Culture

The DNA molecule is not naked in the nucleus. Instead, it is folded in a very organized way by the help of different proteins to establish a unique spatial organization of the genetic information. This 3D spatial genome organization is fundamental for the regulation of our genes and has to be established de novo by each individual during early embryogenesis. Researchers at the MPI of Immunobiology and Epigenetics in Freiburg in collaboration with colleagues from the Friedrich Mischer Institute in Basel now reveal a yet unknown and critical role of the protein HP1a in the 3D genome re-organization after fertilisation. The study published in the scientific journal Nature identifies HP1a as an epigenetic regulator that is involved in establishing the global structure of the genome in the early Drosophila embryo.

The information of the human genome is encoded by approximately 3 billion DNA base pairs and packaged into 23 pairs of chromosomes. If all chromosomes could be disentangled and linearly aligned, they would be a thin thread of about 2 meters. The DNA molecule must be extensively packaged to fit inside the nucleus, the size of which is in the micrometer range. "The DNA thread is not simply stuffed into the cell nucleus. Instead, it is folded in a very organized way to ensure that different parts of the genome, sometimes several thousand base pairs away from each other, can intercommunicate for appropriate gene functions," says Nicola Iovino, group leader at the MPI of Immunobiology and Epigenetics in Freiburg.

Part of this packaging are histone proteins acting as spools around which DNA is winded and thereby compacted. This complex of DNA and proteins is called chromatin. As such, chromatin is the fundament for further packaging of the genetic material into chromosomes whose structure is mostly known for its characteristic cross shape. The chromosomes themself occupy distinct positions within the nucleus, known as chromosome territories, that also enable efficient packaging and organization of the genome.

The full machinery contributing to this 3D chromatin organization remains unexplored. Now the lab of Nicola Iovino at the MPI in Freiburg, in collaboration with Luca Giorgetti from the Friedrich Miescher Institute in Basel (Switzerland), was able to show the fundamental role of the heterochromatin protein 1a (HP1a) in the reorganization of the 3D chromatin structure after fertilization. By combining powerful Drosophila genetics with 3D genome modeling, they discovered that HP1a is required to establish a proper chromatin 3D structure at multiple hierarchical levels during early embryonic development.

Early embryos as a model to study chromatin reprogramming

The degree of packaging as well as the corresponding gene activity is influenced by epigenetic modifications. These are small chemical groups that are installed on the histones. "Proteins that carry out these epigenetic modifications can be thought of as being either writers, erasers or reader of the given epigenetic modification. We discovered that the reader protein HP1a is required to establish chromatin structure during early embryonic development in Drosophila", says Fides Zenk, first-author of the study.

Early embryonic development is a particularly interesting time window to study the processes governing the organization of chromatin. At fertilization, two highly specialized cells - sperm and egg - fuse. The resulting totipotent zygote will ultimately give rise to all the different cells of the body. Interestingly most of the epigenetic modifications that shape chromatin are erased and have to be established de novo. In Drosophila, the lab of Nicola Iovino had previously shown that after fertilization chromatin undergoes major restructuring events. Thus, it is the ideal model system to study the processes underlying the establishment of chromatin structure.

De novo establishment of 3D genome architecture

When the genome of the zygote is activated for the first time after fertilization, it triggers global de novo 3D chromatin reorganization including a clustering of highly compacted regions around the centromere (pericentromeric), the folding of chromosome arms and the segregation of chromosomes into active and inactive compartments. "We identified HP1a as an important epigenetic regulator necessary to maintain individual chromosome integrity but also central for establishing the global structure of the genome in the early embryo," says Nicola Iovino.

3D genome simulation

These findings and data collected in Drosophila embryos have then been used by collaborators from the Friedrich Miescher Institute (FMI) lead by Luca Giorgetti to build realistic three-dimensional models of chromosomes. This is possible because chromosomes inside the cell nucleus are polymers, very large molecules composed of chains of smaller components (monomers) - in this case consecutive DNA base pairs and the DNA-binding proteins that together constitute the chromatin fiber. Like all other polymers, be it silk, polyethylene or polyester, chromatin obeys a general set of physical laws described by a branch of physics known as 'polymer physics'. These laws can be encoded into computer programs and used to simulate the three-dimensional shape of chromosomes in the nucleus.

"The advantage of this approach is that it allows simulating the effects of very large numbers of mutations. This enables researchers to explore scenarios that are beyond experimental reach, such as the simultaneous depletion of many different proteins that would require years of lab work. By comparing simulations with the outcome of experiments, this approach also allows to test alternative hypotheses concerning the mechanisms that lay at the basis of experimental observations," says Luca Giorgetti, group leader at the Friedrich Miescher Institute in Basel.

In this case, FMI researchers used polymer models of the entire Drosophila genome to ask the question: based on the basic laws of polymer physics, is it possible that the depletion of a single protein - HP1 - leads to a massive change in the associations and shape of chromosomes in the nucleus? Or are additional mechanisms needed to explain the experimental observations? "We found that removal of the protein to its binding sites in the simulations accounted for the full set of experimental results, thus providing further confirmation that HP1 plays a key role in establishing the three-dimensional structure of the genome" says Yinxiu Zhan, co-first-author of the study.

Leesburg, VA, April 15, 2021--A Scientific E-Poster to be presented at the 2021 ARRS Virtual Annual Meeting found that as the United States Medical Licensing Examination (USMLE) Step 1 transitions from a numerical score to pass or fail--as early as January 2022--radiology residency program directors will likely rely on USMLE Step 2 Clinical Knowledge (CK) scores as an objective and standardized metric to screen applicants.

"However," wrote lead investigator Rebecca Zhang of the University of Maryland School of Medicine in Baltimore, "program directors remain unsure whether they will require Step 2 CK scores at the time of application or before interviewing applicants."

To evaluate the anticipated importance of various application metrics when Step 1 becomes pass or fail, Zhang's team distributed an anonymous and voluntary 14-item electronic survey to 308 active members of the Association of Program Directors in Radiology, performing secondary analyses to compare responses based on the current use of a Step 1 scoring screen.

With 29% of respondents completing the online survey, a majority (64%) of program directors noted that an applicant's Step 2 CK score will likely be one of the top three most important factors in assessing applicants, followed by class ranking (51%) and the Medical Student Performance Evaluation or Dean's Letter (37%). Most (90%) of respondents predicted their programs may or definitively will require Step 2 CK scores before reviewing an application, and 50% of respondents anticipated extending interview invitations at a later date to receive Step 2 CK scores.

Acknowledging that additional research may identify other objective metrics for holistic evaluations, "these results did not significantly differ between programs who currently use a Step 1 scoring screen and those who do not," the authors of this ARRS Annual Meeting E-Poster concluded.

Leesburg, VA, April 15, 2021--A Scientific E-Poster to be presented at the 2021 ARRS Virtual Annual Meeting found that in the setting of a high pretest probability of COVID-19 infection or with a quick turnaround of the rapid real-time reverse transcriptase-polymerase chain reaction (RT-PCR) COVID-19 test, a chest x-ray (CXR) scoring system may be used prospectively to predict patient outcomes.

"We developed an accurate and reliable tool for classifying COVID-19 severity, which can be used both at the attending chest radiologist and junior resident level. This study identifies the laboratory, clinical and radiographic data that predict important patient outcomes such as death, intubation, and the need for chronic renal replacement therapy (CRRT)," wrote first author Russell Reeves of Thomas Jefferson University in Philadelphia, PA.

Reeves and colleagues identified patients with nucleic acid-confirmed COVID-19 admitted to an urban multicenter health system from March 16 to April 13, 2020. Three cardiothoracic radiologists and three diagnostic radiology residents then independently scored their admission CXRs, based on extent and severity of COVID-19 pneumonia. Demographic variables, clinical characteristics, and admission laboratory values were collected, while interrater reliability among attending, resident, and the combined group of graders was assessed.

Of the 240 patients (142 males, 98 females; median age, 65 years) who met the inclusion criteria, interrater reliability for CXR scoring was high (mean, 0.686) among the attending, residents, and combination of graders. Furthermore, there was no difference in outcomes across gender, race, ethnicity, or those with either a history of lung cancer or chronic obstructive pulmonary disease. Although CXR severity proved an independent predictor of death (p

"These findings are supported by prior work, validating the utility of CXR for patient prognostication, while adding new insight into COVID-19 infection during the initial presentation," the authors of this ARRS Annual Meeting E-Poster concluded.

A study published this week in The Lancet Public Health examines how we can use our income assistance systems to address drug use and drug-related harm.

The study, led by University of British Columbia (UBC) medical sociologist Dr. Lindsey Richardson and conducted at the British Columbia Centre on Substance Use (BCCSU), tests whether varying the timing and frequency of income assistance payments can mitigate drug-related harms linked to the existing once-monthly payment schedule that is common across North America and Europe. Monthly synchronized income assistance payments have long been linked to considerable and costly increases in drug use and resulting harm, including overdose, hospital admission, treatment interruption and emergency service calls.

The study finds that varying when people who use drugs receive their income assistance payments reduces escalations in drug use around government payment days as well as individual payment days outside the week of the standard government schedule. However, changes also have unintended consequences that may increase individual drug-related harm, specifically exposure to violence. The study confirms preliminary results reported at multiple scientific meetings.

"As drug use and drug-related harm continue to be a defining public health challenge that has only been exacerbated by the COVID-19 pandemic, innovative thinking about how social and preventive approaches can help mitigate these harms is critical," says Dr. Richardson, research scientist at BCCSU, associate professor at UBC and principal investigator of the study. "These complex findings signal the potential for the income assistance system to address both the consequences of poverty as well as the severe drug-related harm seen each month around payments."

Researchers at the BCCSU followed 194 participants in Vancouver, British Columbia for six-month periods between 2015 and 2019 to evaluate the impact of alternative payment schedules. In British Columbia, income assistance is distributed on the last Wednesday of each month.

Two interventions were evaluated in comparison with the standard monthly cheque distribution: a staggered schedule where participants receive payments monthly on a day that does not fall during the week of synchronized government disbursement; and a split and staggered schedule, where participants receive semi-monthly payments two weeks apart on days that do not fall during the week of synchronized government disbursement.

The study found:

Intervention participants were about one-third as likely to increase their drug use on government payment days when they received their payments either desynchronized from government payments or desynchronized and in smaller increments, particularly in terms of the frequency of use and quantity of substances used.

Intervention participants were about one-half as likely to increase their drug use on their individual payment days when they received their payments.

Study analyses also identified that participants in the staggered study group may be more likely to be exposed to violence.

While conducted locally, the study's findings have important applications for contexts that see drug-related harm concentrate around income support payments. The study illustrates the importance of experimental research in anticipating the intended and unintended effects of social and other policy reforms. It also points to the importance of preventive, in addition to reactive responses such as naloxone administration to the ongoing crisis of drug use, drug toxicity and overdose.

There have been longstanding calls for upstream interventions to address the inequitable distribution of drug-related harm among disadvantaged populations. This study responds with an innovative experimental study specifically focusing on a known social determinant of health, applying sociological knowledge about the social drivers of drug use to a long-identified challenge for individuals, service providers and first responders.

Importantly, the findings of the study do not justify the drug testing of benefit recipients nor the retrenchment or withdrawal of benefits for people who use drugs, practices that are largely deemed unfair, immoral and objectionable.

The study authors urged that any changes to income assistance schedules must accommodate the complexity of people's lives and avoids a one-size-fits-all approach by allowing for choice in preferred schedule, providing flexibility to change as life circumstances change and focusing on the autonomy and dignity of recipients.

Tokyo, Japan - A team of scientists led by the Institute of Biomaterials and Bioengineering at Tokyo Medical and Dental University (TMDU) have created novel molecules that prevent human immunodeficiency virus (HIV) particles from attacking immune cells. This is accomplished by injecting compounds mimicking the protein the virus usually uses to enter the cells. This work may lead to new treatments for HIV that may be more effective at stopping the proliferation of the virus with fewer side effects.

HIV is a very dangerous pathogen because it attacks the very immune cells, including T helper cells, that are needed for the body to fight back. An HIV particle first gains entrance to a T helper cell by attaching to a CD4 protein on its surface. Once inside, the reproduction machinery of the T helper cell is hijacked to make copies of HIV, ultimately killing the host cell. Many treatments, such as antiretroviral drugs, attempt to block this reproduction process, but finding a way to prevent the HIV from attaching in the first place would be a better approach.

Now, a team of researchers led by Tokyo Medical and Dental University (TMDU) created a new family of molecules that act as decoy CD4 proteins. The HIV particles preferentially attach with the fake molecules, instead of those at the surface of a cell. The scientists found that adding a polyethylene glycol (PEG) improved the pharmacokinetics. "Hybrid molecules that mimic CD4 and also have a PEG unit attached with an uncleavable linker showed better anti-HIV activity with lower cytotoxicity," first author Takuya Kobayakawa says.

Computer simulations run by the team supported the hypothesis that the hybrid molecule works better because it can interact electrostatically with a carboxylate group on the virus. In tests with a rhesus macaque, the hybrid molecule remained in the system longer compared with the parent compound. "These CD4 mimics have strong synergistic interactions with neutralizing antibodies for fighting HIV," senior author Hirokazu Tamamura says. New combined treatment protocols may be developed to help take advantage of the new molecules. The work is published in the Journal of Medicinal Chemistry as "Hybrids of Small-Molecule CD4 Mimics with Polyethylene Glycol Units as HIV Entry Inhibitors." (DOI:10.1021/acs.jmedchem.0c01153).

It is often said that before air travel our skies were bluer yet how, in the 21st century, could we ever know what light and colors were like one hundred years ago? Recently, a group of researchers from EPFL's Audiovisual Communications Laboratory, in the School of Computer and Communication Sciences (IC), had a unique opportunity to try to find out.

Normally hidden treasures locked away in the vaults of a handful of museums, the researchers were offered access to some of the original photographic plates and images of the scientist and inventor Gabriel Lippmann, who won the 1908 Nobel Prize in physics for his method of reproducing colors in photography.

In a paper just published in the Proceedings of the National Academy of Sciences (PNAS) the authors explain that most photographic techniques take just three measurements, for red, green and blue, however they discovered that Lippmann's historical approach typically captured 26 to 64 spectral samples of information in the visible region. His technique, based on the same interference principles that recently enabled gravitational waves to be detected and which is the foundation of holography and much of modern interferometric imaging, has been almost completely forgotten today.

"These are the earliest multi-spectral light measurements on record so we wondered whether it would be possible to accurately recreate the original light of these historical scenes," said Gilles Baechler, one of the paper's authors, "but the way the photographs were constructed was very particular so we were also really interested in whether we could create digital copies and understand how the technique worked."

The researchers found that the multi-spectral images reflected from a Lippmann plate contained distortions, although the reproduced colors looked accurate to the eye. When they examined the full spectrum reflected from a Lippmann plate, and compared it to the original, they measured a number of inconsistencies, many of which have never been documented, even in modern studies.

"We ended up modeling the full process from the multi-spectral image that you capture, all the way to recording it into the photograph. We were able to capture the light reflected back from it and measure how it differed from the original," explained Baechler. So, could the team replicate century old light?

"With the historic plates there are factors in the process that we just cannot know but because we understood how the light differed, we could create an algorithm to get back the original light that was captured. We were able to study invertibility, that is, given a spectrum produced by a Lippmann photograph we know it is possible to undo the distortions and reconstruct the original input spectrum. When we got our hands dirty and made our own plates using the historical process, we were able to verify that the modeling was correct," he continued.

While fully modeling a Nobel-prize-winning imaging technique is of significant interest in its own right, the researchers believe that revisiting Lippmann's photographic technique can inspire new technological developments this century.

The team has already built a prototype of a digital Lippmann camera and is particularly intrigued by the possibilities of multi-spectral image synthesis as well as new multi-spectral camera, printing and display designs.

"This enables us to contrast the subjective perception of stress with an objective measurement method and compare the two," explains Nina Minkley. Contrary to expectations, it turned out that the effort invested in the task does not increase with its difficulty, nor does the stress level. The study was featured in the journal Frontiers in Education on 12. April 2021.

Simple questionnaire surveys criticised

To date, the stress experience of students has mostly been surveyed with questionnaires. But this approach has been criticised, because many factors have an effect on one's own perception that have nothing to do with the task. "For example, women often report higher stress levels than men," points out Nina Minkley. The researchers can only speculate why this is the case. In the current study, they used an objective method of measuring stress levels.

They equipped 209 secondary school students who were working on biology tasks with chest straps that monitor the heart rate. They also had the participants fill out several questionnaires on their self-concept, their interest in biology and their perception of the tasks. "When we are relaxed, the individual heartbeats differ slightly, whereas when we are stressed, they are less variable," explains Nina Minkley. Thus, the change in heart rate variability is an objective measurement of the stress level.

Mental effort causes stress

Comparing the questionnaire answers with the measured heart rates revealed that it was mainly mental engagement, i.e. the effort the students invested in solving the tasks, that correlated with the objective stress level. Contrary to expectations, however, more difficult tasks did not increase stress. "Perhaps some tasks can be so difficult that students don't even try to work on them," concludes Nina Minkley. "Such objective measures could be used in future studies primarily to survey subjective cognitive stress dimension."

Almost half a century ago the creators of Star Wars imagined a life-sustaining planet, Tatooine, orbiting a pair of stars. Now, 44 years later, scientists have found new evidence that that five known systems with multiple stars, Kepler-34, -35, -38, -64 and -413, are possible candidates for supporting life. A newly developed mathematical framework allowed researchers at New York University Abu Dhabi and the University of Washington to show that those systems -- between 2764 and 5933 light years from Earth, in the constellations Lyra and Cygnus -- support a permanent "Habitable Zone", a region around stars in which liquid water could persist on the surface of any as yet undiscovered Earth-like planets. Of these systems, Kepler-64 is known to have at least four stars orbiting one another at its center, while the others have two stars. All are known to have at least one giant planet the size of Neptune or greater. This study, published in Frontiers in Astronomy and Space Sciences, is proof-of-principle that the presence of giant planets in binary systems does not preclude the existence of potentially life-supporting worlds.

"Life is far most likely to evolve on planets located within their system's Habitable Zone, just like Earth. Here we investigate whether a Habitable Zone exists within nine known systems with two or more stars orbited by giant planets. We show for the first time that Kepler-34, -35, -64, -413 and especially Kepler-38 are suitable for hosting Earth-like worlds with oceans," says corresponding author Dr Nikolaos Georgakarakos, a research associate from the Division of Science at New York University Abu Dhabi.

The scientific consensus is that the majority of stars host planets. Ever since 1992, exoplanets have been discovered at an accelerating pace: 4375 have been confirmed so far, of which 2662 were first detected by NASA's Kepler space telescope during its 2009-2018 mission to survey the Milky Way. Further exoplanets have been found by NASA's TESS telescope and missions from other agencies, while the European Space Agency is due to launch its PLATO space craft to search for exoplanets by 2026.

Twelve of the exoplanets discovered by Kepler are "circumbinary", that is, orbiting a close pair of stars. Binary systems are common, estimated to represent between half and three quarters of all star systems. So far, only giant exoplanets have been discovered in binary systems, but it is likely that smaller Earth-like planets and moons have simply escaped detection. Gravitational interactions within multi-star systems, especially if they contain other large bodies such as giant planets, are expected to make conditions more hostile to the origin and survival of life: for example, planets might crash into the stars or escape from orbit, while those Earth-like exoplanets that survive will develop elliptical orbits, experiencing strong cyclical changes in the intensity and spectrum of radiation.

"We've known for a while that binary star systems without giant planets have the potential to harbor habitable worlds. What we have shown here is that in a large fraction of those systems Earth-like planets can remain habitable even in the presence of giant planets," says coauthor Prof Ian Dobbs-Dixon, likewise at New York University Abu Dhabi.

Georgakarakos et al. here build on previous research to predict the existence, location, and extent of the permanent Habitable Zone in binary systems with giant planets. They first derive equations that take into account the class, mass, luminosity, and spectral energy distribution of the stars; the added gravitational effect of the giant planet; the eccentricity (i.e. degree of ellipticity of the orbit), semi-major axis, and period of the hypothetical Earth-like planet's orbit; the dynamics of the intensity and spectrum of the stellar radiation that falls upon its atmosphere; and its "climate inertia", that is, the speed at which the atmosphere responds to changes in irradiation. They then look at nine known binary star systems with giant planets, all discovered by the Kepler telescope, to determine whether Habitable Zones exist in them and are "quiet enough" to harbor potentially life-sustaining worlds.

The authors show for the first time that permanent Habitable Zones exist in Kepler-34, -35, -38, -64, and -413. Those zones are between 0.4-1.5 Astronomical Units (au) wide beginning at distances between 0.6-2 au from the center of mass of the binary stars.

"In contrast the extent of the Habitable Zones in two further binary systems, Kepler-453 and -1661, is roughly half the expected size, because the giant planets in those systems would destabilize the orbits of additional habitable worlds. For the same reason Kepler-16 and -1647 cannot host additional habitable planets at all. Of course, there is the possibility that life exists outside the habitable zone or on moons orbiting the giant planets themselves, but that may be less desirable real-estate for us," says coauthor Dr Siegfried Eggl at the University of Washington.

"Our best candidate for hosting a world that is potentially habitable is the binary system Kepler-38, approximately 3970 light years from Earth, and known to contain a Neptune-sized planet," says Georgakarakos.

"Our study confirms that even binary star systems with giant planets are hot targets in the search for Earth 2.0. Watch out Tatooine, we are coming!"

Researchers in the Department of Neurology at Tohoku University, which is led by professor Masashi Aoki, have developed a classification scheme for neuromyelitis optica spectrum disorder, a rare autoimmune disease that until recently was thought to be a type of multiple sclerosis (MS). The new taxonomy for the disease replaces one borrowed from MS but which was inappropriate for what is in fact a distinct condition.

An autoimmune disease, neuromyelitis optica spectrum disorder (NMOSD), was for a long time thought to be a type of multiple sclerosis (MS), but it has recently been identified as an entirely different illness. As a result of this confusion, identification of NMOSD suffered from a clinical classification scheme borrowed from MS but is inappropriate due to its unique characteristics. A new classification scheme that focuses instead on the degree of deterioration of astrocytes, a specialized central nervous system cell involved in repair processes, has now been developed.

A paper by Yoshiki Takai and Tatsuro Misu at Department of Neurology, Tohoku University, describing the new classification scheme appears online in the journal Brain on March 12.

NMOSD is a rare but serious illness also known as Devic's disease that produces an inflammation of the spinal cord (myelitis) and optic nerve (optic neuritis) that can lead to blindness and paralysis. Similar to multiple sclerosis, the disorder produces a deterioration of myelin, the fatty layer around neurons that insulates them and allows their electrical impulses to be rapidly transmitted. Deterioration of the myelin slows down or even inhibits this transmission of nerve signals.

As a result of this similarity, NMOSD was long thought to be a sub-type of multiple sclerosis. But NMOSD has recently been identified as a distinct autoimmune illness with more severe symptoms than MS and with a separate set of causes. The demyelinating process in NMOSD is only a product of a newly identified and more fundamental disease process: astrocytopathy, or destruction of astrocytes. These specialized and star-shaped central nervous system cells perform a range of functions, including delivery of nutrients to nervous tissue, regulation of blood flow in the brain, and repair processes after injury or infection.

However, the two diseases, MS and NMOSD, remain difficult for clinicians to distinguish especially in the early stages because both illnesses produce optic neuritis and myelitis.

As a result of this confusion between the two illnesses, up to now, diagnosis of NMOSD has used the same disease classification system as MS, which depends upon the degree of demyelination.

"There was no disease classification system unique and appropriate to this distinct disease," said Yoshiki Takai of the Department of Neurology at Tohoku University. "So we decided to come up with one ourselves."

The researchers developed an NMOSD classification scheme that depends not on the degree of demyelination but instead upon differences in the morphology (in essence the shape) of astrocyte degeneration.

This astrocyte degeneration comes in four main types that the researchers have named astrocyte lysis, progenitor, protoplasmic gliosis, and fibrous astrogliosis, each with their own set of characteristic markers identifiable from astrocyte lesions, or damage to the astrocytes. Astrocyte lysis, or extensive loss or complete destruction of astrocytes, a characteristic of the most acute type of such damage (meaning sudden onset and short duration), is a feature highly specific to NMOSD. The other three types describe subacute or chronic forms of the disease (meaning slow onset that can worsen over time).

The classification scheme is the first taxonomy of astrocytopathy to be published.

The researchers hope that in both clinical practice and experimental study, this classification scheme will be used as the standard for all astrocyte-related disease mechanisms both for NMOSD and across the fields of neurodegenerative diseases and neuron regeneration.

Patients who are overweight or obese have more severe COVID-19 and are highly likely to require invasive respiratory support, according to a new international study.

The research, led by the Murdoch Children's Research Institute (MCRI) and The University of Queensland and published in Diabetes Care, found obese or overweight patients are at high risk for having worse COVID-19 outcomes. They are also more likely to require oxygen and invasive mechanical ventilation compared to those with a healthy weight.

MCRI researcher Dr Danielle Longmore said the findings, which highlighted the relationship between obesity and increased COVID-19 disease burden, showed the need to urgently introduce strategies to address the complex socio-economic drivers of obesity, and public policy measures such as restrictions on junk food advertising.

"Although taking steps to address obesity in the short-term is unlikely to have an immediate impact in the COVID-19 pandemic, it will likely reduce the disease burden in future viral pandemics and reduce risks of complications like heart disease and stroke," she said.

The study looked at hospitalised SARS-CoV-2 patients from 18 hospitals in 11 countries including China, America, Italy, South Africa and The Netherlands.

Among the 7244 patients aged 18 years and over, 34.8 per cent were overweight and 30.8 per cent were obese.

COVID-19 patients with obesity were more likely to require oxygen and had a 73 per cent greater chance of needing invasive mechanical ventilation. Similar but more modest results were seen in overweight patients. No link was found between being overweight or obese and dying in hospital from COVID-19.

Cardiovascular and pre-existing respiratory diseases were associated with increased odds of in-hospital deaths but not a greater risk for needing oxygen and mechanical ventilation. For patients with pre-existing diabetes, there was increased odds of needing invasive respiratory support, but no additionally increase in risk in those with obesity and diabetes.

Men were at an increased risk of severe COVID-19 outcomes and needing invasive mechanical ventilation. In those aged over 65 years, there was an increased chance of requiring oxygen and higher rates of in-hospital deaths.

The University of Queensland's Dr Kirsty Short, who co-led the research, said almost 40 per cent of the global population was overweight or obese.

"Obesity is associated with numerous poor health outcomes, including increased risk of cardiometabolic and respiratory disease and more severe viral disease including influenza, dengue and SARS-CoV-1," she said.

Dr Short said while previous reports indicated that obesity was an important risk factor in the severity of COVID-19, almost all this data had been collected from single sites and many regions were not represented. Moreover, there was a limited amount of evidence available about the effects of being overweight or obese on COVID-19 severity.

"Given the large scale of this study we have conclusively shown that being overweight or obese are independent risk factors for worse outcomes in adults hospitalised with COVID-19," she said.

MCRI Professor David Burgner, who co-led the research, said the data would help inform immunisation prioritisation for higher-risk groups.

"At the moment, the World Health Organization has not had enough high-quality data to include being overweight or obese as a risk factor for severe COVID-19 disease. Our study should help inform decisions about which higher-risk groups should be vaccinated as a priority," he said.

https://www.sciencedirect.com/journal/acta-pharmaceutica-sinica-b/vol/11/issue/3

The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association, Acta Pharmaceutica Sinica B (APSB) is a monthly journal, in English, which publishes significant original research articles, rapid communications and high quality reviews of recent advances in all areas of pharmaceutical sciences -- including pharmacology, pharmaceutics, medicinal chemistry, natural products, pharmacognosy, pharmaceutical analysis and pharmacokinetics.

Featured papers in this issue are:

Isorhapontigenin protects against doxorubicin-induced cardiotoxicity via increasing YAP1 expression by authors Panxia Wang, Minghui Wang, Yuehuai Hu, Jianxing Chen, Yanjun Cao, Cui Liu, Zhongkai Wu, Juan Shen, Jing Lu and Peiqing Liua (https://doi.org/10.1016/j.apsb.2020.10.017). Doxorubicin (Dox) decreased the expression of Yes-associated protein 1 (YAP1). YAP1 alleviated Dox-induced cardiomyopathy in transcription factor TEA domain 1 (TEAD1)1-dependent manner. Isorhapontigenin effectively protected against Dox-induced cardiomyopathy and improved cardiac function by increasing the expression of YAP1.

Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing by authors Zhiru Wang, Wenting Kang, Ouwen Li, Fengyu Qi, Junwei Wang, Yinghua You, Pengxing He, Zhenhe Suo, Yichao Zheng and Hong-Min Liu (https://doi.org/10.1016/j.apsb.2020.11.005). In addition to inhibiting cancer cells proliferation, USP7 inhibitor can also downregulate PD-L1 expression to enhance anti-tumor immune response simultaneously. Hence, USP7 inhibitor is an anti-proliferation agent as well as a novel therapeutic agent in a PD-L1/PD-1 blockade strategy that can promote the immune response of a tumor.

An injectable micelle-hydrogel hybrid for localized and prolonged drug delivery in the management of renal fibrosis by authors Xianyan Qin, Yingying Xua, Xu Zhou, Tao Gong, Zhi-Rong Zhang and Yao Fu (https://doi.org/10.1016/j.apsb.2020.10.016). Localized delivery, comparing to systemic drug administration, offers a unique alternative to enhance efficacy, lower dosage, and minimize systemic tissue toxicity by releasing therapeutics locally and specifically to the site of interests. The authors developed, a localized drug delivery platform ("plum?pudding" structure) with controlled release and long-acting features through an injectable hydrogel ("pudding") crosslinked via self-assembled triblock polymeric micelles ("plum") to help reduce renal interstitial fibrosis.

Other articles published in the issue include:

Reviews

Targeting redox-altered plasticity to reactivate synaptic function: A novel therapeutic strategy for cognitive disorder
Pei Wang, Fang Wang, Lan Ni, Pengfei Wu, Jianguo Chen
https://doi.org/10.1016/j.apsb.2020.11.012

Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment
Jinghui Zhang, Jiajun Fan, Xian Zeng, Mingming Nie, Jingyun Luan, Yichen Wang, DianwenJu, KaiYin
https://doi.org/10.1016/j.apsb.2020.10.022

Natural products as LSD1 inhibitors for cancer therapy
Yuan Fang, Chao Yang, Zhiqiang Yu, Xiaochuan Li, Qingchun Mu, Guochao Liao, Bin Yu
https://doi.org/10.1016/j.apsb.2020.06.007

Original Articles

S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling
Pingping Luo, Ming Zheng, Rui Zhang, Hong Zhang, Yingxia Liu, Wei Li, Xiaoming Sun, Qian Yu, George L. Tipoe, Jia Xiao
https://doi.org/10.1016/j.apsb.2020.11.006

A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/ FOXC1 axis
Tailin He, Jialin Shang, Chenglong Gao, Xin Guan, Yingyi Chen, Liwen Zhu, Luyong Zhang, Cunjin Zhang, Jian Zhang, Tao Pang
https://doi.org/10.1016/j.apsb.2020.11.002

Constitutive androstane receptor induced-hepatomegaly and liver regeneration is partially via yes-associated protein activation
Yue Gao, Shicheng Fan, Hua Li, Yiming Jiang, Xinpeng Yao, Shuguang Zhu, Xiao Yang, Ruimin Wang, Jianing Tian, Frank J. Gonzalez, Min Huang, Huichang Bi
https://doi.org/10.1016/j.apsb.2020.11.021

Ultra-short-course and intermittent TB47-containing oral regimens produce stable cure against Buruli ulcer in a murine model and prevent the emergence of resistance for Mycobacterium ulcerans
Yamin Gao, H.M. Adnan Hameed, Yang Liu, Lingmin Guo, Cuiting Fang, Xirong Tian, Zhiyong Liu, Shuai Wang, Zhili Lu, Md Mahmudul Islam, Tianyu Zhang
https://doi.org/10.1016/j.apsb.2020.11.007

A multifunctional cross-validation high-throughput screening protocol enabling the discovery of new SHP2 inhibitors
Yihui Song, Min Zhao, Yahong Wu, Bin Yu, Hong-Min Liu
https://doi.org/10.1016/j.apsb.2020.10.021

Functional metabolomics reveal the role of AHR/GPR35 mediated kynurenic acid gradient sensing in chemotherapy-induced intestinal damage
Di Wang, Danting Li, Yuxin Zhang, Jie Chen, Ying Zhang, Chuyao Liao, Siyuan Qin, Yuan Tian, Zunjian Zhang, Fengguo Xu
https://doi.org/10.1016/j.apsb.2020.07.017

Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors
Xiaowei Wu, Mengdi Dai, Rongrong Cui, Yulan Wang, Chunpu Li, Xia Peng, Jihui Zhao, Bao Wang, Yang Dai, Dan Feng, Tianbiao Yang, Hualiang Jiang, Meiyu Geng, Jing Ai Mingyue Zheng, Hong Liu
https://doi.org/10.1016/j.apsb.2020.09.002

Design, synthesis, molecular modelin and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis
Fanxun Zeng, Shiliang Li, Guantian Yang, Yating Luo, Tiantian Qi ,Yingfan Liang, Tingyuan Yang, Letian Zhang, Rui Wang, Lili Zhu, Honglin Li, Xiaoyong Xu
https://doi.org/10.1016/j.apsb.2020.10.008

Novel PF74-like small molecules targeting the HIV-1 capsid protein: Balance of potency and metabolic stability
Lei Wang, Mary C. Casey, Sanjeev Kumar, V. Vernekar Rajkumar, Lalji Sahani, Karen A. Kirby, Haijuan Du, Huanchun Zhang, Philip R. Tedbury, Jiashu Xie, Stefan G. Sarafianos, Zhengqiang Wang
https://doi.org/10.1016/j.apsb.2020.07.016

A smart MnO2-doped graphene oxide nanosheet for enhanced chemo-photodynamic combinatorial therapy via simultaneous oxygenation and glutathione depletion
Peng Liu, Xin Xie, Miao Liu, Shuo Hu, Jinsong Ding, Wenhu Zhou
https://doi.org/10.1016/j.apsb.2020.07.021

The inner surface of blood vessels is lined by a wafer-thin layer of cells known as the endothelium, which forms a crucial barrier between blood and the surrounding tissue. The single-layered cell structure promotes the exchange of oxygen and nutrients, while simultaneously preventing the uncontrolled leakage of blood components. Only when the metabolic needs of the surrounding tissue increase, e.g., during growth, wound healing or tumor development, do endothelial cells abandon this stable cell association in order to divide and form new blood vessels. The signals that trigger this activation have been throroughly studied. Previously, however, little was known about how endothelial cells maintain their stable resting state. This is what scientists at Berlin Institute of Health (BIH) at Charité have now investigated together with an international team of researchers. They have published their findings in the journal Nature Cell Biology.

Michael Potente is a cardiologist and blood vessel researcher. He arrived at the BIH from the Max Planck Institute for Heart and Lung Research just a few months ago, and is now moving into his new laboratory in the recently opened Käthe Beutler Building on Campus Berlin Buch. There he will conduct research at the BIH & MDC Center for Vascular Biomedicine. "Even in these turbulent times, we have been working vigorously on our major project to better understand blood vessels," explains the Professor of Vascular Biomedicine. "Blood vessels are everywhere in the body, and they also play a key role in many illnesses."

Normally, blood vessels in the adult body are in a stable resting state. New vascular capillaries sprout only rarely, for example, during the female menstrual cycle, wound healing or during pathological processes such as tumor growth. The signals that stimulate the endothelial cells to divide are largely known. "We wanted to understand instead what keeps endothelial cells in a dormant state - also known as quiescence," says Michael Potente.

The scientists from his team already had a good idea where to look: "There are factors that prevent cells from proliferating. One such factor is FOXO1, which controls the transcribing of genetic information in cells; if we switch off FOXO1 in endothelial cells, this leads to excessive vessel growth. Conversely, we can stop blood vessel formation by specifically switching on this factor. We wanted to find out how exactly FOXO1 does this," explains Jorge Andrade, one of the three lead authors of the paper.

S-2-hydroxyglutarate as "endothelial calming factor"?

To do this, the scientists transferred a continuously active form of FOXO1 into endothelial cells. This caused the endothelial cells to stop dividing and remain in a state of inactivity. To find out how FOXO1 does this, the researchers investigated the metabolism of the cells. For this purpose, they isolated all metabolic products from the cells, which are also known as metabolites. "In this process, we saw that the concentration of 2-hydoxyglutarate, in particular, increased due to FOXO1. This metabolite has already become very well known in cancer medicine," reports Ana Costa, another lead author of the paper. However, the researchers found that this is a special form of 2-hydroxyglutarate called S-2-hydroxyglutarate. "This variant differs in structure and function from the metabolite produced in some cancer cells," Costa says.

To confirm the role of S-2-hydroxyglutarate as a possible "endothelial calming factor," the scientists conducted further experiments on endothelial cells. They added the substance to normal endothelial cells in various concentrations and for different lengths of time. "We observed that S-2-hydroxyglutarate alone is able to keep endothelial cells in a state of quiescence," explains Chenyue Shi, the third lead author of the paper. Further research showed that S-2-hydroxyglutarate exerts its effect by controlling the transcription of growth-controlling genes. In mouse models, the metabolite also prevented the growth of new vessels, but had no negative effects on existing blood vessels. When the scientists removed S-2-hydroxyglutarate, endothelial cells regained their ability to form new blood vessels.

Targeted influence on blood vessels

"Especially given the fact that 'too many' or 'too few' new blood vessels play a role in many diseases, it is enormously important for us to better understand the basic mechanisms underlying these processes," is how Potente summarizes the results. "Our long-term goal is to be able to therapeutically influence the development and function of blood vessels in a targeted manner, and if possible, without any side effects. We have come one step closer to this goal with our work."

The information of the human genome is encoded by approximately 3 billion DNA base pairs and packaged into 23 pairs of chromosomes. If all chromosomes could be disentangled and linearly aligned, they would be a thin thread of about 2 meters. The DNA molecule must be extensively packaged to fit inside the nucleus, the size of which is in the micrometer range. "The DNA thread is not simply stuffed into the cell nucleus. Instead, it is folded in a very organized way to ensure that different parts of the genome, sometimes several thousand base pairs away from each other, can intercommunicate for appropriate gene functions," says Nicola Iovino, group leader at the MPI of Immunobiology and Epigenetics in Freiburg.

Part of this packaging are histone proteins acting as spools around which DNA is winded and thereby compacted. This complex of DNA and proteins is called chromatin. As such, chromatin is the fundament for further packaging of the genetic material into chromosomes whose structure is mostly known for its characteristic cross shape. The chromosomes themself occupy distinct positions within the nucleus, known as chromosome territories, that also enable efficient packaging and organization of the genome.

The full machinery contributing to this 3D chromatin organization remains unexplored. Now the lab of Nicola Iovino at the MPI in Freiburg, in collaboration with Luca Giorgetti from the Friedrich Miescher Institute in Basel (Switzerland), was able to show the fundamental role of the heterochromatin protein 1a (HP1a) in the reorganization of the 3D chromatin structure after fertilization. By combining powerful Drosophila genetics with 3D genome modeling, they discovered that HP1a is required to establish a proper chromatin 3D structure at multiple hierarchical levels during early embryonic development.

Early embryos as a model to study chromatin reprogramming

The degree of packaging as well as the corresponding gene activity is influenced by epigenetic modifications. These are small chemical groups that are installed on the histones. "Proteins that carry out these epigenetic modifications can be thought of as being either writers, erasers or reader of the given epigenetic modification. We discovered that the reader protein HP1a is required to establish chromatin structure during early embryonic development in Drosophila", says Fides Zenk, first-author of the study.

Early embryonic development is a particularly interesting time window to study the processes governing the organization of chromatin. At fertilization, two highly specialized cells - sperm and egg - fuse. The resulting totipotent zygote will ultimately give rise to all the different cells of the body. Interestingly most of the epigenetic modifications that shape chromatin are erased and have to be established de novo. In Drosophila, the lab of Nicola Iovino had previously shown that after fertilization chromatin undergoes major restructuring events. Thus, it is the ideal model system to study the processes underlying the establishment of chromatin structure.

De novo establishment of 3D genome architecture

When the genome of the zygote is activated for the first time after fertilization, it triggers global de novo 3D chromatin reorganization including a clustering of highly compacted regions around the centromere (pericentromeric), the folding of chromosome arms and the segregation of chromosomes into active and inactive compartments. "We identified HP1a as an important epigenetic regulator necessary to maintain individual chromosome integrity but also central for establishing the global structure of the genome in the early embryo," says Nicola Iovino.

3D genome simulation

These findings and data collected in Drosophila embryos have then been used by collaborators from the Friedrich Miescher Institute (FMI) lead by Luca Giorgetti to build realistic three-dimensional models of chromosomes. This is possible because chromosomes inside the cell nucleus are polymers, very large molecules composed of chains of smaller components (monomers) - in this case consecutive DNA base pairs and the DNA-binding proteins that together constitute the chromatin fiber. Like all other polymers, be it silk, polyethylene or polyester, chromatin obeys a general set of physical laws described by a branch of physics known as 'polymer physics'. These laws can be encoded into computer programs and used to simulate the three-dimensional shape of chromosomes in the nucleus.

"The advantage of this approach is that it allows simulating the effects of very large numbers of mutations. This enables researchers to explore scenarios that are beyond experimental reach, such as the simultaneous depletion of many different proteins that would require years of lab work. By comparing simulations with the outcome of experiments, this approach also allows to test alternative hypotheses concerning the mechanisms that lay at the basis of experimental observations," says Luca Giorgetti, group leader at the Friedrich Miescher Institute in Basel.

In this case, FMI researchers used polymer models of the entire Drosophila genome to ask the question: based on the basic laws of polymer physics, is it possible that the depletion of a single protein - HP1 - leads to a massive change in the associations and shape of chromosomes in the nucleus? Or are additional mechanisms needed to explain the experimental observations? "We found that removal of the protein to its binding sites in the simulations accounted for the full set of experimental results, thus providing further confirmation that HP1 plays a key role in establishing the three-dimensional structure of the genome" says Yinxiu Zhan, co-first-author of the study.

Words categorize the semantic fields they refer to in ways that maximize communication accuracy while minimizing complexity. Recent studies have shown that human languages are optimally balanced between accuracy and complexity. For example, many languages have a word that denotes the colour red, but no language has individual words to distinguish ten different shades of the colour. These additional words would complicate the vocabulary and rarely would they be useful to achieve precise communication.

A study published on 23 March in the journal Proceedings of the National Academy of Sciences of the United States of America analysed how artificial neural networks develop spontaneous systems to name colours. A study by Marco Baroni, ICREA research professor at the UPF Department of Translation and Language Sciences (DTCL), conducted with members of Facebook AI Research (France).

Optimal trade-offs between complexity and accuracy may be a universal property that arises in discrete communication systems, not related to specific features of human biology

For this study, the researchers formed two artificial neural networks trained with two generic deep learning methods. As Baroni explains: "we made the networks play a colour-naming game in which they had to communicate about colour chips from a continuous colour space. We did not limit the "language" they could use, however, when they learned to play the game successfully, we observed the colour-naming terms these artificial neural networks had developed spontaneously".

The results show that modern AI systems naturally adopt similar behaviours to humans

The authors found that the emerging colour vocabulary has exactly the same property of optimizing the complexity/accuracy trade-off found in human languages. Furthermore, this result is only maintained while the systems communicate via a discrete channel: when they are allowed to use continuous signals (such as whistles or non-linguistic hand gestures), their language loses efficiency.

From the point of view of cognitive science, the results suggest that optimal trade-offs between complexity and accuracy may be a universal property that arises in discrete communication systems, not related to specific features of human biology. Baroni adds: "the results show that modern AI systems naturally adopt similar behaviours to humans, which is nonetheless surprising".

This suggests that an efficient categorization of colours (and possibly other semantic domains) in natural languages is not dependent on specific human biological constraints, but is a general property of discrete communication systems.

The corona pandemic has had a major impact on the Nordic news media. At the same time as advertising revenues have fallen drastically, interest among the audience for professional news coverage has increased, according to a new report from Nordicom at the University of Gothenburg. Several Nordic media companies have also reported record sales of digital subscriptions as a result of the pandemic.

Covid-19 swept over the Nordic region and the rest of the world with full force in the spring of 2020. A year later, the pandemic still has the world in a strong grip. However, both the health-related and the economic consequences of the virus have varied between the Nordic countries. The same goes for the political response.

There are also differences within the Nordic region when it comes to the consequences of the pandemic for the media sector. Nordicom at the University of Gothenburg has, on behalf of the Nordic Council of Ministers, mapped the development of the private news media during the pandemic year of 2020. The study was carried out in collaboration with media researchers from all the Nordic countries.

"The national markets for professional news media in the Nordic region all have their unique structure, with a large variation in terms of size, range, financing models and financial strength. The view of state support for private media also looks different in the Nordic countries. An extensive economic and societal crisis - such as the corona pandemic - exposes many of these differences", says Ida Willig, professor at Roskilde University and one of the editors behind the report.

Falling advertising revenue but increased revenue from the audience

The rapid slowdown in the Nordic economies during the spring of 2020 immediately led to a dramatic decline in the willingness to invest in the Nordic advertising markets. The fall in advertising was particularly large in printed newspapers, where the decline in Denmark, Finland, Norway and Sweden amounted to around 25 per cent in 2020. This corresponds to a loss of revenue of about EUR 290 million. At the same time, investment in online advertising increased in three out of four countries.

"The restrictions following the pandemic have changed the behaviour of the advertising market in a very significant way. While many physical stores have had a difficult time, online shopping has grown strongly, which has increased interest in advertising online. This is a development that has benefited global advertising platforms such as Google and Facebook and disadvantaged national and local advertising media", says Jonas Ohlsson, director of Nordicom.

At the same time as the private news media have found it increasingly difficult to retain their advertisers, the opposite has happened in the audience market. In 2020, a significant increase in the reach of news media of various kinds was reported from all the Nordic countries - not least online.

The increased interest in news has also led to an increased willingness to pay for the digital content of the news media. The results of the report point to a clear increase in the proportion of households in the Nordic countries that choose to pay for news online.

"The professional news media have played an important role in the pandemic, both to disseminate information and to scrutinize political decisions. Several studies also show that trust in the Nordic news media's coverage has increased in 2020. The fact that more Nordic people have chosen to pay for news is a sign that professional journalism has strengthened its position among the audience during the pandemic", says Ida Willig.

Record-high state support

The dramatic fall in the advertising market in the spring of 2020 was followed by an intense debate on special support measures for the media sector in the Nordic region. The result of this was direct state support for private news media in all Nordic countries during 2020. In total, this amounted to a record amount of EUR 275 million, about a third of which consisted of special pandemic support.

However, the differences between the Nordic countries were large. In relation to population size, direct support for private news media was about ten times larger in Sweden and Denmark than it was in Finland in 2020.

"The Nordic media system has historically been characterised by an active media policy, which has involved both a large publicly funded public service sector and special support measures for private news media. Over the past decade, this model has become increasingly politicised, and the Nordic countries have increasingly chosen different paths in the formulation of national media policy. The influx of audiences to both the public service and the private news media during the pandemic has shown the value of the Nordic model. It gives increased topicality to media policy issues even after the pandemic", says Jonas Ohlsson.