disease where a critical enzyme called complex I is reduced - and that the TMEM126A protein binds to a number of complex I subunits and additional proteins that help build the enzyme, known as assembly factors.

"Now we know that TMEM126A is important in helping to build this protein needed to provide energy for the mitochondria organelles, we can look at future therapies that can perhaps bypass TMEM126A function and find other ways to help cells make energy," Professor Ryan said.

First author Dr Luke Formosa adds: "Now that we know what TMEM126A does in mitochondria, we can start to investigate treatments that might work for individuals with mutations in this gene, which could lead to less severe loss of vision and hearing."

Read the full paper in PNAS journal titled: Optic atrophy-associated TMEM126A is an assembly factor for the ND4-module of mitochondrial complex I

Journal

Proceedings of the National Academy of Sciences

DOI

10.1073/pnas.2019665118

Portopulmonary hypertension (PoPH) is a form of pulmonary arterial hypertension (PAH). PoPH occurs in approximately 15% of patients with PAH, and is reportedly found in 2-6% of patients with portal hypertension and 1-2% of patients with liver cirrhosis according to studies from Europe and America. However, the real-world data on PoPH in Japan are largely unknown, with many questions on the condition's etiology and prevalence.

Led by doctorate student Shun-ichi Wakabayashi of Shinshu University, the goal of this investigation is to clarify the actual state of PoPH among patients with chronic liver disease by screening all such patients treated at Shinshu University Hospital.

Although there is considerable uncertainty on the impact of PoPH, it is known that the prognosis of liver disease becomes poor when PoPH is also present. As there are no symptoms specific to PoPH and patients with chronic liver disease may exhibit symptoms similar to PoPH with disease progression, a brief but reliable questionnaire is needed to identify accompanying PoPH.

The corresponding author of the study, associate professor Satoru Joshita, states, "In this single-center study, we will clarify the frequency, etiology, and pathophysiology of PoPH by screening all patients with chronic liver disease for PoPH at our institution. We seek to clarify the risk factors for PoPH onset to ultimately improve the prognosis of PoPH patients by early diagnosis and timely treatment."

This research will be conducted as a joint endeavor by the Departments of Gastroenterology and Cardiovascular Medicine of Shinshu University School of Medicine, and will run until October 30, 2027.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249435

Examples of complex systems exist everywhere. Neuron connections and protein-protein interactions are two systems of this type found in organisms, but complex systems also exist in cities, economic models, and even in social networks. The common denominator is that they are made up of many interrelated elements which can be represented and studied as a network.

For more than a decade, scientists have been studying the possibility of finding more than one type of structural organization within a single network, and this is the subject of the doctoral thesis defended by María José Palazzi, as part of the UOC's doctoral programme in Network and Information Technologies.

"The idea was to identify and explore the existence of more than one structural pattern within a single network. We wanted to see to what degree this could be an anecdotal or frequent event in real-life networks, and to try to understand some of the mechanisms that cause this type of structure to emerge," explained Palazzi, a researcher with the research group Complex Systems (CoSIN3) at the UOC's Internet Interdisciplinary Institute (IN3). Palazzi's thesis was supervised by Javier Borge, lead researcher of CoSIN3, and co-supervised by fellow researcher Albert Solé, professor at the Faculty of Computer Science, Multimedia and Telecommunications.

The researchers analysed several real-life cases. One of these involves patterns of interaction between users and so-called "memes" in online environments, and the way these change over time. Specifically, the researchers focused on Twitter and used hashtags to help them analyse these data.

Palazzi studied on Twitter, among other events, the 2019 Spanish general elections and the Charlie Hebdo attack in 2015. For the elections, she retrieved over 30 million tweets from more than 1.8 million users and more than 124,000 hashtags from among all the content posted online between 12 April and 6 May 2019. For the Twitter activity linked to the Charlie Hebdo attack, she looked at over six million tweets from more than 2 million users and more than 102,000 hashtags posted on 8 and 9 January 2015.

"The system tends to be organized in a modular structure, with an internal hierarchy that normally responds to the different interests of users," said Palazzi. For example, when a news item goes viral, the system reorganizes itself into a nested structure in which the elements with few connections ("specialists") form subsets with other elements with more connections ("generalists").

The specialists, who are less active on the social network, only interact with the generalists, but the generalists, who are more active and post tweets more frequently, may also interact with other generalists. Once interest in the event has waned, the system reverts to its normal modular organization.

Another of the real-life cases involved the study of the patterns that emerge from interactions between software developers and the data files that make up a free software project. "We found that the patterns evolve into a block or modular structure and that, as the project progresses, these modules are organized internally in a hierarchical way," explained Palazzi.

A breakthrough in network analysis

The contribution of this thesis to the field of study is a breakthrough in the structural analysis of networks. "There was a small gap in our understanding of the conditions required for the coexistence of macro-scale, network-wide patterns such as nestedness, and modularity, which is mesoscale, the groups that make up the network," summed up Palazzi.

The neutron reflexometry method has given scientists an atomic-level insight into the behaviour of Bcl-2, a protein that promotes cancerous cell growth. The new study was carried out by Umeå chemists in collaboration with the research facilities ESS and ISIS and is published in Nature Communications Biology.

Elevated function of the cell-protecting membrane protein Bcl-2 can promote cancer and cause resistance to cancer treatment. Developing an understanding of the way it does this could inform the development of anti-cancer drugs.

It may seem counter-intuitive, but cell death is crucial to overall health, and is managed by a series of proteins from the Bcl-2 family. These proteins work together at the membrane surface of intracellular organelles - the mitochondria - to determine a cell's wellbeing. However, overproduction of the cell-protecting Bcl-2 members can interrupt this delicate balance and inhibit signals for cell death. This can cause cancerous cells to continue to grow, and not respond to cancer treatment.

However, how cell-protecting and cell-killing proteins of the Bcl-2 family interact with one another in their intracellular membrane environment is not fully understood, since a picture of their structure and behaviour in this environment was not available.

In this study, the researchers used the novel combination of neutron reflectometry (NR) and NMR spectroscopy to study full-length human Bcl-2 protein located in its unique membrane environment, providing insight into the key structural and dynamic features.

Also partner in the research collaboration is European Spallation Source (ESS), an international Big Science facility currently under construction in Lund, Sweden, that will use neutrons for materials research within e.g. structural chemistry. Dr Hanna Wacklin-Knecht, ESS and Physical chemistry Division at Lund University, has contributed with expertise to optimize samples and experiment conditions as well as providing the deuterated lipids for the follow-up studies on the function of Bcl-2s that have been conducted later.

"The project with Professor Gröbner is an excellent example of how close collaboration with the research facilities ESS and ISIS helps new research groups to use neutrons in their pioneering research and prepares them to become early users of ESS. The collaboration was made possible thanks to the Swedish Research Council's specially targeted project grants to promote neutron research in Sweden," says Hanna Wacklin-Knecht, ESS Life Scientist.

The NR experiments were performed in collaboration with Dr Luke Clifton at the ISIS Neutron and Muon Source research facility in Oxfordshire, England on one of the leading instruments in the world for this type of experiment. These studies made it possible for the Umeå researchers to determine the relative distribution of Bcl-2 protein across the membrane. The results showed that the protein is in the membrane rather than on the surface, as previously thought.

The NMR experiments looked at individual protein segments and their behaviour in the membrane, and suggest that the part of the protein that acts as a molecular switch is on, or close to, the membrane interface. However, the main protein body that blocks cell-killing partners is restricted within the membrane. The researchers' results have led to a significant breakthrough in the understanding of how Bcl-2 exerts its cell-protective function at the membrane level by simply inhibiting cell-killing proteins there.

"We have discovered the location and behaviour of the Bcl-2 protein in its native membrane. It is a breakthrough, not only in understanding the molecular cell-protecting function of Bcl-2, but also its notorious role in cancers, thereby making this protein a prime target in the hunt for novel cancer therapies," says Professor Gerhard Gröbner, Department of Chemistry at Umeå University.

In future experimental studies, Gerhard Gröbner hopes to discover how the position of Bcl-2 in the membrane is related to the way that it prompts cell death.

"Together, we now plan to unravel the active state of Bcl-2 protein when caught in the act of binding cell-killing proteins at the membrane."

During the last 30 years, medical and dental research has attracted a large number of scientists and practitioners working on aspects of high medical relevance that involve a combination of genetic and tissue regeneration approaches. These developments in stem cell and tissue engineering have provided medical and dental researchers with new insights and given rise to new ideas as to how everyday clinical practice can be improved. Many research groups are dealing with questions like: How can we help injured tissues and organs heal? Can lost tissue be regenerated? How can we create solid protocols that apply across all stem cell therapies?

Advanced single-cell sequencing technology used

A team of researchers led by Thimios Mitsiadis, professor at the Institute of Oral Biology at the University of Zurich, and Dr. Andreas Moor, professor at the Department of Biosystems Science and Engineering at ETH Zurich, has now created the first-ever single cells atlas of the human teeth. By using advanced single-cell sequencing technology, they were able to distinguish every single cell that is part of the dental pulp and the periodontium. "Our study provides an unprecedented understanding of the composition of these two tissues, which are subject to tooth-specific and bacterially-linked pathologies such as caries and periodontitis. Both the dental pulp and the periodontium contain stem cells that possess a great regenerative potential," states first co-author Pierfrancesco Pagella, senior researcher in Mitsiadis' team.

The study identified great cellular heterogeneity in the dental pulp and the periodontium. Unexpectedly, the team found that the molecular signatures of the stem cell populations were very similar. "We think their different behavior is possibly brought about by their distinctive microenvironment," says Pagella. The findings suggest that the microenvironmental specificity is the potential source of the major functional differences of the stem cells located in the various tooth compartments.

New cell-based dental therapies possible

The study demonstrates the complexity of dental tissues and represents a major contribution to a better understanding of the cellular and molecular identity of human dental tissues. "Single-cell approaches can help us understand the interactions of dental pulp and periodontal cells involved in immune responses upon bacterial insults. Therefore, single-cell analysis could be useful for diagnostic purposes to support the early detection of dental diseases," last author Thimios Mitsiadis explains. The findings thus open up new avenues for cell-based dental therapeutic approaches.

According to Mitsiadis, these advances in dental research can lead to more appropriate therapies, successful regeneration of damaged parts of the teeth, and even more precise diagnostic tools in case of dental pathologies. "These innovations are the consequence of the fusion between bioinformatics and modern dentistry," he concludes.

For a long time, historical linguists have been using the comparative method to reconstruct earlier states of languages that are not attested in written sources. The method consists of the detailed comparison of words in the related descendant languages and allows linguists to infer the ancient pronunciation of words which were never recorded in any form in great detail. That the method can also be used to infer how an undocumented word in a certain language would sound, provided that at least some information on that language, as well as information on related languages is available, has been known for a long time, but so far never explicitly tested.

Two researchers from SOAS University of London and the Max Planck Institute for the Science of Human History have recently published a paper in the renowned international journal for historical linguistics, Diachronica. In the article, they describe the results of an experiment in which they applied the traditional comparative method to explicitly predict the pronunciation of words in eight Western Kho-Bwa linguistic varieties spoken in India. Belonging to the Trans-Himalayan family (also known as Sino-Tibetan and Tibeto-Burman language family), these varieties have not yet been described in much detail and many words had not yet been documented in field work. The scholars started their experiment with an existing etymological dataset of Western Kho-Bwa varieties that was collected during fieldwork in the Indian state of Arunachal Pradesh between 2012 and 2017. Within the dataset, the authors observed multiple gaps in which the word forms for certain concepts were missing.

"When conducting fieldwork, it is inevitable that you miss out on some words. It's kind of annoying when you observe that afterwards, but in this case, we realized that this was the perfect opportunity to test how well the methods for linguistic reconstruction actually work," says Tim Bodt, first author of the study.

The researchers set up a computer-assisted workflow to predict the missing word forms. The classical methods are traditionally applied manually, but the new computational solutions helped the scholars to increase the efficiency and reliability of the process, and all results were later manually checked and refined. To increase the transparency and validity of the experiment, they then registered their predictions online.

"Registration is incredibly important in many scientific fields because it ensures that researchers adhere to good scientific practice, but as far as we know it has never been done in historical linguistics," says Johann-Mattis List, who carried out the computational analyses of the study.

"By registering our predictions online, we made sure we could no longer modify our predictions in light of the results we obtained during our subsequent verification process," Bodt, adds.

With predictions in hand, Bodt then traveled to India to verify the predicted words with native speakers of the Western Kho-Bwa languages. After asking the participating local language consultants to provide their words for the concepts under investigation, the authors compared these attested words with their earlier predictions. Based on the proportion of correctly predicted sounds per word form, the predictions were correct in 76% of all cases, which is remarkable given the limited amount of information that was used to predict the word forms. Moreover, the scholars were able to identify several reasons why certain predictions did not match the actual attested forms in the languages.

"The more we know about a language family in general, the better we can predict unknown word forms. This is all possible, because languages change their sound systems in a surprisingly regular manner," says List. "Despite the fact that so little was known about the Western Kho-Bwa languages and their linguistic history, we were able to show through our experiment that regular sound changes result in predictable word forms. In turn, our experiment has greatly improved our understanding of the Western Kho-Bwa languages and their linguistic history."

Apart from giving a concrete example for the power of the methodology of historical linguistics and the value of their experiment for linguistic studies, the authors identify certain additional benefits of predicting words in linguistic research.

"Predicting words increases the transparency and efficiency of our research and our fieldwork. This is crucial in light of rapid language loss and limited funding for descriptive linguistic work. Moreover, it also has an educational aspect since it encourages speakers to reflect on their own linguistic heritage," says Bodt.

The researchers hope that the results of their ground-breaking experiment will encourage other linguistic field workers, descriptive linguists, and historical linguists to follow suit, and make more explicit and conscious use of the regularity of sound change and predictions of word forms.

Scientific studies rarely focus on long non-coding RNA molecules (lncRNAs), even though they potentially regulate several diseases. The role of several lncRNAs in anti-viral inflammatory response regulation has recently been reported. Considering their significant regulatory function in immune response, researchers from the Azrieli Faculty of Medicine of Bar-Ilan University sought to identify lncRNAs co-expressed with human genes involved in immune-related processes during severe SARS-CoV-2 infection in the lungs.

Recent studies demonstrated that patients afflicted with severe SARS-CoV-2 infections present increased levels of pro-inflammatory plasma cytokines, as opposed to milder cases, highlighting the release of inflammatory cytokines as being central to COVID-19 severity. However, the underlying molecular mechanisms responsible for dysfunctional immune responses during COVID-19 infection remain elusive.

In a paper recently published in the journal Viruses, the researchers demonstrated that lncRNAs are indeed potential regulators of anti-viral response during severe SARS-CoV-2 infection. Using the available transcriptome data from the lung cells of severely affected COVID-19 patients and SARS-CoV-2 infected lung-cell-lines, they constructed a gene co-expression network that can measure the relationship of gene expression patterns across a group of samples. This analysis enables them to identify four differentially expressed lncRNAs that are found to be strongly correlated to the protein-coding genes in a novel network enriched for different immune-related processes associated with dysregulated cytokine production. These four lncRNAs were also identified as "hubs" - important nodes in this co-expression network, signifying their association with cytokine over-production due to fierce immune response.

The finding suggests that the aberrant expression of lncRNAs can be associated with cytokine storms and anti-viral responses during severe SARS-CoV-2 infection. Thus, the present study uncovers the potential associations of lncRNAs in cytokine and interferon signaling during the response to severe SARS-CoV-2 infection in the lungs. This could provide valuable insight into pro-inflammatory cytokine production and how to mitigate it. It could also potentially be utilized as a future drug target to combat the hyper-inflammation caused by SARS-CoV-2 infection.

"It is remarkable that a major part of the human genome is filled in by non-coding regulatory elements, formerly known as "junk DNA". Among these are the long non-coding RNAs (lncRNAs). These lncRNAs are receiving more and more recognition as the potential regulators of several diseases," says Dr. Milana Frenkel-Morgenstern, of Bar-Ilan University's Azrieli Faculty of Medicine, who led the study with Prof. David Karasik.

This study sheds light on the mechanisms behind COVID-19 severity and dysfunctional immune responses. Understanding the molecular interactions behind the immune dysfunction during severe COVID-19 infection in the lungs should help inform the design and development of novel approaches for treating severe COVID-19 patients.

The researchers plan to validate their findings on human samples in collaboration with several of Israel's health care centers. Further, they will aim to determine which drugs from their COVID-19 drug database may inhibit the cytokine storm generation in COVID-19, and will design experiments to test the efficacy of those drugs.

This study was supported by a grant from the COVID-19 Data Science Institute (DSI) at Bar-Ilan University and a PBC fellowship for outstanding postdoctoral researchers from China and India (to Dr. Sumit Mukherjee, who participated in the research) from the Israel Council for Higher Education.

COLUMBUS, Ohio - A new treatment is among the first known to reduce the severity of acute respiratory distress syndrome caused by the flu in animals, according to a new study.

Tests in mice infected with high doses of influenza showed that the treatment could improve lung function in very sick mice and prevent progression of disease in mice that were pre-emptively treated after being exposed to the flu.

The hope is that it may also help humans infected with the flu, and potentially other causes of acute respiratory distress syndrome (ARDS) such as SARS-CoV-2 infection.

Specific cells in mice are less able to make key molecules after influenza invades the lungs, reducing their ability to produce a substance called surfactant that enables lungs to expand and contract. The shortage of surfactant is linked to ARDS, an illness so serious that it typically requires mechanical ventilation in an ICU.

Researchers bypassed the blocked process in mice by re-introducing the missing molecules alone or in combination as an injected or oral treatment. The results: normalized blood oxygen levels and reduced inflammation in mouse lungs - effects that could make a person well enough for hospital discharge.

"The most important and impressive thing in this study is the fact that we have benefits even when we treat late in the disease process. If we could develop a drug based on these findings, you could take somebody who's going to have to go on a ventilator and stop that completely," said Ian Davis, professor of veterinary biosciences at The Ohio State University and senior author of the study. "There's nothing out there now that can do this for ARDS that will bring them back to that degree, and certainly not for flu."

ARDS can also result from infections, cancer, trauma and many other ailments. Though this therapy has been tested in the context of the flu, Davis said its reliance on fixing a broken cell function in the host rather than killing the virus suggests it has potential to treat virtually any lung injury.

The study was published online recently in the American Journal of Respiratory Cell and Molecular Biology.

The experimental treatment consists of molecules known as liponucleotides, which are essential for making surfactant in the lungs. Davis analyzed lung cells from flu-infected mice and determined that the pathway to surfactant production was disrupted, with one of the two necessary liponucleotides completely undetectable.

"The thinking before was that the reason there was less surfactant in mice with flu-related ARDS was because cells are dying. This defect is in some ways better - if cells are dying, there's not much you can do, but if there's a problem with the cell's metabolism, maybe you can fix it," Davis said.

And fix it - in mice - he did, developing therapies containing the missing liponucleotide molecule alone or combined with one or two others.

Davis and colleagues inoculated mice with high doses of H1N1 influenza and then treated some mice with liponucleotides once daily for five days and others just a single time five days after exposure. The mice receiving daily treatment were protected from getting seriously ill, and the very sick mice treated on the fifth day, whose severe blood-oxygen loss and lung inflammation had cause ARDS, showed significant improvement.

"Obviously that's what you need in someone with severe influenza - we want to take someone who is already in the ICU and help them get out faster, or head going to the ICU off at the pass," Davis said.

Liponucleotides don't kill the flu virus - which is the point.

"I've always been interested in finding new therapies to treat lung injury," he said. "The problem with anti-viral drugs is you probably need a different drug for every virus. Also, many viruses can quickly mutate to become resistant to these drugs.

"Our approach is to fix the patient. Once the virus has caused the injury - the inflammation - it doesn't really matter if it stays or goes away."

There's still a lot to learn. The agents have a strong anti-inflammatory effect, but don't fully restore the surfactant-production process - and Davis isn't sure why that is. Studies so far have been based on findings in a single type of lung cell, but the scientists haven't confirmed that those cells are the ones responding to the therapy - any number of other cells in the immune system, blood vessels or heart could also play a role.

Despite the unknowns, Davis said that because the missing liponucleotides naturally exist in mammals, including humans, they are considered safe and unlikely to cause side effects, even if they go unused in the body.

The Ohio State Innovation Foundation has filed patents covering the scope of Davis' discoveries, which may also extend to patients suffering from other forms of lung damage that cause inflammation and a drop in blood oxygen levels.

A research group led by Professor Xiang David LI from the Research Division for Chemistry and the Department of Chemistry, The University of Hong Kong, has developed a novel chemical tool for elucidating protein interaction networks in cells. This tool not only facilitates the identification of a protein's interacting partners in the complex cellular context, but also simultaneously allows the 'visualisation' of these protein-protein interactions. The findings were recently published in the prestigious scientific journal Molecular Cell.

In the human body, proteins interact with each other to cooperatively regulate essentially every biological process ranging from gene expression and signal transduction, to immune response. As a result, dysregulated protein interactions often lead to human diseases, such as cancer and Alzheimer's disease. In modern biology, it is important to comprehensively understand protein interaction networks, which has implications in disease diagnosis and can facilitate the development of treatments.

To dissect complex protein networks, two questions need to be answered: the 'who' and 'how' of protein binding. The 'who' refers to the identification of a protein's interacting partners, whereas the 'how' refers to the specific 'binding regions' that mediate these interactions. Answering these questions is challenging, as protein interactions are often too unstable and too transient to detect. To tackle this issue, Professor Li's group has previously developed a series of tools to 'trap' the protein-to-protein interactions with a chemical bond. This is possible because these tools are equipped with a special light-activated 'camera' - diazirine group that capture every binding partner of a protein when exposed to UV light. The interactions can then be examined and interpreted. Unfortunately, the 'resolution' of this 'camera' was relatively low, meaning key information about how proteins interact with each other was lost. To this end, Professor Li's group has now devised a new tool (called ADdis-Cys) that has an upgraded 'camera' to improve the 'resolution'. An alkyne handle installed next to the diazirine makes it possible to 'zoom in' to clearly see the binding regions of the proteins. Coupled with state-of-the-art mass spectrometry , ADdis-Cys is the first tool that can simultaneously identify a protein's interacting partners and pinpoint their binding regions.

In the published paper, Professor Li's lab was able to comprehensively identify many protein interactions -- some known and some newly discovered -- that are important for the regulation of essential cellular processes such as DNA replication, gene transcription and DNA damage repair. Most importantly, Professor Li's lab was able to use ADdis-Cys to reveal the binding regions mediating these protein interactions. This tool could lead to the development of chemical modulators that regulate protein interactions for treating human diseases. As a research tool, ADdis-Cys will find far-reaching applications in many areas of study, particularly in disease diagnosis and therapy.

The researchers in this study reached this conclusion by drawing on network modelling research and mapped the job landscapes in cities across the United States during economic crises.

Knowing and understanding which factors contribute to the health of job markets is interesting as it can help promote faster recovery after a crisis, such as a major economic recession or the current COVID pandemic. Traditional studies perceive the worker as someone linked to a specific job in a sector. However, in the real-world professionals often end up working in other sectors that require similar skills. In this sense, researchers consider job markets as being something similar to ecosystems, where organisms are linked in a complex network of interactions.

In this context, an effective job market depends on many aspects, such as diversity and the number of job offers or training opportunities that workers have in order to acquire new skills, for example. In this scientific study, researchers have found that cities where all of these factors are very similar respond differently in regard to recovering from an economic crisis. Why? "We have discovered that the difference comes, in part, from the jobs 'map', a network that tells us how jobs within a city are related, according to the similarity of the skills required to perform those jobs," explains Esteban Moro, an associate professor at the UC3M's Department of Mathematics and co-author of the study, who is currently a visiting professor at the MIT Media Lab.

"When that map is extremely limited, in other words, when there is very little chance of finding another similar job (what we call "job connectivity"), cities are less prepared for a job crisis. In contrast, when that map offers lots of possibilities of moving from one job to another similar one, the city is better prepared. It also has an effect on workers' wages: workers in cities that have a more diverse network earn more than those in the same occupation in cities where this network is more limited," adds Esteban Moro.

Ecology, complex networks and job connectivity

In ecology and other domains where complex networks are present, resilience has been closely linked to the "connectivity" of the networks. In nature, for example, ecosystems with lots of connections have proven to be more resistant to certain shocks (such as changes in acidity or temperature) than those with fewer connections. Inspired by this idea and drawing on previous network modelling research, the authors of the study modelled the relationships between jobs in several cities across the United States. Just as connectivity in nature fosters resilience, they predicted that cities with jobs connected by overlapping skills and geography would fare better in the face of economic shock than those without such networks.

In order to validate this, the researchers examined data from the Bureau of Labor Statistics for all metropolitan areas in the US from the beginning to the end of the Great Recession (2008-2014). Based on this data, they created maps of the job landscape in each area, including the number of specific jobs, their geographical distribution, and the extent to which the skills they required overlapped with other jobs in the area. The size of a given city, as well as its employment diversity, played a role in resilience, with bigger, more diverse cities obtaining better results than smaller and less-diverse ones. However, by controlling size and diversity and taking job connectivity into account, predictions of peak unemployment rates during the recession improved significantly. In other words, cities where job connectivity was higher before the crash were significantly more resilient and recovered faster than those with less-connected markets.

Even in the absence of temporary crises like the Great Recession or the COVID pandemic, phenomena, such as automation, might radically change the job landscape in many areas in the coming years. How can cities prepare for this disruption? The researchers in this study extended their model to predict how job markets would behave when facing job loss due to automation. They found that while cities of similar sizes would be affected similarly in the early stages of automation shocks, those with well-connected job networks would provide better opportunities for displaced workers to find other jobs. This prevents widespread unemployment and, in some cases, even leads to more jobs being created as a result of the initial automation shock.

The findings of this study suggest that policymakers should consider job connectivity when planning for the future of employment in their regions, especially where automation is expected to replace a large number of jobs. Furthermore, increased connectivity does not just result in lower unemployment, it also contributes to a rise in overall wages. These results provide a new perspective on discussions about the future of employment and may help guide and complement current decisions about where to invest in job creation and training programmes, say researchers.

During the Bronze Age, Mesopotamia was witness to several climate crises. In the long run, these crises prompted the development of stable forms of State and therefore elicited cooperation between political elites and non-elites. This is the main finding of a study published in the journal PNAS and authored by two scholars from the University of Bologna (Italy) and Eberhard Karls Universität Tübingen (Germany).

This study investigated the impact of climate shocks in Mesopotamia between 3100 and 1750 bC. The two scholars looked at these issues through the lenses of economics and adopted a game-theory approach. They applied this approach to the first detailed database on climate and institutional evolution of the 44 most important states of Mesopotamia.

"Severe and prolonged droughts pushed elites of landowners to grant political and property rights to the non-elites, who had the skills and tools to stem the damages brought by climate change. Elites did so to persuade non-elites that a sufficient part of the crops would be shared through the production of public goods", explains Carmine Guerriero, a professor at the Department of Economics at the University of Bologna and one of the authors of this study. "On their end, non-elites promoted institutional changes, embracing a culture of cooperation to persuade elites of their commitment to future cooperations".

Three severe droughts seem to confirm these intuitions. In the last stages of the Urban Revolution (3800-3300 b.C.), religious groups stepped in and eventually coordinated the effort of building the first human-made canals. Then, during the Protodynastic Period (3100-2550 b.C.), the Palatine military promoted the cooperation between farmers, granting them protection and the resources of the military enlistment. During the Imperial Period (2350-1750 b.C.), a valuable and climate shock-independent alternative to agricultural activities was put forward by corporations of merchants that had increasingly taken hold. Conversely, periods of milder climate promoted the cooperation between non-elites and elites while elites were not forced to give up their power and non-elites were not obliged to adopt a culture of intense cooperation.

"Because of their primarily agricultural economic systems, some developing countries are experiencing climate change in a way that resembles that of Mesopotamian States, and they will also experience politically relevant consequences", adds Guerriero. "On the one hand, unfavourable climate shocks can promote cooperation between normally contrasting parties by granting more rights to non-elites. On the other hand, favourable climate conditions allow for the cooperation between elites and non-elites through less inclusive social orders and with some degree of cultural accumulation. Therefore, two major objectives in this sense are spreading a strong culture of cooperation and avoiding the random transfer of more inclusive social orders in developing countries".

All in all, analyzing events concerning lost civilizations can offer useful insights to understand and solve issues of present times. "The past offers a more encouraging perspective against which we can measure the gravity of today's crises including the pandemic", suggests Guerriero. "Moreover, the past shows the importance of an interdisciplinary approach involving social and natural sciences to obtain a more precise evaluation of short-, medium- and long-term effects of climate change".

This paper appeared in the journal PNAS with the title "Climate Change and State Evolution". It reports about a research project funded by the Alma Idea Programme of the University of Bologna and the Programme for Young Researchers "Rita Levi Montalcini". The authors are Giacomo Benati, Eberhard Karls Universität Tübingen, and Carmine Guerriero, University of Bologna. Federico Zaina (Research Fellow at the Department of Architecture, Construction and Constructed Environment Engineering of the Polytechnic University of Milan) and Laura Righi (Research Fellow at John XXIII Foundation of Religious Sciences) also took part in the study.

CHAMPAIGN, Ill. -- People up to age 40 living in economically depressed municipalities in the Greater Santiago, Chile, metropolitan area were three times more likely to die as a result of the infection than their counterparts in wealthier areas, researchers report in the journal Science. People ages 41-80 in low socioeconomic-status municipalities also suffered more from the pandemic than their peers in more affluent areas, the team found.

The study used new methods to analyze COVID-19 death counts, reported cases, testing rates and delays in testing results across location, time and age group. The results reveal striking disparities between high and low socioeconomic-status municipalities, and also help explain the factors that contribute to differences in COVID-19-related infections and mortality in these regions, said Pamela Martinez, a professor of microbiology and of statistics at the University of Illinois Urbana-Champaign who led the research with Gonzalo Mena, a postdoctoral fellow at the University of Oxford.

Greater Santiago is composed of 34 municipalities and is home to nearly 7 million people. The researchers used anonymized mobile phone data available through the Facebook Data for Good initiative to assess residents' mobility during the pandemic.

"People living in municipalities with low socioeconomic status did not reduce their mobility during lockdowns as much as those in more affluent municipalities," the researchers wrote. "This supports the hypothesis that people in poorer regions cannot afford to stay at home during lockdowns."

Access to COVID-19 testing and health care services in lower-income communities also appear to have contributed to the observed differences in health outcomes, the researchers report.

In the early weeks of the pandemic, COVID-19 testing was more available to people in the affluent parts of the metropolitan area than in the poorer locations, the researchers found. People in less affluent regions also appear to have waited longer for their test results.

"Because public health authorities plan their response based on the number of reported infections in a given area, this led to a poorer health care response in lower income areas than was needed," Martinez said. "This likely contributed to higher death counts in those areas."

This dynamic changed somewhat a few months into the pandemic - with testing ramping up in the poorer areas by late August, but the disparities in testing availability continued from mid-March to the end of September, the time period assessed.

"The Greater Santiago metropolitan area experienced more than 70% more deaths between May and July 2020 than in previous years, and places at the lower end of the socioeconomic spectrum were affected the most," Martinez said.

Access to health care also was less abundant in the economically depressed areas, another contributor to worse health outcomes there, the researchers report.

"We found that the south and west zones of the Greater Santiago metropolitan area had four times fewer beds per 10,000 residents and four times fewer people enrolled in the private health system than the east zone, which includes all of the most affluent municipalities," Martinez said. "We also discovered that more than 90% of the deaths attributed to COVID-19 in the south and west zones occurred in places other than health care facilities."

In the more affluent east zone, 55% of COVID-19-attributed deaths occurred outside health care facilities, she said.

Perhaps most strikingly, the team found that people under the age of 40 in less affluent parts of the region experienced significantly higher COVID-19-related mortality than their peers in wealthier areas.

"The infection-fatality rate for people 0-40 years old was 3.1 times higher in municipalities with the lowest socioeconomic status," Mena said. "Our results show that the socioeconomic inequalities we documented disproportionately affected younger people."

Understanding how demographic and socioeconomic factors contribute to health outcomes is essential to designing health care responses, the authors wrote.

"Our results align with the recent literature on uneven health risks globally, which has highlighted how socially and economically deprived populations are more vulnerable to the burden of epidemics," they wrote.

Cryopreservation, or the long-term storage of biomaterials at ultralow temperatures, has been used across cell types and species. However, until now, the practical cryopreservation of the fruit fly (Drosophila melanogaster) — which is crucial to genetics research and critical to scientific breakthroughs benefiting human health — has not been available.
“To keep alive the ever-increasing number of fruit flies with unique genotypes that aid in these breakthroughs, some 160,000 different flies, laboratories and stock centers engage in the costly and frequent transfer of adults to fresh food, risking contamination and genetic drift,” said Li Zhan, a postdoctoral associate with the University of Minnesota College of Science and Engineering and the Center for Advanced Technologies for the Preservation of Biological Systems (ATP-Bio).In new research published in Nature Communications, a University of Minnesota team has developed a first-of-its-kind method that cryopreserves fruit fly embryos so they can be successfully recovered and developed into adult insects. This method optimizes embryo permeabilization and age, cryoprotectant agent composition, different phases of nitrogen (liquid vs. slush), and post-cryopreservation embryo culture methods.
Researchers were able to:

show that the method is broadly applicable and easily adopted by non-specialists, with it being successfully implemented in 25 distinct strains for fruit flies from different sources (e.g., laboratories);

demonstrate that for most strains, more than 50% of embryos hatch and more than 25% of the resulting larvae develop into adults after cryopreservation; and

show that flies retain normal sex ratio, fertility and original mutation after successive crypropreservation through generations and long-time storage in liquid nitrogen.

“Our multi-disciplinary team is pleased to contribute an accessible protocol to cryopreserve numerous strains of Drosophila, an important biomedical model, while also hopefully informing other insect and related species embryo preservation,” said study co-author John Bischof, director of the Institute for Engineering in Medicine and a professor in the College of Science and Engineering and Medical School.
As humans share more than half of their genes with the fruit fly, Drosophila research and its implications for human health are significant.
“By studying mutants in the Drosophila model system, it can reveal how those genes function in human development and disease,” said Tom Hays, head of the Department of Genetics, Cell Biology and Development in the Medical School and College of Biological Sciences. "Fly studies have provided crucial insights on human diseases from Alzheimer’s to Zika and revealed genetic pathways and mechanisms underlying embryonic development, olfaction and innate immunity.”
Beyond training individuals in this method, the University of Minnesota team is looking to adapt it to other applications.
"It will be important to understand the genetics that influence cryopreservation in Drosophila and other insects," said study co-author Mingang Li, a research associate in the Department of Genetics, Cell Biology and Development. "This method could support research aimed at pest control for Drosophila suzukii, a fruit fly that infests ripening fruits and has become a pest in the Americas and Europe, as well as for malaria research in Anopheles mosquitoes."
Funding for the research was provided by the U.S. National Institutes of Health, the National Science Foundation, ATP-Bio from the Institute for Engineering in Medicine, and the University’s Doctoral Dissertation Fellowship.

A team of scientists has found that women's football was common across Japan between the Meiji restoration and the start of the Second World War. In the process, they also uncovered the oldest known photograph of women playing football in Japan, from 1916.

The history of men's football in Japan is well documented. In particular, the introduction of association football into Japan in the late 19th and 20th centuries has been extensively investigated. The same degree of attention had not been paid to women's football.

A team of researchers from six institutions, including Associate Professor Yoshihiro Sakita of Hokkaido University's Graduate School of Education, has reported the first study into the history of women's football in Japan. Their findings, published in the journal Japan Journal of Physical Education, Health and Sports Science, focus on the extent and popularity of women's football in pre-war Japan -- the Meiji, Taisho and early Showa eras.

The researchers examined 422 books carrying historical records of 286 public high schools for girls from Hokkaido (northern Japan) to Kyushu (southern Japan). The researchers first focused their attention on whether young women at higher educational institutions, which trained them to become teachers, had instructors, guidance books or extracurricular activities involving football. They then examined how the sport proliferated at the 286 schools to which the female teachers were dispatched, investigating how girls engaged with football--either via the regular curriculum, club activities, free time or athletic meetings--as well as their instructors, uniforms, equipment and rules.

The researchers found 53 of the books (19%) had descriptions or photos of football played by girls from 1902 to 1940. The descriptions, however, included casual play, involving throwing the ball with their hands and competitions to kick the ball highest or furthest--elements which are not features of present-day association football, or soccer. Football was one of the sports enthusiastically adopted at public high schools for girls, especially in the Taisho era (1912-26), just like boys and men eagerly took up the sport in the pre-war period.

The researchers also discovered the oldest photo of women's football in Hundred Years' History, a book published in 1986 detailing the history of the Oita Prefectural Public High School for Girls (now, the Oita Prefectural Oita Uenogaoka High School). The photo was of a match held in 1916. In the archives of the Oita Prefectural Library, they also discovered another photo of girls playing football in 1918. The previously known oldest photos were from picture postcards showing girls playing football at Kagawa Prefectural Marugame Public High School for Girls around 1919-1920. These photos had been reprinted in the Shikoku Shimbun newspaper on December 2, 2011, attracting much public attention at the time.

The researchers plan to expand the scope of their research to higher educational institutions for women and private high schools for women and investigate not only books of historical records but also newsletters for alumni to find more details about women's soccer in prewar Japan.