Culture

BIRMINGHAM, Ala. - Science has long known that recovery from experimental heart attacks is improved by injection of a mixture of heart muscle cells, endothelial cells and smooth muscle cells, yet results have been limited by poor engraftment and retention, and researchers worry about potential tumorigenesis and heart arrhythmia.

Now research in pigs shows that using the exosomes naturally produced from that mixture of heart muscle cells, endothelial cells and smooth muscle cells -- which were all derived from human induced pluripotent stem cells -- yields regenerative benefits equivalent to the injected human induced pluripotent stem cell-cardiac cells, or hiPSC-CCs.

Exosomes are membrane-bound extracellular vesicles that contain biologically active proteins, RNAs and microRNAs. Exosomes are well known to participate in cell-to-cell communication, and they are actively studied as potential clinical therapies.

"The hiPSC-CC exosomes are acellular and, consequently, may enable physicians to exploit the cardioprotective and reparative properties of hiPSC-derived cells while avoiding the complexities associated with tumorigenic risks, cell storage, transportation and immune rejection," said Ling Gao, Ph.D., and Jianyi "Jay" Zhang, M.D., Ph.D., University of Alabama at Birmingham corresponding authors of the study, published in Science Translational Medicine. "Thus, exosomes secreted by hiPSC-derived cardiac cells improved myocardial recovery without increasing the frequency of arrhythmogenic complications and may provide an acellular therapeutic option for myocardial injury."

At UAB, Gao was a postdoctoral fellow in Biomedical Engineering, a joint department of the UAB School of Medicine and the UAB School of Engineering. Zhang is chair of the department.

Studies in large animals are necessary to identify, characterize and quantify responses to potential treatments. Prior to this current study, the feasibility of hiPSC-CC exosomes for cardiac therapy had been shown only in mouse models and in vitro work.

In the UAB experiments, juvenile pigs with experimental heart attacks had one of three treatments injected into the damaged myocardium: 1) a mixture of cardiomyocytes, endothelial cells and smooth muscle cells derived from human induced pluripotent stem cells, 2) exosomes extracted from the three cell types, or 3) homogenized fragments from the three cell types.

The researchers had two primary findings from the pig studies. First, they found that measurements of left-ventricle function, infarct size, wall stress, cardiac hypertrophy, apoptosis and angiogenesis in animals treated with hiPSC-CCs, hiPSC-CC fragments or hiPSC-CC exosomes were similar and significantly improved compared to animals that recovered without any of the three experimental treatments. Second, they found that exosome therapy did not increase the frequency of arrhythmia.

In experiments with cells or aortic rings grown in culture, they found that exosomes produced by hiPSC-CCs promoted blood vessel growth in cultured endothelial cells and isolated aortic rings. Furthermore, the exosomes protected cultured hiPSC-cardiomyocytes from the cytotoxic effects of serum-free low-oxygen media by reducing the programmed cell death called apoptosis and by maintaining intracellular calcium homeostasis, which has a direct beneficial effect on heart conductivity. The exosomes also increased cellular ATP content, which is beneficial since deficiencies in cellular ATP metabolism are believed to contribute to the progressive decline in heart function for patients with left ventricle hypertrophy and heart failure.

The researchers also found that some of these in vitro beneficial effects could also be mediated by synthetic mimics of the 15 most abundant microRNAs found in the hiPSC-CC exosomes. The researchers noted that knowledge of the potential role of microRNAs in clinical applications is still far from complete.

RIVERSIDE, Calif. -- A team of researchers led by biomedical scientist Declan F. McCole at the University of California, Riverside, has found that the drug tofacitinib, also called Xeljanz and approved by the FDA to treat rheumatoid arthritis and ulcerative colitis, can repair permeability defects in the intestine.

"Our work could help improve identification of patients who will be better responders to this drug," said McCole, a professor of biomedical sciences in the School of Medicine.

Study results appear in the Journal of Crohn's and Colitis.

Affecting roughly 1 million Americans, ulcerative colitis, an inflammatory bowel disease, is a chronic disease of the large intestine, in which the lining of the colon becomes inflamed and leaky.

A single layer of cells that plays a critical role in human health, the intestinal epithelium provides a barrier while also allowing nutrient and water absorption. Intestinal epithelial cells are critical for regulating immune function, communicating with the intestinal microbiota, and protecting the gut from pathogen infection -- all of which critically depend on an intact epithelial barrier. The body's largest pool of immune cells can be found directly beneath the epithelial cell layer.

The current study is a follow-up to two recently published studies from McCole's lab. In the first study, published in December 2019, the researchers used a cell culture model system to show that tofacitinib can directly act on epithelial cells that line the gut to correct defects in the barrier properties of these cells that occur in inflammation. The second study, published in July 2020, showed a loss-of-function mutation in the gene "protein tyrosine phosphatase non-receptor Type 2," or PTPN2, disrupted normal beneficial interactions between epithelial cells and macrophages -- a type of white blood cell that constitutes a considerable fraction of intestinal immune cells -- and increased gut leakiness.

In the new study, the authors show tofacitinib can reverse gut leakiness in mice caused by loss of PTPN2 activity. Until now, the effects of tofacitinib on intestinal barrier function in an animal model were largely unknown.

McCole explained that increased intestinal permeability -- or leakiness -- is a feature of inflammatory bowel disease and plays a critical role in promoting inflammation. His team also tested tofacitinib in a system where PTPN2 expression was reduced in human intestinal epithelial cell lines and macrophages that were then cultured together to study the effects on epithelial permeability. The team also studied mice that had increased gut leakiness resulting from removal of PTPN2 only in macrophages. The researchers found tofacitinib repaired inflammation-induced permeability defects in both the cell culture system and in mice.

"Patients with the loss-of-function mutations in PTPN2 have an increased risk of inflammatory bowel disease," McCole said. "Our work improves our understanding of how this drug is useful for treating ulcerative colitis and suggests that patients with loss-of-function mutations in the PTPN2 gene may have a better response to tofacitinib. This could help with improved targeting of drug treatments to specific groups of patients."

210 scientists from around the world highlight the state of the world's plants and fungi in a landmark Plants, People, Planet Special Issue, in collaboration with the Royal Botanic Gardens, Kew

The Special Issue, 'Protecting and sustainably using the world's plants and fungi', brings together the research - from 210 scientists across 42 countries - behind the 2020 State of the World's Plants and Fungi report, also released today by the Royal Botanic Gardens, Kew.

This is the first time that over 200 scientists have come together and collaborated to deliver a vital update, not only on the status of the world's plant life, but also the world's fungi. Humanity's existence and well-being depends on plants and fungi - from our food and energy, to our physical and mental health. The scientists' findings plot a global roadmap that sets out what we must do to protect and sustainably use plants and fungi, now and in the future.

The data and expert opinion behind Kew's report have, for the first time, been published in a landmark Plants, People, Planet Special Issue and are freely available to read and share. This Special Issue points the way forward for future research and conservation efforts around the world for the benefit of people and the sustainable future of our planet. It highlights the strength of researchers working together and the importance of collaboration between scientific journals and botanic gardens like RBG Kew.

"We are delighted to be partnering with Kew to publish the scientific papers behind the State of the World's Plants and Fungi 2020 report," said Prof. Simon Hiscock, Editor in Chief of Plants, People, Planet. "Plants, People, Planet was founded to highlight how fundamentally important plants are to people and all life on Earth. We embrace Kew's transformative agenda to curate, conserve and explore the world's plant and fungal diversity as outlined in this landmark collection," he added.

"The data in this year's report paint a picture of a world that has turned its back on the incredible potential of the plant and fungal kingdoms to address some of the biggest challenges we face," said Professor Alexandre Antonelli, Director of Science at the Royal Botanic Gardens, Kew. "We have particularly earmarked the gaps in our knowledge, the changes we are seeing, the species being named new to science and the shocking pace of biodiversity loss."

"The rigour and collaborative nature of the scientific work underlying the articles in the New Phytologist Foundation's Plants, People, Planet, which accompany the State of the World's Plants and Fungi report, is testimony to the incredible wealth of knowledge that exists and is now being brought to surface," added Professor Antonelli. "This has been a truly fantastic and rewarding collaboration; Plants, People, Planet is a prestigious journal that shares Kew's mission and provides free access to its contents for the benefit of all. I hope this work will help inform decisions here in the UK and all over the world as we start the most critical decade our planet has ever faced".

Using the research included in the Plants, People, Planet Special Issue we can understand and make use of the full extent of plant and fungal diversity while recognising the threats to their survival, so that we can halt biodiversity loss and unlock its full potential.

A new precision drug which stops cancer from repairing its DNA has shown promise in an early-stage clinical trial - highlighting the potential of a new class of drugs known as ATR inhibitors.

The drug candidate, tested in humans for the first time, was shown to be well tolerated and stopped the growth of tumours in over half of patients treated.

People in the trial had a range of advanced, heavily pre-treated cancers including breast, bowel and prostate tumours. It is remarkable to see the new drug - which works by blocking a key molecule called ATR, involved in repairing DNA - showing promising clinical benefit in a phase I trial, in patients who were very sick.

The trial, led by The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, involved 21 patients with advanced solid tumours with defects in various genes which help coordinate DNA repair. Eleven patients had tumours with defects or deletions affecting a key gene called ATM.

The aim of the trial was to evaluate the safety of the ATR inhibitor BAY1895344 and to identify the maximum tolerated dose that could be safely given to a group of cancer patients who had already previously been treated with multiple other drugs.

The researchers found that the drug was well tolerated by patients - and better still, that there were encouraging signs that it was effective against advanced cancers with defects in the ATM gene.

The new results are published in the prestigious journal Cancer Discovery today (Tuesday), and the trial was funded by the manufacturer of the drug, Bayer.

The team found that BAY1895344 stopped tumour growth in eight out of the 21 patients and shrunk the tumours of another four patients with ATM mutations - which is remarkably positive for a phase I trial, since its primary aim is to test the safety of a drug, rather than its effectiveness.

The effectiveness of the drug seemed to be long lasting, with an average period of response of 316 days. In addition, three out of four patients who saw their tumours shrink remained on treatment for more than a year.

The most common side effect reported was anaemia, which was managed with the help of blood transfusions and did not usually require the treatment to be stopped.

The researchers also analysed the biochemical and pharmacological effects of the drug, and were able to show that it exercised its effects in patients by increasing damage to DNA.

DNA damage is the fundamental cause of cancer - leading to mutations in key genes that allow cancer cells to divide uncontrollably. But it can also be a key weakness of tumours that can be exploited, since cancer cells can be killed by further damaging their DNA or stopping them from repairing it.

The new study supports further investigation of a treatment strategy that targets the DNA repair protein ATR, especially in patients whose cancers already have certain defects in DNA repair genes like ATM or BRCA1 - weakening their ability to cope with DNA damage.

Further clinical trials are warranted to further evaluate the safety and efficacy before it can be licensed by a regulatory authority. Clinical trials investigating BAY 1895344 as a single agent or in combination with other drugs are now under way, and the hope is that it could be developed into a new targeted treatment for patients with a variety of cancers with certain defects in DNA repair.

Recently, another phase I trial led by The Institute of Cancer Research (ICR) and The Royal Marsden also showed benefits for an ATR inhibitor (called berzosertib) in patients with very advanced tumours, either on its own or with chemotherapy.

Other cancer drugs that attack DNA repair mechanisms already exist. The ICR pioneered the genetic targeting of the first approved precision medicine attacking cancer's ability to repair DNA, the PARP inhibitor olaparib.

In future, ATR inhibitors may become a new class of targeted drugs that could help overcome resistance to other precision medicines like PARP inhibitors.

The ICR, a charity and research institute, will be focusing on how to overcome drug resistance in its new Centre for Cancer Drug Discovery, which is nearing completion. The ICR is now raising money for the Centre's state-of-the-art equipment, so that researchers in the building can get off to the strongest possible start.

Study leader Professor Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:

"Our new trial shows that this promising new treatment is safe and can benefit some patients even with very advanced cancers.

"The new drug, which is currently known only by the code BAY1895344, works by blocking a molecule called ATR which is involved in repairing DNA. It seems to be especially effective in patients whose tumours have defects in a gene called ATM which mean their ability to repair DNA is already weakened - suggesting that this could become a new form of targeted treatment.

"It is very promising to see patients responding in an early-stage trial like this, and we are looking forward to further clinical trials to test the drug's efficacy."

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:

"It is exciting to see a new class of precision medicine showing such promise in early trials. At the ICR, we have pioneered ways of treating cancer by exploiting the weaknesses that tumours often have in repairing their DNA. I am hopeful that later-stage trials will show that this new class of ATR inhibitors can prove effective against cancers with defective systems for DNA repair, and we are keen to investigate whether they could prevent tumours from developing resistance to another important class of medicine called PARP inhibitors, which work in a similar way.

"One of our main goals is to find new targeted treatments and drug combinations that can tackle cancer evolution and drug resistance - and this will be the main focus of research in our pioneering new Centre for Cancer Drug Discovery."

CHICAGO: Hospital resources and infrastructure dedicated to improving quality and safety are essential for achieving safe and high-quality surgical outcomes. A comprehensive review of four key principles of the American College of Surgeons (ACS) Quality Verification Program demonstrates the importance of an overall hospital culture of quality and safety, including top- and mid-level, quality-focused leadership and a committee dedicated to quality improvement. Results of the review are published as an "article in press" on the Journal of the American College of Surgeons website in advance of print.

"This peer-reviewed article highlights how important it is for hospitals to have infrastructure and resources for building a surgical quality improvement program. Leadership, in the corporate suite, mid-level leadership involved in improving quality, committees focused on surgical quality and safety, and an overall culture of safety and high-reliability help assure the delivery of high-quality care to patients," said Chelsea Fischer, MD, MS, ACS Clinical Scholar in Residence and co-first-author of the literature review.

The ACS Quality Verification Program helps surgeons and hospitals identify the resources needed for robust surgical quality improvement. The program is based on a set of principles or standards at the foundation of surgical quality. These principles were gleaned from the knowledge and experience of surgical experts as well as the ACS' experience with 3,000 hospitals that participate in the ACS Quality Program. The principles were published in the Optimal Resources for Surgical Quality and Safety, also known as the ACS Red Book.

"By using the ACS Red Book framework, the ACS Quality Verification Program provides a structured mechanism by which hospitals can focus on their surgical quality efforts in a standardized manner. The program has been developed to assure hospital leadership, surgeons, clinical staff, and patients that there's a core infrastructure in place underpinning quality across all departments and divisions of surgery," said David B. Hoyt, MD, FACS, article coauthor and ACS Executive Director.

The basis of the Quality Verification Program rests on 12 standards: leadership commitment and engagement, surgical quality officer, surgical quality and safety committee, safety culture, data collection and surveillance, continuous quality improvement using data, case review, surgeon review, surgical credentialing and privileging, standardized and team-based processes of care, disease-based management, and compliance with regulatory performance metrics.

The literature review in JACS is the first of three investigations to examine the evidence that supports these standards. The study gathered and analyzed evidence associated with the first four principles that address institutional and administrative factors necessary for high quality surgical care: a top-down commitment to quality, mid-level leadership, and committee structure, including the scope and governance of a quality program and infrastructure.

"This article provides a robust body of evidence for the foundation of the ACS Quality Verification Program. The program is based on standardization and a system approach to surgical care. This program has been developed to reduce patient complications, minimize waste for surgical care teams, and increase the value of surgery for our patients," explained article coauthor, Clifford Y. Ko, MD, MSHS, FACS,

FASCRS, Director of the ACS Division of Research and Optimal Patient Care.

The U.S. National Library of Medicine's Medline database was searched for articles published between its inception in 1964 and January 2019. Articles evaluated the relationship between one of the Red Book principles and patient or organizational quality outcomes. Two reviewers synthesized and summarized information from these studies.

After identifying 5,332 studies involving the four principles, a total of 477 were selected for systematic review. Several primary studies also were included for assessment.

Leadership

Individual articles covering 30 years of research on senior or executive leadership in health care were included in four systematic reviews. Evidence from these investigations showed clinical quality improved when senior leaders were engaged and committed to quality. Higher levels of incident reporting that reduced medical errors, better compliance with guidelines, improved efficiency and safety, and interventions targeted at improving specific health outcomes were some of the findings linked to the actions of executive leaders.

Providing resources or visibly engaging in quality and safety endeavors also fostered successful quality improvement efforts.

Surgical Quality Officer

Medline articles and systematic reviews of studies over 32 years related effective mid-level management in quality improvement with better patient and organizational outcomes. The evidence showed that a surgical quality officer positively affected quality improvement efforts and the way they were conducted.

Surgical Quality and Safety Committee

The evidence indicated that a quality and safety committee must have wide clinical representation, well-defined goals, and clear lines of communication and authority to ensure quality improvement efforts will be effective.

Culture of Safety and Reliability

Medline articles and studies covering a 20-year period showed that organizational culture improved patient outcomes and safety in the workplace. Among the most effective aspects of institutional culture were education programs, communication tools, leadership walk-arounds, and comprehensive unit-based programs.

"Principles related to leadership, resources, and culture help keep surgery safe and reliable. With these concepts in place, hospitals can deliver consistent, quality surgical care to patients and improve patient outcomes," said Dr. Fischer.

Philadelphia, September 28, 2020--Researchers at Children's Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania have identified a cellular pathway that can be targeted with a naturally occurring drug to stimulate lung tissue regeneration, which is necessary for recovery from multiple lung injuries. The findings, which were published today in Nature Cell Biology, could lead to better therapies for patients with lung disease, including acute respiratory distress syndrome (ARDS) due to COVID-19.

"Using cutting-edge technology, including genome-wide and single-cell analyses, we have identified a specific cellular pathway involved in lung tissue regeneration and found a drug that enhances this process," said senior author G. Scott Worthen, MD, a physician-scientist in CHOP's Division of Neonatology and member of the Penn-CHOP Lung Biology Institute. "These findings provide identification of precision targets and thus allow for rational development of therapeutic interventions for lung disease caused by COVID-19 and other illnesses."

Conditions like pneumonia, influenza and ARDS - one of the known complications of COVID-19 - can damage the lining of the air sacs in the lungs, known as the alveolar epithelium, which prevents oxygen from passing from the lungs to the bloodstream and can lead to death. Patients with COVID-19 who develop ARDS become critically ill, and to date, no drugs have been developed specifically to treat ARDS in COVID-19 patients. Understanding which genetic targets and pathways are involved in regenerating epithelial tissue is critical in developing effective therapies for ARDS and similar conditions.

Previous research has shown that type II alveolar pneumocytes (AT2) are important cells involved in lung repair, both through self-renewal and transdifferentiation into type I alveolar pneumocytes (AT1), which facilitate gas exchange between the lung air sacs and nearby capillaries. Yet prior to this study, it was unknown what changes in gene accessibility occurred in AT2 cells following disease-related injury to promote repair and how regenerating AT2 cells influence interactions with nearby mesenchymal cells, which are also important in tissue repair.

Using genome-wide analyses, the research team assessed changes in AT2 after lung injury, which opens up the chromosomes within the cells and makes specific genes available to the machinery of the cell. The researchers then used single-cell analysis of AT2 cells and mesenchymal cells to better understand how the two cell types interact during injury and what cell signaling pathways are involved. The two approaches converged on a single pathway, in which a transcription factor known as STAT3 increased the expression of brain-derived neurotrophic factor (BDNF), which in turn increased lung tissue regeneration.

In further analyzing this pathway, the researchers identified a naturally-occurring compound known as 7,8-Dihydroflavone (7,8-DHF), which targeted a receptor in the pathway, stimulating and accelerating lung tissue repair in multiple mouse models of lung injury.

"We believe these findings could lead to the development of a new therapeutic that could help patients recovering from COVID-19 and similar diseases," said the study's first author, Andrew J. Paris, MD, Instructor of Medicine and a pulmonary specialist in the Perelman School of Medicine at the University of Pennsylvania. "Based on the results of this study, we think 7,8-DHF is an excellent candidate for entering clinical trials for patients with lung diseases."

Mitochondria are present in all eukaryotic cells: in our cells, in mammalian cells, in the cells of plants and even of fungi. Mitochondria produce energy for cells to function as multicellular organisms, and are known as the "powerhouses" of the cell. Inside mitochondria lie the genetic information for making this energy.

EPFL biophysicist Suliana Manley and her team collaborated with Jean-Claude Martinou's cell biology group from the University of Geneva to look deep within living cells. Inside mitochondria there rests RNA granules that are smaller than the diffraction limit of light, i.e. smaller than one one-thousandth the width of a strand of hair. Using super-resolution microscopy, they discovered that mitochondrial RNA's are packaged into tiny liquid droplets that can fuse together and break apart. The results are published in today's issue of Nature Cell Biology.

"The organization of genetic information contained within mitochondria is highly dynamic thanks to this liquid-like aspect of its RNA granules," explains Manley. "The way they continuously exchange material gives us insight into how mitochondria are able to make sure they have the genetic information they require to produce energy within cells."

What led the scientists to inspect RNA granules is linked to the unique identity of mitochondria. In fact, the mitochondrial genome is independent of the cell's genome, so the genetic identity of the mitochondria is separate from the genetic identity of the cell and the rest of the organism. Mitochondria's genome is only around 16 thousand base pairs long whereas the DNA of the human cell, more than 100,000 times as long, consists of 3 billion base pairs. The mitochondria's genome is inherited from the maternal lineage, so the way your cells produce energy essentially comes from your mother. Mitochondria is hypothesized to have its origins in bacteria: 1.5 billion years ago during the course of evolution, bacteria may have been engulfed by another cell to start an endo-symbiotic relationship; with time, the bacteria evolved to become this highly specialized organelle that produces energy for the cell.

Determining the way mitochondria work is important for understanding how the cell functions, but also for understanding how a cell malfunctions. Especially in cells that require large amounts of energy like nerve and muscle cells, dysfunctional mitochondria can have devastating consequences, resulting in severe disease.

Some birds can achieve extraordinary cognitive performance - but their brains were considered to be rather disorganized compared to those of mammals. Scientists from Bochum (RUB), Düsseldorf (HHU), Jülich (FZJ), and Aachen (RWTH), now for the first time, show striking similarities between the neocortex of mammals and sensory brain areas of birds: Both are wired in horizontal layers and vertical columns. The finding refutes 150-year-old assumptions. Decisive insights were provided by a method developed by Jülich and Düsseldorf brain researchers. The results have been published this week in the journal "Science".

Birds and mammals have the largest brains relative to their body size. Otherwise they have little in common, so the assumption of scientists for more than hundred years: Mammalian brains have a cerebral cortex that is made up of six horizontal layers and columns that run perpendicular to these layers. The avian brain in contrast appears to be poorly organized at first glance, and only shows accumulations of cells with more or less density.

"In view of the astonishing cognitive performance that birds can achieve, however, it was suspected that their brain is higher organized than previously assumed," says Prof. Dr. Onur Güntürkün, head of the Biopsychology work unit at the Faculty of Psychology at the RUB and an expert on the cognition of birds.

Indeed, researchers around Dr. Christina Herold (C. and O. Vogt Institute for Brain Research, HHU) and Dr. Martin Stacho (RUB) have now succeeded in proving that the brains of birds and mammals look surprisingly similar in their organization.

The fibers in the bird brain run horizontally and vertically, just like in the neocortex of mammals.

Previously, it was not possible to map the fiber structure of larger areas of the avian brain with the required accuracy. Commonly used techniques are either limited to small tissue samples or lack resolution and sensitivity to reveal microstructural features that define the brain's neuronal organization. The level in between therefore remained in the dark.

"3D PLI has a slightly lower resolution than tracing methods, but is capable of analyzing large tissue volumes in a reasonable time - a decisive advantage," explains Dr. Markus Axer, head of the fibre architecture group at the Forschungszentrum Jülich. Using this method, the researchers were able to analyze three complete pigeon brains at a resolution of 1.3 micrometers (millionths of a millimeter). Per brain, 250 sections were scanned at high resolution and reconstructed in 3D.

"3D PLI is a technique that contributes significantly to a deeper understanding of the brain's connectivity and makes it possible to identify similarities and differences in neuronal networks across species," emphasizes Prof. Katrin Amunts, Director of the two institutes in Jülich and Düsseldorf.

Because the method is computationally very challenging, the researchers use the FENIX supercomputing platform, to process the data. FENIX is a European network of High Perfomance Computing Centers that includes Jülich Supercomputing Centre, and is part of the new EBRAINS infrastructure developed by the Human Brain Project. EBRAINS provides neuroscientists worldwide with a set of advanced new methods and resources, including the 3D atlases of the human brain, BigBrain and Julich-Brain, which were created in Jülich and Düsseldorf.

Further tracing experiments in Bochum made it possible to examine the cross-linking of cells in the bird brain in detail. The technique uses tiny crystals that spread into the smallest branches of the nerve cells in brain slices. "Here, similarly, the structure was shown to consist of columns in which signals are transmitted from top to bottom and vice versa, and long fibers running horizontally," explains Onur Güntürkün. However, this structure is only found in the sensory areas of the bird brain. Other areas, such as associative areas, are organized differently.

The bone marrow is the soft tissue inside our bones. Its main role is to produce stem cells that will go on to become various cells of the blood, including white blood cells that fight infections, red blood cells that carry oxygen throughout the body, and platelets that control bleeding.

But the bone marrow also contains fat cells, the adipocytes, which were for a long time thought of as "passive fillers" of the marrow cavity. In recent years, however, bone marrow adipocytes have been shown to carry out a far more important role within the microenvironment of the bone marrow than initially thought.

The ratio between blood-forming cells (red color) and adipocytes (yellow color) is not constant. It changes with age, between different parts of the skeleton, and in various disease conditions or cancer treatments like chemo- and radio-therapy, which cause a condition called "bone marrow aplasia". Changes in the cells' ratio produce so-called "yellow-to-red" and "red-to-yellow" shifts in the color of the bone marrow, which is used for monitoring its condition.

This monitoring however is not entirely standardized, but relies on assessments by pathologists of histological images. In research, the relative health of bone marrow samples is also assessed qualitatively, through histological images. This subjectivity, although greatly compensated for, can still cause diagnostic and research limitations.

Publishing in Frontiers Endocrinology, scientists led by Olaia Naveiras at EPFL, introduce MarrowQuant, a new digital pathology software that can "read" histological images of bone marrow and "describe" them quantitatively, building maps based on values to complement the images. The potential applications of this approach can revolutionize digital histology.

Its code already uploaded on GitHub, MarrowQuant is described as "a user-friendly algorithm for the quantification of H&E bone marrow tissue biopsies in whole slide images."

In the paper, the researchers use MarrowQuant to build the first-ever quantitative map of the heterogeneity of bone marrow throughout the skeleton of mice suffering from age-induced and radiation-induced aplasia.

"The work was a massive effort only possible thanks to the long and fruitful collaboration with EPFL's BioImaging and Optics Platform [BIOP]," says Naveiras who is also the President of the International Bone Marrow Adiposity Society (BMAS).

MarrowQuant, uses the open-source software QuPath, and can systematically quantify multiple bone components in histological images without bias. It does this by discerning and quantifying the areas occupied by various parts of the bone marrow - including the vasculature and the bone itself.

One of the potential uses of MarrowQuant will be to re-examine historical sample collections of bone samples and even data from old clinical trials.

"MarrowQuant has already been extremely well received by the digital pathology community," says Naveiras. "Moreover, the very selective Image Database Resource (IDR) has selected the associated dataset for publication, which includes over 300 annotated images."

Professor Olaia Naveiras' lab is part of EPFL's Swiss Institute for Experimental Cancer Research (ISREC), situated in the School of Life Sciences.

Droughts are, after floods and storms, the costliest natural hazard. The expected increa,se in the frequency and intensity of drought events due to climate change reinforces the necessity to improve the quality and reliability of information about the economic impacts of droughts and the need for more accurate cost analyses to embed these estimates into the assessment of the costs of climate change.

A new study realized with the contribution of the CMCC Foundation, recently published on Land Use Policy, proposes a novel method to assess the overall economic effects of agricultural droughts using a coupled agronomic-economic approach that accounts for the direct and indirect impacts of this hazard in the economy.

"Our results reveal", commented researcher David García-León, lead author of the study, "over the period analyzed, droughts of different severity hit Italy and drought-induced economic losses ranged in Italy between 0.55 and 1.75 billion euros".

David García-León, who was Marie Sk?odowska-Curie Postdoctoral Fellow at CMCC@Ca'Foscari Division and he's now at the European Commission, Joint Research Centre, focused his research on assessing the overall macro-economic effects (% GDP) of agricultural drought impacts in Italy using a coupled CGE-econometric approach. The other authors of the study are the CMCC researchers Gabriele Standardi and Andrea Staccione, respectively working at CMCC Divisions ECIP - Economic analysis and Climate Impacts and Policy and RAAS - Risk Assessment and Adaptation Strategies.

In this study, the authors focused on agricultural droughts, which represent the impact on crop yields. "We used a satellite-based indicator of agricultural drought, the vegetation indicator fAPAR - fraction of Absorbed Photosynthetically Active Radiation -", Dr. García-León explains, "to detect and monitor the impacts on vegetation growth and productivity of environmental stress factors, especially plant water stress due to drought".

"This data", CMCC researcher Andrea Staccione adds, "have been then correlated with the geo-referenced data of land use and agricultural production at the farm-level provided by the Italian Council for Agricultural Research and Economics (Consiglio per la Ricerca in agricoltura e l'analisi dell'Economia Agraria - CREA) in order to assess the direct impacts of agricultural droughts on crop productivity."

The study distinguished between three types of drought severity levels (mild, moderate and extreme), and three representative years of each state were selected to describe each scenario: solar years 2003, 2006 and 2011 were studied as extreme, moderate and mild dry years, respectively. After the estimation of the direct impacts of droughts on crop yields using statistical models calibrated for each crop, the authors estimated the indirect impacts at the sectoral, regional and country-wide level. "Local-level, crop-dependent productivity shocks were fed into a regionalised Computable General Equilibrium model specifically calibrated for the Italian economy", CMCC researcher Gabriele Standardi explains. "Our estimates indicate that the total damages caused by agricultural droughts in the Italian economy can range from 0.01?0.10% of Italian GDP, that is, from approximately EUR 0.55 to EUR 1.75 billion. These damages concentrate but extend beyond the agricultural sector, with substantial identified impacts on food industry manufacturing and wholesale and trade services". This estimated overall effect on GDP is coherent with other outcomes obtained in different studies and, in particular, the agricultural production loss identified under severe drought conditions (EUR 2 billion) is consistent with the figure reported by the Italian Association of farmers in 2017, considered an extreme dry year. The spatial distribution of the identified losses showed large regional heterogeneity, according to the geographical configuration of droughts in a specific year, and on the specific crops cultivated in the different areas analysed. Moreover, the simulations suggested the presence of a recomposition of land use and production, that is a land-use substitution effect from less to more drought-resistant crops following a drought (e.g. olive).

"In the end, Andrea Staccione concludes, "it's important to highlight that our approach is fully systematic and scalable and thus could be applied to more specific areas or could be expanded to implement large pan-European drought cost assessments. Our study therefore might improve policy approaches to managing drought risks, while pointing out the best pre-impact (mitigation) and post-impact (response) interventions to be included in drought plans".

The proposed methodology shows its full potential as a support to decision-making processes on land use and drought management. For example, regional risk maps could help to identify areas with the highest exposure and vulnerability. The analyses of the drought risk on specific regions could also contribute to defining insurance tools that reflect the costs produced by drought events and, consequently, appropriate compensation tools.

Forecasting the spreading of a pandemic is paramount in helping governments to enforce a number of social and economic measures, apt at curbing the pandemic and dealing with its aftermath.

Now researchers present an efficient model to study and forecast the spreading dynamics and containment across different regions of the world.

- We discover that social distancing measures are more effective than travel limitations across borders in delaying the epidemic peak, says Professor of theoretical physics, Francesco Sannino, University of Southern Denmark and Danish Institute of Advanced Science, continuing:

Development in individual regions

- The results corroborate our finding that the travel across regions sparks the epidemic diffusion, which then develops in each region independently.

Virus-induced pandemics like Covid-19 are a threat to humans not only because of the number of human lives taken but also because of the profound and long-lasting impact on the economy and social dynamics.

While different empirical models already exist to describe the epidemic dynamics locally and globally, a coherent framework is missing. Using a powerful language and methodology borrowed from high energy physics, Professor Sannino and his colleague Giacomo Cacciapaglia from University of Lyon, can now study and forecast the spreading dynamics and containment across different regions of the world.

- We plan on embarking on a world-wide monitoring to make global projections that will help governments and industries make containment plans and strategize about reopening society and how to best implement border control, says Professor Sannino.

Researchers from the Llobet group have developed a new molecular material made out of oligomers and used it as a catalyst in water oxidation, achieving unprecedented current densities for molecular catalysts. The paper "Water oxidation electrocatalysis using ruthenium coordination oligomers adsorbed on multiwalled carbon nanotubes" has been published in Nature Chemistry.

The generation of electro-anodes and cathodes for water splitting devices based on molecular complexes anchored onto solid surfaces is gaining traction thanks to their versatile and modular properties through ligand design. After studying the catalytic behaviour of oligomers of general formula {[Ru(tda)(4,4'- bpy)]n(4,4'-bpy)} (where n is 1, 2, 4, 5 or 15), the scientists from ICIQ's Llobet team set out to anchor them onto graphitic surfaces. "We decided to design an oligomeric material based on our powerful Ru(tda) catalyst to move from homogeneous to heterogeneous applications. We had to anchor the catalyst on a surface to find a tangible application on water-splitting devices," explains Marcos Gil-Sepulcre, postdoctoral researcher and group coordinator at the Llobet group and first co-author of the paper.

In collaboration with international partners such as Johannes Elemans at the Institute for Molecules and Materials Radboud University and Christina Scheu at the Max-Planck-Institut fu?r Eisenforschung GmbH in Du?sseldorf, the scientists carried out multiple Microscopy studies to characterize the hybrid materials. In addition, Grazing-incidence small-angle X-ray scattering (GIWAXS) was carried out at the Alba synchrotron by Marc Malfois and Eduardo Solano. Further, Density-functional theory (DFT) calculations, conducted by the ICIQ Maseras group, to explore the nature of the interaction between the oligomers and the graphitic surfaces. X-ray absorption spectroscopic (XAS) measurements were also employed, in collaboration with the group of D. Moonshiram at IMDEA Nanociencia, to analyse the oligomers at the graphitic surfaces, and evaluate their fate during and after catalysis. This way the researchers confirmed the molecular nature of the oligomer and found out that it is adsorbed to the graphitic surface via aromatic catalyst-surface C-H-π interactions - an anchoring strategy that has never been described for molecular catalysts up to now.

A single monomer of the oligomer employed is unable to anchor because its interactions with the surface are too weak. Finding strength in numbers, once multiple units are introduced, the large number of C-H-π interactions stabilise the whole chain. The conformation of the hybrid material (a nanotube surrounded by oligomers) is the reason behind its high efficiency: all the ruthenium atoms in the oligomers are active catalytic centres - as opposed to dumping tones of oxides on electrodes as usually done in material science.

The resulting hybrid molecular material behaves as a rugged and powerful electro-anode for the water oxidation reaction achieving unprecedented current densities for molecular catalysts in the whole range of pH, but especially at neutral pH. "To our knowledge, there's no coordination polymer, MOF or COF, or organometallic material that works under neutral conditions, gives these currents and is stable," claims Gil-Sepulcre.

The work provides the basis for designing robust and efficient hybrid molecular electro-anode materials for the oxidation of water-based on Ru complexes, that can be extended to other transition metals and other catalytic reactions. The team is already working on implementing the hybrid material on photoelectrochemical cells to test its applications in a water-splitting device.

Many cells in our bodies are on the move and somehow seem to "know" where to go. But how do they learn the location of their destination? This question is key to understanding phenomena such as the renewal of cells in our body, the migration of cancer cells, and especially how wounds heal. Edouard Hannezo and his group at the Institute of Science and Technology Austria (IST Austria) in collaboration with Tsuyoshi Hirashima and his student at Kyoto University propose a new model of information transfer in which cells utilize long-distance traveling waves in a self-organized manner to close a wound. This study was recently published in the journal Nature Physics.

The researchers built a mathematical model to describe the interactions within a layer of cells on a substrate, similar to a layer of skin. These cells contain chemical signalers--proteins--that allow them to sense other cells around them, so whether they are pushed or pulled, and to control their own movement. What the scientists found is that the intricate interplay of cell movement, sensing of the environment, and states of protein activation within the cells combine to create coupled mechanical and chemical traveling waves in which directional information is encoded.

Feedback loops

The mechanical wave appears as denser and sparser regions of cells alternating in space and time. The chemical wave appears as protein activity and is triggered by cell movement and mechanical feedback. The cells' chemistry in turn drives cell shape changes and movement closing a feedback loop with cell mechanics. In this coupled system these mechanical and chemical waves arise spontaneously due to feedback and amplification.

In a normal unwounded layer of cells, these waves propagate without a preferred direction, but when an artificial wound is introduced on one side, waves re-orient to propagate exclusively away from the wound. The researchers thus hypothesized that the waves could be a communication tool, allowing cells very far from the wound--and thus not directly "seeing" it--to sense which way to go.

Reading the Waves

A density wave makes the neighbors of a cell push and pull on it along the direction in which the wave is traveling. Since the forces exerted on the cell are equal and opposite between the crests and troughs of each wave, the result is that the cell just moves small distances back and forth without any net motion. In effect, the cell has no way of knowing the direction the wave came from and thus has no information about the location of the wound.

This is where the second wave of protein activity comes in. It hits the cell slightly after the density wave due to the delay that it takes for proteins to activate. And because protein activity controls the speed at which the cells move, a delay between the two waves allows for cells to move quickly when being pulled in the direction of the wound, and slowly when being pushed away. In this way, cells can break symmetry and start to move in the preferred direction towards the wound.

Out-of-equilibrium Experiments

The researchers at Kyoto University observed this out-of-equilibrium behavior of wound healing during in vitro experiments with real cells on a substrate. They used a novel microscopy technique to allow them to measures protein activity within each cell: the protein was modified so that it lit up when activated thus revealing waves of protein activation propagating throughout the cell layer. The researchers were able to quantitatively predict the wave patterns, which they then also observed experimentally. More strikingly, they also found that the delay between the two waves was close to the theoretically predicted optimum for allowing cells to extract maximum information from the waves.

This mechanism of self-organization is remarkable for allowing robust and spontaneous communication of direction over large distances within cell layers. It demonstrates one way in which coordinated behavior can arise in our bodies helping them to heal and grow.

Evolution leaves its traces in particular in genomes. Pinpointing its influence is a laborious process - but one in which Dr. Jürgen Schmitz and his team at the University of Münster are at home. Five years ago, the team made public a web app which can compare the genomes of humans and animals and thus help to provide an understanding of evolutionary developments. The Münster researchers are now going one step further: their new software - "2-n-way" - can compare any genomes from and for anyone and systematically search for regions which are characterized by the presence or absence of certain sequences - or, to put it simply, what is missing and where in the genome and when it got lost or when it newly emerged. This makes it possible to recognize relationships among species or individuals. The Münster researchers have now published details of their new development - which, like its predecessor - is freely available on the internet - in the journal Genome Research.

Jürgen Schmitz, a biologist and zoologist at the Institute of Experimental Pathology at Münster University's Faculty of Medicine, led the study together with Dr. Gennady Churakov and for him it represents a "unique, forward-pointing opportunity to take a close look at the mutability of multiple genomes". It means that not only genome evolutions can be analysed, but also the occurrence of genetic diseases as a result of deletions or insertions - i.e. the loss of a DNA segment or the insertion of a new one. The decisive difference between the new model and its predecessor, GPAC - which has been used hundreds of thousands of times since it was activated - is that 2-n-way can sequence any number of genomes. "The tool is a response to the modern genomic era - and it is a piece of software which, despite the complexity behind it, can be used by anyone, whether a non-medical layperson, a student or a professor. Last but not least, the tool links up a very wide range of areas, such as evolution, population genetics and medicine" says Schmitz.

The term "2-n-way" is derived from two abbreviations used by specialists: "2-way" stands for the linear alignment of sequences to be compared; and "n-way" means the combination of individual components and the subsequent multiple comparison. But users do not need to know such background information. "They only have to download on the internet the genomes they want to compare. One source, for example, is the website of the National Center for Biotechnology Information (NCBI) in the USA. The genomes fed into 2-n-way are then aligned with each other by the software. The genes which are of particular interest are selected from the genomic "coordinates" - or "loci", to give them their proper technical term. "The search can be geared for example to some or all of the so-called jumping genes, i.e. those genes which have changed their position in the genome," Schmitz explains.

If for example a search is made for certain jumping genes in humans, chimpanzees or rhesus monkeys, the results are given in a table with "plus" and "minus". If the evaluation contains two finds and an exact gap in the rhesus monkey, then the conclusion is that humans and chimpanzees have inherited the jumping gene from a common ancestor and are therefore closely related - while the rhesus monkey still displays the original locus without any insertion and is therefore only distantly related. However, the software not only indicates whether a certain insertion is present, but also the region in which it is to be found. In addition to the table of correlations, 2-n-way also provides the user with a list of DNA sequences for all loci.

Although the new tool has only just been made public, the team of researchers is already looking ahead - working on the simplification of the individual creation of 2-ways, i.e. the alignment. "This is a process which, at the moment, can take up a lot of time - which is a bit annoying," says Schmitz. Otherwise, he comments, the tool "has been tested intensively and is absolutely perfect".

A team of researchers from Cologne and Helsinki has discovered a mechanism that prevents hair loss: hair follicle stem cells, essential for hair to regrow, can prolong their life by switching their metabolic state in response to low oxygen concentration in the tissue. The team was led by Associate Professor Sara Wickström (University of Helsinki and Max Planck Institute for the Biology of Ageing) and the dermatologist Professor Sabine Eming (University of Cologne), and included researchers from the University of Cologne's Cluster of Excellence in Aging Research CECAD, the Max Planck Institute for the Biology of Ageing, Collaborative Research Centre 829 'Molecular Mechanisms Regulating Skin Homeostasis', the Center for Molecular Medicine (CMMC) (all in Cologne), and the University of Helsinki. The paper 'Glutamine Metabolism Controls Stem Cell Fate Reversibility and Long-Term Maintenance in the Hair Follicle' has been published in Cell Metabolism.

Every day, tissues such as the skin and its hair follicles are exposed to environmental damage like ultraviolet radiation. Damaged material is continuously removed and renewed. On average, 500 million cells and 100 hairs are shed every day, amounting to 1.5 gram of material. The dead material is replaced by stem cells, which are specialized, highly proliferative and long-lived. Tissue function relies on the activity and health of these stem cells; compromised function or reduced number leads to aging. 'Although the critical role of stem cells in aging is established, little is known about the mechanisms that regulate the long-term maintenance of these important cells. The hair follicle with its well understood functions and clearly identifiable stem cells was a perfect model system to study this important question', said Sara Wickström.

To understand what made stem cells functionally distinct from their differentiated daughter cells, the team investigated the transcriptional and metabolic profiles of the two cell populations. 'Intriguingly, these studies showed that stem cells and daughter cells have distinct metabolic characteristics', said Dr. Christine Kim, co-leading scientist of the study. 'Our analyses further predicted that Rictor, an important but relatively poorly understood molecular component of the metabolic master regulator mTOR pathway, would be involved.' The mTOR signal transduction regulates processes like growth, energy, and oxygen consumption of cells.

In more detailed analyses, the team showed that stem cell depletion was due to the loss of metabolic flexibility. At the end of each regenerative cycle, during which a new hair is made, the stem cells will return to their specific location and resume a quiescent state. Dr. Xiaolei Ding, the other co-leading scientist, explained: 'The key finding of this study is that this so called "fate reversibility" requires a shift from glutamine metabolism and cellular respiration to glycolysis. The stem cells reside in an environment with low oxygen availability and thus use glucose rather than glutamine as a carbon source for energy and protein synthesis. This shift is triggered by the low oxygen concentration and Rictor signaling. The removal of Rictor impaired the ability of this stem cell fate reversal, triggering slow, age-dependent exhaustion of the stem cells and age-induced hair loss.' Ding and Eming had recently generated a genetic mouse model to study Rictor function and observed that mice lacking Rictor had significantly delayed hair follicle regeneration and cycling, which indicated impaired stem cell regulation. 'Interestingly, with aging these mice showed hair loss and reduction in stem cell numbers', said Ding.

'A major future goal will be to understand how these preclinical findings might translate into stem cell biology in humans and potentially could be pharmaceutically harnessed to protect from hair follicle aging', said Eming. 'We are particularly excited about the observation that the application of a glutaminase inhibitor was able to restore stem cell function in the Rictor-deficient mice, proving the principle that modifying metabolic pathways could be a powerful way to boost the regenerative capacity of our tissues.'