Culture

A single cell contains the genetic instructions for an entire organism. This genomic information is managed and processed by the complex machinery of chromatin -- a mix of DNA and protein within chromosomes whose function and role in disease are of increasing interest to scientists.

A Northwestern University research team -- using mathematical modeling and optical imaging they developed themselves -- has discovered how chromatin folds at the single-cell level. The researchers found chromatin is folded into a variety of tree-like domains spaced along a chromatin backbone. These small and large areas are like a mixed forest of trees growing from the forest floor. The overall structure is a 3D forest at microscale.

Chromatin is responsible for packing DNA into the cell nucleus. In humans, that's about six feet of DNA in each cell. The new work suggests that chromatin is more structured and hierarchical in single cells than previously thought. Learning how chromatin correctly operates will help scientists understand what goes wrong with it in cancer and other diseases.

"By integrating theoretical and experimental work, we have produced a new chromatin folding picture that helps us see how the 3D genome is organized at the single-cell level," said Igal Szleifer, the Christina Enroth-Cugell Professor of Biomedical Engineering at Northwestern's McCormick School of Engineering. He co-led the research team with Vadim Backman.

Details of the interdisciplinary study will be published Jan. 10 in the journal Science Advances.

"If genes are the hardware, chromatin is the software," said Backman, the Walter Dill Scott Professor of Biomedical Engineering and director of the Center for Physical Genomics and Engineering. "If the structure of chromatin changes, it can alter the processing of the information stored in the genome, but it does not alter the genes themselves. Understanding chromatin folding holds the key to understanding how cells differentiate and how cancer happens."

Advances in genomic, imaging and information technologies are just beginning to enable scientists to better understand how chromatin works. The Northwestern researchers used a Partial Wave Spectroscopic (PWS) microscope, optical imaging developed by Backman and colleagues, to peer deep into live cells and "sense" alterations in chromatin packing. They also used electron imaging.

"Our paradigm-shifting picture of chromatin folding is an important missing piece in the holistic view of genomic structure," said Kai Huang, the study's first author. Huang is a postdoctoral fellow in Backman's research group. "The results should inspire new strategies to fight cancer."

The expansion of Medicaid coverage for low-income adults permitted by the Affordable Care Act (ACA) was associated with a six percent reduction in total opioid overdose deaths nationally, according to new research from NYU Grossman School of Medicine and University of California, Davis.

Published online January 10 in JAMA Network Open, the study is the first to look at whether the ACA-related Medicaid expansion is associated with county-level opioid overdose mortality. The researchers analyzed cause-of-death data from the National Vital Statistics System from 3,109 counties within 49 states and the District of Columbia between 2001 and 2017--looking at changes in opioid overdose rates in counties that expanded Medicaid and compared those to changes that occurred in the same time period in counties within states that did not expand Medicaid.

Drug overdose remains a leading cause of injury death in the United States and is responsible for more than 70,000 deaths annually. After examining the association of Medicaid expansion with county-by-year counts of opioid overdose deaths and by class of opioid, the researchers found that:

Medicaid expansion may have prevented between 1,678 and 8,132 opioid overdose deaths in 2015 to 2017 in the 32 states that expanded Medicaid between 2014 and 2016.

Adoption of Medicaid expansion was associated with a six percent lower rate of total opioid overdose deaths, 11 percent lower rate of death involving heroin, and a 10 percent lower rate of death involving synthetic opioids other than methadone (such as fentanyl).

Unexpectedly, an 11 percent increase in methadone overdose mortality was observed with Medicaid expansion.

"Our findings suggest that as states invest more resources in addressing the opioid overdose epidemic, policymakers should pay attention to the role that expanding Medicaid can play in reducing opioid overdose deaths by providing greater access to health care, and in particular, to treatment for opioid use disorder," said Magdalena Cerdá, DrPH, associate professor and director of the Center for Opioid Epidemiology and Policy in the Department of Population Health at NYU Langone Health, and the study's senior author. "At a broader level, the findings of this study suggest that providing expanded access to health care may be a key policy lever to address the opioid overdose crisis."

One concerning finding from the study was the association of Medicaid expansion with an 11 percent increase in overdose deaths involving methadone. According to Cerdá, Medicaid beneficiaries are more likely to receive prescriptions for methadone to treat pain, compared to the general population. While the dispensing of methadone to treat opioid use disorder is highly effective and standardized, the use of methadone to treat pain is associated with greater risk of overdose reflecting in part wide variation in prescribing practices.

"Past research has found Medicaid expansion is associated with not only large decreases in the number of uninsured Americans, but also considerable increases in access to opioid use disorder treatment and the opioid overdose reversal medication naloxone," said Nicole Kravitz-Wirtz, PhD, MPH, assistant professor with the Violence Prevention Research Program in the Department of Emergency Medicine at UC Davis, and the study's lead author. "Ours was the first study to investigate the natural follow-up question: Is the expansion associated with reductions in local opioid overdose deaths? On balance, the answer appears to be yes."

Study Limitations

Cerdá and colleagues cite a number of study limitations. First, the research relies on coding of death certificate data. Since coding has changed over time, some deaths due to opioid overdoses may be misclassified. A second limitation is that the investigators looked at deaths among the whole population as opposed to just Medicaid beneficiaries. Any effect detected may be an underestimate of the effect that would be observed among Medicaid beneficiaries, says Cerdá.

Finally, although the researchers looked at the relationship of Medicaid expansion and overdose mortality, they did not directly examine pathways such as how Medicaid expansion affects access to treatment for opioid use disorder, how it affects opioid misuse and nonfatal overdoses, or how it affects access to naloxone, a medication used to counter the effects of opioid overdose. Each of these additional pathways are worthy of future study and are likely important levers to pull in terms of addressing the opioid overdose crisis, says Cerdá.

Congenital Zika Syndrome (CZS) refers to a collection of developmental malformations associated with Zika virus (ZIKV) congenital infection. This syndrome includes devastating conditions that have a huge impact on the rest of the life of the individual and their family, such as smaller (microcephaly) and unfolded (lissencephalic) brains, retinal abnormalities, enlarged ventricles of the heart, a lack of the inter-hemispheric connections and calcifications in the brain.

Brazil has been widely affected by ZIKV, but ~75% of CZS have been found in the socio-economically disadvantaged region of the Northeast.

In a new study, researchers from the University of Oxford and the Federal University of Rio de Janeiro have found that this rise in cases of CZS is linked to poor diet among the infants' mothers.

Professor Zoltán Molnár of the University of Oxford's Department of Physiology, Anatomy & Genetics, who participated in the study and has a long-term collaboration with the lead author Associate Professor Patricia Garcez of the Federal University of Rio de Janeiro Brazil partially supported by the Medical Research Council and Royal Society, said: 'We knew that areas of Brazil with the lowest socioeconomic status had the highest level of developmental impairment in babies due to CZS, which is why we looked at the possible link between ZIKV and one of the potentially most important co-factors, nutrition.

'This study showed that developmental impairment caused by ZIKV congenital infection is made much worse by environmental co-factors, specifically diets poor in protein, which explains why the devastating effects of CZS vary across ZIKV endemic regions.'

The link between Zika virus infection and the CZS has been demonstrated in previous studies, which helped researchers understand how the infection affected brain growth and development of blood vessels. These showed that ZIKV infects the cells that develop into the brain and alter genes and proteins related to the normal cell cycle and blood vessel development.

The current study also used a mouse model to replicate the effects of Zika infection in mice that had a low-protein diet, and found that several of the pathological signs found in humans appeared in the undernourished mice in a similar way.

Professor Molnár added: 'When we replicated the effects seen in humans who had poor diets in mice we saw similar effects in the foetuses, such as placental damage as well as poor embryonic body growth and a reduction in brain size of newborns born to undernourished pregnant mouse.

'The mouse mothers were clearly less able to fight against ZIKV, which was shown by a robust and persistent ZIKV infection in the spleens of undernourished mothers, in contrast to healthy mice. Our undernourished mouse model helped us to identify the cellular mechanisms that are responsible for the differences in humans.'

'Improving diet alone will not protect against ZIKV infections, but it can determine the severity of the CZS.

'While we need more work to translate these findings to human disease, our mouse model helped us to identify significant differences in the regulation patterns of key molecular pathways, and particular genes identified within developing brains reflect how a poor nutritional status increases the adverse effects of ZIKV infection.'

The study was partially funded by a joint MRC Grant between Professor Zoltán Molnár of the University of Oxford and Associate Professor Patricia Garcez of the Federal University of Rio de Janeiro.

Computational biologists led by Prof. Yvan Saeys (VIB-UGent Center for Inflammation Research) developed a new bioinformatics method to better study communication between cells. This method, called NicheNet, helps researchers to gain insight into how the gene expression of cells is regulated by interacting cells. NicheNet has a broad range of potential applications in fields like immunology and tumor biology, and was already successfully used by the collaborating group of Prof. Martin Guilliams (VIB-UGent Center for Inflammation Research).

Cell neighbors

In multicellular organisms cells don't function on their own, but they produce signaling molecules that influence gene expression in interacting cells. This intercellular communication plays an important role in many biological processes, such as the development and functioning of cells. Studying intercellular communication is not only important to understand fundamental biology, but also to gain insights into diseases like cancer. Interactions between cancer cells and other cells in the microenvironment of the tumor are crucial for its growth.

An example of a process in which intercellular communication is essential, is the differentiation of macrophages, a type of immune cell. This process is affected by other cell types in the environment, or 'niche', of the macrophage.

Researchers from the group of Martin Guilliams (VIB-Ghent University), who work in close collaboration with the Saeys lab, wanted to study this process for Kupffer cells, a macrophage in the liver blood stream. They generated a lot of gene expression data of all cells involved.

"But, using this type of data to unravel how cells communicate is not a trivial task'', says Yvan Saeys. "We needed to develop a new sophisticated algorithm to tackle this problem."

Machine learning for talking cells

Guided by post-doc Wouter Saelens and Yvan Saeys, PhD student Robin Browaeys started developing such a new method to analyze how cells might signal each other.

Browaeys explains: "Our idea was to make use of the enormous amount of available knowledge on intercellular signaling that was acquired over the years, and use this knowledge to find out which intercellular communication processes are going on in the data we had. To do this, we had to apply several machine learning and statistical techniques, including network algorithms that are also used to analyze social networks, for example."

Saelens summarizes: "In essence, you can compare our newly developed method, NicheNet, with a hypothetical biologist who not only knows everything that is already published about intercellular communication, but who can also apply all this knowledge on complex, big datasets. Making reasonable predictions on intercellular communication is something that would have required weeks of literature study in the past, but this can now be done with the push of a button."

Testing NicheNet

A first test case for NicheNet was the Kupffer cell niche data generated by the Guilliams lab. Researchers from that lab were able to experimentally validate some of the signals that NicheNet predicted. "Thanks to NicheNet, we looked into factors that we would not have thought about ourselves", confirms Martin Guilliams. "For us, NicheNet was an essential tool to help unravel the Kupffer cell niche".

"In addition to the Kupffer cell story, we have also been applying NicheNet to investigate cell-cell communication in the tumor microenvironment", adds Saeys. "We used NicheNet on single-cell data that was published earlier, but we are now working on novel single-cell datasets generated by collaborating research groups. How different types of treatment affect the cellular interactions within the tumor microenvironment, and how this influences the tumor, are some of the questions we are trying to address with NicheNet."

These different applications illustrate the value of NicheNet for generating novel hypotheses about how cells communicate in fundamental biological processes and diseases.

Stellar black holes form when massive stars end their life in a dramatic collapse. Observations have shown that stellar black holes typically have masses of about ten times that of the Sun, in accordance with the theory of stellar evolution. Recently, a Chinese team of astronomers claimed to have discovered a black hole as massive as 70 solar masses, which, if confirmed, would severely challenge the current view of stellar evolution. The publication immediately triggered theoretical investigations as well as additional observations by other astrophysicists. Among those to take a closer look at the object was a team of astronomers from the Universities of Erlangen-Nürnberg and Potsdam. They discovered that it may not necessarily be a black hole at all, but possibly a massive neutron star or even an 'ordinary' star. Their results have now been published as a highlight-paper in the renowned journal Astronomy & Astrophysics*.

The putative black hole was detected indirectly from the motion of a bright companion star, orbiting an invisible compact object over a period of about 80 days. From new observations, a Belgian team showed that the original measurements were misinterpreted and that the mass of the black hole is, in fact, very uncertain. The most important question, namely how the observed binary system was created, remains unanswered. A crucial aspect is the mass of the visible companion, the hot star LS V+22 25. The more massive this star is, the more massive the black hole has to be to induce the observed motion of the bright star. The latter was considered to be a normal star, eight times more massive than the Sun.

A team of astronomers from Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and the University of Potsdam had a closer look at the archival spectrum of LS V+22 25, taken by the Keck telescope at Mauna Kea, Hawaii. In particular, they were interested in studying the abundances of the chemical elements on the stellar surface. Interestingly, they detected deviations in the abundances of helium, carbon, nitrogen, and oxygen compared to the standard composition of a young massive star. The observed pattern on the surface showed ashes resulting from the nuclear fusion of hydrogen, a process that only happens deep in the core of young stars and would not be expected to be detected at its surface.

'At first glance, the spectrum did indeed look like one from a young massive star. However, several properties appeared rather suspicious. This motivated us to have a fresh look at the archival data', said Andreas Irrgang, the leading scientist of this study and a member of the Dr. Karl Remeis-Observatory in Bamberg, the Astronomical Institute of FAU.

The authors concluded that LS V+22 25 must have interacted with its compact companion in the past. During this episode of mass-transfer, the outer layers of the star were removed and now the stripped helium core is visible, enriched with the ashes from the burning of hydrogen.

However, stripped helium stars are much lighter than their normal counterparts. Combining their results with recent distance measurements from the Gaia space telescope, the authors determined a most likely stellar mass of only 1.1 (with an uncertainty of +/-0.5) times that of the Sun. This yields a minimum mass of only 2-3 solar masses for the compact companion, suggesting that it may not necessarily be a black hole at all, but possibly a massive neutron star or even an 'ordinary' star.

The star LS V+22 25 has become famous for possibly having a massive black hole companion. However, a closer look at the star itself reveals that it is a very intriguing object in its own right, as whilst stripped helium stars of intermediate mass have been predicted in theory, only very few have been discovered so far. They are key objects to understanding binary star interactions.

A group of scientists, among them several from GSI Helmholtzzentrum für Schwerionenforschung and from Technical University of Darmstadt, succeeded to experimentally determine characteristics of nuclear processes in matter ten million times denser and 25 times hotter than the centre of our Sun. A result of the measurement is that intermediate-mass stars are very likely to explode, and not, as assumed until now, collapse. The findings are now published in the scientific magazine Physical Review Letters. They stress the fascinating opportunities offered by future accelerator facilities like FAIR in understanding the processes defining the evolution of the Universe.

Stars have different evolutionary paths depending on their mass. Low-mass stars such as the Sun will eventually become white dwarfs. Massive stars, on the other hand, finish with a spectacular explosion known as a supernova, leaving either a neutron star or a black hole behind. The fate of both low- and high-mass stars is well understood but the situation for intermediate-mass stars, which weigh between seven and eleven times as much as the Sun, has remained unclear. This is surprising since intermediate-mass stars are prevalent in our Galaxy.

"The final fate of intermediate-mass stars depends on a tiny detail, namely, how readily the isotope neon-20 captures electrons in the stellar core. Depending on this electron capture rate, the star will be either disrupted in a thermonuclear explosion or it will collapse to form a neutron star," explains Professor Gabriel Martínez-Pinedo of GSI's research department Theory and the Institut für Kernphysik, TU Darmstadt. Professor Karlheinz Langanke, Research Director of GSI and FAIR, adds: "This work started when we realized that a strongly suppressed, and hence previously ignored and experimentally unknown, transition between the ground states of neon-20 and fluorine-20 was a key piece of information needed to determine the electron capture rate in intermediate mass stars." By a combination of precise measurements of the beta-decay of fluorine-20 and theoretical calculations, an international collaboration of physicists with participation from GSI and TU Darmstadt, has now succeeded in determining this important rate. The experiment took place under conditions far more peaceful than those found in stars, namely at the Accelerator Laboratory of the University of Jyväskylä. The measurements showed a surprisingly strong transition between the ground states of neon-20 and fluorine-20 that leads to electron capture in neon-20 occurring at lower density than previously believed. For the star, this implies that, in contrast to previous assumptions, it is more likely to be disrupted by a thermonuclear explosion than to collapse into a neutron star. "It is amazing to find out that a single transition can have such a strong impact on the evolution of a big object like a star," says Dag Fahlin Strömberg, who, as a PhD student at TU Darmstadt, was responsible for large parts of project's simulations.

Since thermonuclear explosions eject much more material than those triggered by gravitational collapse, the results have implications for galactic chemical evolution. The ejected material is rich in titanium-50, chromium-54, and iron-60. Therefore, the unusual titanium and chromium isotopic ratios found in some meteorites, and the discovery of iron-60 in deep-sea sediments could be produced by intermediate-mass stars and indicate that these have exploded in our galactic neighbourhood in the distant (billions of years) and not so distant (millions of years) past.

In the light of these new findings the most probable fate of intermediate-mass stars seems to be a thermonuclear explosion, producing a subluminous type Ia supernova and a special type of white dwarf star known as an oxygen-neon-iron white dwarf. The (non-)detection of such white dwarfs in the future would provide important insights into the explosion mechanism. Another open question is the role played by convection -- the bulk movement of material in the interior of the star -- in the explosion.

At existing and future accelerator centres like the international FAIR project (Facility for Antiproton and Ion Research) currently under construction at GSI, new not yet investigated isotopes and their properties can be investigated. Thus, scientists continue to bring the universe into the laboratory to answer the unsolved questions about our cosmos.

Researchers at Karolinska Institutet in Sweden and their colleagues in Germany, the USA and Finland have studied the safety of very long-term antipsychotic therapy for schizophrenia. According to the study, which is published in the scientific journal World Psychiatry, mortality was higher during periods when patients were not on medication than when they were.

People with schizophrenia have an average life expectancy ten to twenty years below the norm, and there has long been concern that one of the causes is the long-term use of antipsychotic drugs. Earlier compilations (meta-analyses) of results from randomised studies, however, indicated that the mortality rate for people with schizophrenia on antipsychotic medication was 30 to 50 per cent lower than those who have received placebo.

However, most of the studies done have been shorter than six months, which does not reflect the reality of treatment often being life-long. Researchers from Karolinska Institutet and their international colleagues have now done a long-term follow-up, substantiating previous results and demonstrating that antipsychotic drugs are not associated with increased risk of co-morbid complications, such as cardiovascular disease. The study is the largest conducted in the field to date.

"It's difficult to make comparisons between people on permanent medication and those who aren't, as these groups differ in many ways," says Heidi Taipale, assistant professor at the Department of Clinical Neuroscience at Karolinska Institutet. "One common method of dealing with this has been to try to take account of such differences when making comparisons. However, we chose another method, in which each person was their own control, making it possible for us to make individual comparisons of hospitalisation during periods of antipsychotic medication and periods of no treatment."

The researchers monitored just over 62,000 Finns who had received a schizophrenia diagnosis at some time between 1972 and 2014. This they did by accessing various Finnish registries up until 2015, giving an average follow-up period of over 14 years. They found that the likelihood of being hospitalised for a somatic disease was just as high during the periods when the patients were on antipsychotic drugs as when they were not. The differences in mortality, however, were noticeable. The cumulative mortality rate in the follow-up period at periods of medication and non-medication was 26 and 46 per cent respectively.

The researchers believe that there is overwhelming support for continual antipsychotic treatment for schizophrenia being a safer option than no medication. At the same time, treatment brings the risk of adverse reactions, such as an increase in weight, which can raise the risk of cardiovascular disease. The finding that treatment with antipsychotic drugs does not increase the likelihood of hospitalisation for cardiovascular disease may be attributable, argue the researchers, to the fact that the drugs can also have an antihypertensive effect and can reduce anxiety and the risk of substance abuse. Antipsychotic treatment may also help patients adopt a healthier lifestyle and make them more likely to seek care when needed.

"Antipsychotics get something of a bad press, which can make it difficult to reach out to the patient group with information on how important they are," says Jari Tiihonen, professor of psychiatry at the Department of Clinical Neuroscience, Karolinska Institutet. "We know from previous studies that only half of those who have been discharged from hospital after their first psychotic episode with a schizophrenia diagnosis take antipsychotic drugs. Besides, there are many people with schizophrenia who are on long-term benzodiazepine medication, which is in breach of existing guidelines and is associated with increased mortality risk. Building trust and understanding towards the efficacy and safety of antipsychotic drugs is important, and we hope that this study can contribute to this end."

The gene Cdkn1c could have been considered an open-and-shut case: Mice in which the gene is removed are larger and have bigger brains, so Cdkn1c should function to inhibit growth. This rationale has led to Cdkn1c being studied as a tumour suppressor gene. New research from the group of Simon Hippenmeyer, professor at the Institute of Science and Technology Austria (IST Austria), has now uncovered a novel, opposite role for Cdkn1c. When Cdkn1c is removed only in certain cells of the brain, these cells die, arguing for a new growth promoting role of Cdkn1c. The new research is published today in the journal Nature Communications.

Simon Hippenmeyer and his research group, including co-first authors Susanne Laukoter (PhD student), Robert Beattie (postdoc) and Florian Pauler (senior technical assistant), removed Cdkn1c in a brain region called the cerebral cortex in mice and found a surprising result: Contrary to what had previously been thought, the cortex was smaller, not bigger, than in animals with a normal amount of Cdkn1c. To make sense of this seeming paradox, the researchers compared the effect of Cdkn1c loss in the whole animal with a loss of the gene in just a single tissue or even in single cells in the developing mouse.

Studying brain development and gene function at single cell level with MADM

Using a genetic technique called Mosaic Analysis with Double Markers (MADM) allowed the researchers to knockout a gene of interest in single cells and at the same time, visualize the effect of gene deletion on these cells under the microscope. When they removed the gene Cdkn1c in cells in the whole cortex, the cortex was smaller. "When we take out the gene, cells die. In fact, we see massive death by apoptosis", Hippenmeyer explains.

In a cortex where Cdkn1c was removed, the researchers further modified single cells with MADM to observe their fate. They found that if a cell has two intact copies of Cdkn1c, the cell is protected against death. If a cell has just one intact copy of Cdkn1c, the cell dies. Intriguingly, it does not matter whether the DNA, the "instruction manual" in our cells that defines how products like proteins are made, is active and thus allows generation of proteins, or not. Just having two copies of the intact DNA, the intact instruction manual, is enough to protect a cell from death.

Implications for studies on brain malformations and tumour development

For Hippenmeyer, this study underlines the importance of studying both systemic effects of gene loss (i.e. gene loss in the whole animal) and the effect of gene loss in individual cells. "Our method reveals a new function of Cdkn1c, as taking the gene out in a single cell has a fundamentally different effect from taking it out in the whole animal. Systemic effects may mask the effect observed in individual cells. It is important to also study this in human conditions that lead to malformations of the brain, such as microcephaly."

As Cdkn1c and its role in the development of tumours has been studied extensively, the new research likely also has important implications for this field, says Florian Pauler. "There has been interest in Cdkn1c as it has been regarded as a tumour suppressor. Like the single cells and individual tissue we studied, tumours can also be seen as non-systemic. So, our findings change the way we should think about Cdkn1c, also in tumours."

In the future, Hippenmeyer and his research group will continue to explore the mechanisms and functions of Cdkn1c. "When this piece of DNA is missing, something fundamental is changed and death is triggered in a cell. Of course, we want to now know why and how this happens", Hippenmeyer asserts.

The use of environmental resources has been regulated for centuries with the aim of improving the management and behaviour of private and public actors on an on-going basis. But, does the never-ending introduction of new regulations really have a positive effect? Or, does a surfeit of rules cause malfunctions and lead to disturbing overlaps? In an attempt to answer these questions, researchers from the Universities of Geneva (UNIGE) and Lausanne (UNIL), Switzerland, analysed water governance regulations in six European countries from 1750 to 2006. Their results, published in the journal Ecological Economics, show that rules designed to improve resource management eventually come into conflict in the long run, creating an equal number of positive and negative effects until the system falls apart. At this point, the only way out is for the state to overhaul governance.

Societies have been making rules to control behaviours and the uses of natural resources such as water for centuries. At the same time, however, the competing interests of state and private actors continue to produce environmental problems. In overall terms, the scientific literature is in agreement that developments in the way these regulations are structured are, nevertheless, increasingly positive and effective. But to what extent is this really the case in the long run?

"To assess whether a regulation is positive in the long run, you need to factor in the ecosystem of rules that it is part of, and which it may either reinforce or disrupt", begins Thomas Bolognesi, a researcher at the Institute for Environmental Sciences (ISE) at UNIGE. In fact, a rule that induces a positive impact on the use that it regulates may cause turmoil once it begins to interact with existing regulations, causing the entire system to malfunction, conceived here as transversal transaction costs (TTCs). "And over the very long term", adds the Geneva-based scientist, "the negative effect of TTCs can grow and end up being equivalent to the positive effect generated by the new regulation, creating what we called an institutional complexity trap." The quality of governance is based, therefore, on two key components: the scope, i.e. the set of uses governed by the rules (quantity); and the consistency, i.e. the fact that the rules are defined and followed correctly (quality).

Successive improvements to the system lead to breaking point

To test their hypothesis, Bolognesi and Stéphane Nahrath, a professor at UNIL's Swiss Graduate School of Public Administration (IDHEAP), scrutinised the water governance systems in six European countries (Switzerland, Belgium, Spain, France, Italy and the Netherlands) from 1750 to 2006. "The aim of the study was to determine whether the increase in the scope of the governance reduced the system-wide coherence, and even went as far as overriding the positive effects intended by the additional regulations", says professor Nahrath. The researchers identified three distinct phases in the evolution of the governance in the six countries.

The first phase, which lasted from 1750 to 1850 and was followed by around 50 years of stagnation, covered the launch of the governance process, i.e. the production of framework rules that had relatively little impact. From 1900 to 1980, governance developed and the rules, which grew in precision, generated significant positive effects. But since 1980, we have entered a phase where the negative indirect effect, linked to a drop in the system's coherence, has been reinforced and offsets the previous positive effect, even to the point of supplanting it. "This is due to the creation of a profusion of new rules, especially following the introduction of the New Public Management approach in the 1980s", notes Bolognesi. This proliferation of regulations, which were sometimes designed to regulate the same area but along different lines, had an indirect negative impact on governance and resulted in a decrease in efficiency and clarity, leading to a systemic malfunction. "Consequently, to achieve a positive effect - as slim as it is - more and more rules need to be produced, increasing the risk of malfunction and leading to a vicious circle", continues Nahrath.

System reformed by the state

Contrary to the widespread idea that water governance is constantly improving, the study by the researchers from UNIGE and UNIL demonstrates the conflicts instigated by repeatedly introducing new rules designed to increase the system's efficiency. "If we carry on in the same way, we're going to hit breaking point", warns Bolognesi. "That's why we think it's important that the state and government policy should take charge of environmental governance issues. That way, we can avoid introducing separate rules that generate frictions and uncertainties, and that could create insurmountable obstacles for coordinating the system." As professor Nahrath concludes: "The contractual rules must in no instance take precedence over state rules."

A new study published by biologists at Ludwig-Maximilians-Universitaet (LMU) in Munich demonstrates that there are no simple or universal solutions to the problem of engineering plants to enable them to cope with the challenges posed by climate change.

For plants, climate change promises one thing for sure - increased levels of stress. After all, plants put down roots. They don't have the option of moving to where the weather suits them. Wider fluctuations in temperatures and increasing levels of aridity in many regions around the world are already making their lives more difficult. Plants are highly complex and sensitive systems. Even in zones with stable climates today, variations in light levels can reduce growth rates and crop yields. For example, plants have developed sophisticated cellular mechanisms that protect them against the deleterious effects of high light intensities on photosynthesis. In one such photoprotective process, the excess light energy is dissipated as heat before it can damage the photosynthetic apparatus. This depresses yields but it is very much in the plant's interest.

Three enzymes play a key role in this adaptation process, which are referred to as V, P and Z for short. In a paper published in 2016, which drew a great deal of attention, an American research group overexpressed the genes for these three proteins in tobacco plants, thus increasing the amounts of the enzymes produced in the leaves. They subsequently observed, under field conditions, that these 'VPZ' lines grew faster rates than did control plants with normal levels of the enzymes. LMU biologists Antoni Garcia-Molina and Dario Leister have now performed essentially the same experiment in the model plant Arabidopsis thaliana (thale cress). Their findings appear in the journal Nature Plants.

Their results confirm that, as in the case of tobacco, higher levels of V, P and Z reduce rates of photosynthesis while enabling the plants to adapt more rapidly (in fact, even faster than tobacco) to fluctuating light levels. Crucially however, the Arabidopsis VPZ lines did not grow faster than control plants. On the contrary, overexpression of the three enzymes resulted in retarded growth. "This clearly shows that it's not quite as easy to produce plants that are better adapted as some research groups have confidently suggested," Leister remarks. "In fact, higher levels of photoprotection may actually interfere with the operation of other mechanisms that are important for plant growth."

For Leister, these data essentially demonstrate that targeted adaptation of plants to facilitate successful adjustment to changing climatic conditions is likely to be a very complicated task. They certainly show that one cannot always expect to confer increased resistance to desiccation or optimize yields under fluctuating light levels simply by adjusting the levels of a few proteins. "The physiological processes in plants are tightly interconnected. This makes it impossible to predict the effects of flipping this switch or tightening that screw," he says. This explains why he and his colleagues approach the problem of targeted adaptation from the perspective of systems biology, which takes a 'holistic' view, as he calls it. For example, efforts to increase the yield or biomass by increasing the efficiency of photosynthesis must also ensure that the extra energy available is in fact channeled into increased growth. In principle, enhanced photosynthetic performance should result in the capture of more energy and in higher levels of metabolites. But this extra energy and abundance of chemical compounds must be put to some beneficial use. In the absence of any 'added value', increased rates of photosynthesis can prove to be detrimental to plants.

The analysis of complex relationships like this is the raison d'ètre of the Transregional Collaborative Research Center TR175, of which Leister is the principal coordinator. The scientists involved in the project seek to understand how plants react to biotic and abiotic environmental factors, such as drought, light levels and temperature, by analyzing their impact on the concentrations of all measurable metabolites, transcripts and proteins in plant cells. With the help of these data, they hope to identify the key components that allow plants to cope with varying conditions. In the case of crop plants that are indispensable for human nutrition, the mechanisms that underlie trade-offs between growth rates, increases in biomass and yields must also be taken into consideration. "In the context of climate change, the idea is to help plants to adapt to the changing conditions by introducing targeted genetic changes that allow them to handle the altered environmental parameters," Leister explains. Researchers refer to this strategy as 'assisted evolution'. "In order to have a realistic chance of finding sustainable solutions, we must adopt a systematic approach to the active adaptation of plants to the changing environmental conditions," he says. In this respect, some progress has already been made in certain species of algae that have very short generation times, which permits instances of successful adaptation to be rapidly detected. Such systems can then serve as sources of potentially useful genetic mutations that can be introduced into green plants.

Overall, 93 per cent of the German populace feels valued in their everyday lives, whereas far fewer - but still one out two (52 per cent) - feel disrespected. Most Germans experience high levels of appreciation overall, especially in private contexts such as among family or friends. Disrespect, however, is most commonly experienced in the workplace. East and West Germans feel equally appreciated in their everyday lives - yet also equally disrespected. Rather, how much appreciation and disrespect a person experiences strongly depends on levels of income, education, and the employment status.

These are the results of a study conducted by a team of sociologists at the Otto von Guericke University Magdeburg (OvGU) in Germany. The study is based on the question module "Status Confidence and Anxiety" which was developed for the Innovation Sample of the German Socio-Economic Panel, a long-standing representative survey in Germany. Building on these data, sociologists Prof. Jan Delhey, Dr. Christian Schneickert, and Leonie Steckermeier (MA) investigate who experiences social appreciation and disrespect in Germany, in which contexts and why. According to Prof. Delhey, the study reveals quite surprising results.

Regarding both, experiences of appreciation and disrespect in daily life, individuals' position on the socio-economic ladder makes a huge difference: the higher a person's income and level of education, the more they feel recognized, and the less disrespected. "An individual's employment status is also crucial." Prof. Jan Delhey continues, "Being unemployed goes hand in hand with a significantly higher risk of experiencing less social recognition and more disrespect." In contrast, a person's regional or ethnic background prove negligible: The study does not find significant differences between East and West Germans, nor between migrants and non-migrants

"Anyone interested in the unequal distribution of social recognition and disrespect in everyday-life in Germany," Dr. Christian Schneickert concludes, "should devote attention to socio-economic inequalityies rather than to socio-cultural diversity."

In addition, the researchers investigated the consequences of these everyday-life experiences for individuals' evaluations of their own lives and their satisfaction with democracy: The more people feel socially appreciated, the more satisfied they are with their lives as well as with democracy.

The study was carried out as part of the project "Recognition, Depreciation and Status Seeking" at the Chair for Macrosociology at the OVGU and was funded by the German Research Foundation (DFG).

The empirical analysis was based on survey data from a representative sample of the German population covering 3,580 respondents. The data were collected in 2016 as part of the Innovation Sample of the German Socio-Economic Panel. The data provide detailed insights into the distribution and significance of feelings of appreciation and disrespect.

The study has been published in the prestigious German social science journal Kölner Zeitschrift für Soziologie und Sozialpsychologie (KZfSS), and can be downloaded for free.

A 550 million-year-old fossilized digestive tract found in the Nevada desert could be a key find in understanding the early history of animals on Earth.

Over a half-billion years ago, life on Earth was comprised of simple ocean organisms unlike anything living in today's oceans. Then, beginning about 540 million years ago, animal structures changed dramatically.

During this time, ancestors of many animal groups we know today appeared, such as primitive crustaceans and worms, yet for years scientists did not know how these two seemingly unrelated communities of animals were connected, until now. An analysis of tubular fossils by scientists led by Jim Schiffbauer at the University of Missouri provides evidence of a 550 million-year-old digestive tract -- one of the oldest known examples of fossilized internal anatomical structures -- and reveals what scientists believe is a possible answer to the question of how these animals are connected.

The study was published in Nature Communications, a journal of Nature.

"Not only are these structures the oldest guts yet discovered, but they also help to resolve the long-debated evolutionary positioning of this important fossil group," said Schiffbauer, an associate professor of geological sciences in the MU College of Arts and Science and director of the X-ray Microanalysis Core facility. "These fossils fit within a very recognizable group of organisms -- the cloudinids -- that scientists use to identify the last 10 to 15 million years of the Ediacaran Period, or the period of time just before the Cambrian Explosion. We can now say that their anatomical structure appears much more worm-like than coral-like."

The Cambrian Explosion is widely considered by scientists to be the point in history of life on Earth when the ancestors of many animal groups we know today emerged.

In the study, the scientists used MU's X-ray Microanalysis Core facility to take a unique analytical approach for geological science -- micro-CT imaging -- that created a digital 3D image of the fossil. This technique allowed the scientists to view what was inside the fossil structure.

"With CT imaging, we can quickly assess key internal features and then analyze the entire fossil without potentially damaging it," said co-author Tara Selly, a research assistant professor in the Department of Geological Sciences and assistant director of the X-ray Microanalysis Core facility.

ROCHESTER, Minn. -- A molecular switch has the ability to turn on a substance in animals that repairs neurological damage in disorders such as multiple sclerosis (MS), Mayo Clinic researchers discovered. The early research in animal models could advance an already approved Food and Drug Administration therapy and also could lead to new strategies for treating diseases of the central nervous system.

Research by Isobel Scarisbrick, Ph.D., published in the Journal of Neuroscience finds that by genetically switching off a receptor activated by blood proteins, named Protease Activated Receptor 1 (PAR1), the body switches on regeneration of myelin, a fatty substance that coats and protects nerves.

"Myelin regeneration holds tremendous potential to improve function. We showed when we block the PAR1 receptor, neurological healing is much better and happens more quickly. In many cases, the nervous system does have a good capacity for innate repair," says Dr. Scarisbrick, principal investigator and senior author. "This sets the stage for development of new clinically relevant myelin regeneration strategies."

Myelin, Thrombin and the Nervous System

Myelin acts like a wire insulator that protects electrical signals sent through the nervous system. Demyelination, or injury to the myelin, slows electrical signals between brain cells, resulting in loss of sensory and motor function. Sometimes the damage is permanent. Demyelination is found in disorders such as MS, Alzheimer's disease, Huntington's disease, schizophrenia and spinal cord injury.

Thrombin is a protein in blood that aids in healing. However, too much thrombin triggers the PAR1 receptor found on the surface of cells, and this blocks myelin production. Oligodendrocyte progenitor cells capable of myelin regeneration are often found at sites of myelin injury, including demyelinating injuries in multiple sclerosis.

"These oligodendroglia fail to differentiate into mature myelin regenerating cells for reasons that remain poorly understood," says Dr. Scarisbrick. "Our research identifies PAR1 as a molecular switch of myelin regeneration. In this study, we demonstrate that blocking the function of the PAR1, also referred to as the thrombin receptor, promotes myelin regeneration in two unique experimental models of demyelinating disease."

The Research

The research focused on two mouse models. One was an acute model of myelin injury and the other studied chronic demyelination, each modeling unique features of myelin loss present in MS, Alzheimer's disease and other neurological disorders. Researchers genetically blocked PAR1 to block the action of excess thrombin.

The research not only discovered a new molecular switch that turns on myelin regeneration, but also discovered a new interaction between the PAR1 receptor and a very powerful growth system called brain derived neurotropic factor (BDNF). BDNF is like a fertilizer for brain cells that keeps them healthy, functioning and growing.

Significantly, the researchers found that a current Food and Drug Administration-approved drug that inhibits the PAR1 receptor also showed ability to improve myelin production in cells tested in the laboratory.

"It is important to say that we have not and are not advocating that patients take this inhibitor at this time," says Dr. Scarisbrick. "We have not used the drug in animals yet, and it is not ready to put in patients for the purpose of myelin repair. Using cell culture systems, we are showing that this has the potential to improve myelin regeneration."

Additional research is needed to verify and advance the findings toward clinical practice.

(Boston) - Boston researchers have developed a new way to generate groups of intestinal cells that can be used, among others, to make disease models in the lab to test treatments for diseases affecting the gastrointestinal system. Using human induced pluripotent stem cells, this novel approach combined a variety of techniques that enabled the development of three-dimensional groups of intestinal cells called organoids in vitro, which can expand disease treatment testing in the lab using human cells.

Published online in Nature Communications, this process provides a novel platform to improve drug screenings and uncover novel therapies to treat a variety of diseases impacting the intestine, such as inflammatory bowel disease, colon cancer and Cystic Fibrosis.

Researchers at the Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center used donated human induced pluripotent stem cells (hiPSCs), which are created by reprogramming adult cells into a primitive state. For this study, these cells were pushed to differentiate into intestinal cells using specific growth factors in order to create organoids in a gel. This new protocol allowed the cells to develop without mesenchyme, which typically in other protocols, provides support for the intestinal epithelial cells to grow. By taking out the mesenchyme, the researchers could study exclusively epithelial cells, which make up the intestinal tract.

In addition, using CRISPR technology, the researchers were able to modify and create a novel iPSC stem cell line that glowed green when differentiated into intestinal cells. This allowed the researchers to follow the process of how intestinal cells differentiate in vitro.

"Generating organoids in our lab allows us to create more accurate disease models, which are used to test treatments and therapies targeted to a specific genetic defect or tissue - and it's all possible without harming the patient," said Gustavo Mostoslavsky, MD, PhD, co-director of CReM and faculty in the gastroenterology section at Boston Medical Center. "This approach allows us to determine what treatments could be most effective, and which are ineffective, against a disease."

Using this new protocol, the researchers generated intestinal organoids from iPSCs containing a mutation that causes Cystic Fibrosis, which typically affects several organs, including the gastrointestinal tract. Using CRISPR technology, the researchers corrected the mutation in the intestinal organoids. The intestinal organoids with the mutation did not respond to a drug while the genetically corrected cells did respond, demonstrating their future potential for disease modeling and therapeutic screening applications.

The protocol developed in this study provides strong evidence to continue using human iPSCs to study development at the cellular level, tissue engineering and disease modeling in order to advance the understanding - and possibilities - of regenerative medicine.

"I hope that this study helps move forward our collective understanding about how diseases impact the gastrointestinal tract at the cellular level," said Mostoslavsky, who also is associate professor of medicine and microbiology at Boston University School of Medicine. "The continual development of novel techniques in creating highly differentiated cells that can be used to develop disease models in a lab setting will pave the way for the development of more targeted approaches to treat many different diseases."

Leesburg, VA, January 10, 2020--A deep learning method with a convolutional neural network (CNN) can support the evaluation of small solid renal masses in dynamic CT images with acceptable diagnostic performance, according to an article published ahead-of-print in the March issue of the American Journal of Roentgenology (AJR).

Between 2012 and 2016, researchers at Japan's Okayama University studied 1807 image sets from 168 pathologically diagnosed small (? 4 cm) solid renal masses with four CT phases--unenhanced, corticomedullary, nephrogenic, and excretory--in 159 patients.

Masses were classified as malignant (n = 136) or benign (n = 32) using a 5-point scale, and this dataset was then randomly divided into five subsets.

As lead AJR author Takashi Tanaka explained, "four were used for augmentation and supervised training (48,832 images), and one was used for testing (281 images)."

Utilizing the Inception-v3 architecture CNN model, the AUC for malignancy and accuracy at optimal cutoff values of output data were evaluated in six different CNN models.

Finding no significant size difference between malignant and benign lesions, Tanaka's team did find that the AUC value of the corticomedullary phase was higher than that of other phases (corticomedullary vs excretory, p = 0.022).

Additionally, the highest accuracy (88%) was achieved in the corticomedullary phase images.

Multivariate analysis revealed that the CNN model of corticomedullary phase was a significant predictor for malignancy, "compared with other CNN models, age, sex, and lesion size," Tanaka concluded.