Culture

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.

Philadelphia, April 15, 2021--Researchers at Children's Hospital of Philadelphia (CHOP) have identified a key target that may be responsible for treatment failure in about 30% of patients with hemophilia A. The target, known as B cell activating factor (BAFF), appears to promote antibodies against and inhibitors of the missing blood clotting factor that is given to these patients to control their bleeding episodes. The findings, published in the Journal of Clinical Investigation, raise the possibility of using anti-BAFF therapies, potentially in combination with immune tolerance therapies, to tame the immune response in some patients with severe hemophilia A.

Hemophilia A is the most common inherited bleeding disorder, affecting 1 in 10,000 men worldwide. The condition is the result of a missing coagulation factor known as factor VIII (FVIII), which leads to uncontrolled bleeding episodes, joint disease, and increased risk of death. To control the disease, patients receive infusions of the FVIII protein to replace the missing coagulation factor, but for reasons scientists haven't fully understood, approximately 30% of patients with severe hemophilia A develop neutralizing antibodies known as FVIII inhibitors that prevent the treatment from working, which negatively affects disease management.

Some patients resistant to FVIII protein replacement therapy receive immune tolerance induction (ITI), wherein high doses of FVIII are given over a period of one to two years to build up tolerance. However, ITI is demanding on patients and families, and the treatment - which is both costly and invasive - isn't always effective.

To both uncover the mechanism behind the anti-FVIII immune response and expose a potential target, the researchers explored the possible role of BAFF in regulating FVIII inhibitors. Prior studies have shown that high plasma BAFF levels are implicated in some autoimmune diseases, as well as antibody-mediated transplant rejections. Using both adult and pediatric hemophilia A patient samples and hemophilia A mouse models, the researchers explored their hypothesis that BAFF may play a role in the generation and maintenance of FVIII antibodies.

The research team, led by CHOP and Indiana University School of Medicine, found that BAFF levels were elevated in pediatric and adult patients who were resistant to FVIII replacement therapy; after successful ITI, those BAFF levels decreased to levels similar to non-inhibitor patients. In patients for whom ITI was unsuccessful, BAFF levels remained elevated. Working in mouse models, the researchers found that giving the mice prophylactic anti-BAFF therapy before FVIII treatment prevented inhibitors. In mice with established inhibitors, the researchers found that treating the mice with both anti-BAFF and rituximab, a chimeric antibody that depletes mature B cells, dramatically reduced FVIII inhibitor titers by, at least in part, reducing FVIII-specific plasma cells.

"Our data suggest that BAFF may regulate the generation and maintenance of FVIII inhibitors, as well as anti-FVIII B cells," said co-senior author Valder R. Arruda, MD, PhD, a researcher in the Division of Hematology at CHOP and director of CHOP's NIH-funded Center for the Investigation of Factor VIII Immunogenicity. "Given that an FDA-approved anti-BAFF antibody is currently used to suppress the immune response in autoimmune diseases, future research should explore the use of this treatment in combination with rituximab to achieve better outcomes for hemophilia A patients resistant to FVIII protein replacement therapy."

April 15, 2021 - Decades after their days on the gridiron, middle-aged men who played football in high school are not experiencing greater problems with concentration, memory, or depression compared to men who did not play football, reports a study in Clinical Journal of Sport Medicine. The journal is published in the Lippincott portfolio by Wolters Kluwer.

"Men who played high-school football did not report worse brain health compared with those who played other contact sports, noncontact sports, or did not participate in sports during high school," according to the new research, led by Grant L. Iverson, PhD, of Harvard Medical School. The study offers reassurance that playing high-school football is not, in itself, a risk factor for cognitive or mood disorders or other problems that have been linked to a history of repeated concussions in professional football players.

No increase in cognitive, mood, or pain problems in high-school football players

The researchers analyzed responses to an online survey completed by 407 men aged 35 to 55 years. Of these, 123 reported playing football in high school. The study excluded men with recent concussions or those who played semi-professional football.

Rates of a wide range of brain health problems were assessed for the ex-football players, compared to men who played other contact sports, non-contact sports, or no sports. Men who played contact sports, especially football, had more concussions than the other two groups: more than 80 percent of men who played high-school football reported at least one concussion.

Overall, the former football players were no more likely to have problems with brain health in their mid-thirties to mid-fifties. High-school sports experience was unrelated to problems with depression, anxiety, or anger; concentration or memory problems; or headaches, migraines, neck or back pain, or chronic pain. For football and other contact sports, rates of brain health problems were unrelated to years playing sports.

There were a few significant differences between groups. Men who played high-school football were more likely to report sleep problems: 39 percent, compared to about 20 to 30 percent of the other groups. Ex-football players were also more likely to be prescribed medications for headaches or chronic pain.

The study identified several factors that predicted an increased rate of memory problems, including sleep difficulties, anxiety, history of concussions, and feeling depressed. Although some of these factors were more common among former football players, playing football itself was not a significant predictor.

Reports of long-term neurological abnormalities among former National Football League (NFL) players have raised concerns over the brain health of men who played football at the high-school level. Previous studies have found no increase in mental health, cognitive, or mood problems in former high-school football players. The new research - partly supported by the NFL - is the first to focus on middle-aged men.

Dr. Iverson and colleagues emphasize that, "without question," some men who played high-school football will develop problems with psychological health and cognitive function later in life. However, these risks "do not seem to be greater than the rates in men who did not play football."

The researchers note that there are strong associations between depression and anxiety, headaches and migraine, chronic pain, and memory problems, which commonly occur together and are "mutually amplifying." Dr. Iverson and colleagues conclude, "[E]vidence-based treatment and rehabilitation for these problems can substantially reduce symptoms and improve functioning and quality of life."

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with a high fatality rate. Currently, chemotherapy is the major treatment option, but the clinical result is unsatisfactory. A research team led by biologists at City University of Hong Kong (CityU) has identified and characterised a set of specific super-enhancers that stimulate the activity of the related critical cancer genes. The research has also discovered that the deletion of certain specific super-enhancers can reduce tumour cell growth. The latest findings may help discover new effective drug targets for TNBC patients to improve their survival chance.

Traditionally, cancer research has been focused on identifying gene mutations in different types of breast cancer. In contrast, how the epigenetic circuit affects cancers remains poorly characterised.

Epigenetic change: another way to induce cancers

While genetic mutation is a change in one or more parts of the DNA sequence, an epigenetic change also changes a gene's DNA, but not at the sequence level. Instead, special marks, called epigenetic marks, are added to or removed from the DNA sequence to change how a protein works in the body. And specific epigenetic marks are contained in super-enhancers. Deregulation, meaning abnormal regulation, of super-enhancers can therefore induce high production of cancer driver proteins and promote cancer formation.

To find out how these super-enhancers can affect TNBC cells, Dr Rebecca Chin Yuet-ming, a cancer biologist, and Dr Wang Xin, a computational biologist, both from the Department of Biomedical Sciences at CityU, joined hands together to lead the study. Their findings were published in the scientific journal Nature Communications, titled "Defining super-enhancer landscape in triple-negative breast cancer by multiomic profiling".

Integrating multi-level epigenomic sequencing data for 21 cell lines with gene expression data and clinical information for over 4,000 patient samples, Dr Wang's team used the method of multiomic profiling to perform in-depth data mining and built a specific super-enhancer-target regulatory network for all types of breast cancer.

A key regulator of cancer growth

"Our integrated analyses reveal that the clustering of super-enhancers is sufficient to characterise different subtypes of breast cancer," said Dr Wang. "Importantly, based on the regulatory network, we identify the gene FOXC1 as a key regulator of cancer growth and metastasis which is driven by a TNBC-specific super-enhancer. The FOXC1 is predictive of patients' survival and help develop therapeutic strategies targeting epigenetic circuits."

A number of key cancer driver genes (oncogenes), including FOXC1 and MET, are known to promote cancer growth and are associated with worse survival in TNBC patients. However, very little is known about how these genes being specifically highly expressed in TNBC. "Our network biology analysis uncovers FOXC1 as the master regulator of a large set of genes in metastasis. Using CRISPR/Cas9 technology, we further directly demonstrate that super-enhancer drives FOXC1 expression, and importantly, enhances cancer growth in mouse models," said Dr Chin.

By performing analysis on in-house clinical samples, the teams also learnt that FOXC1 upregulation is associated with higher tumour grade, cell division rate, and tumour-infiltrating immune cells.

Another TNBC-specific gene

The researchers went a step further and applied the integrated method to discover another new TNBC-specific gene ANLN. ANLN has been shown to be correlated with TNBC recurrence and poor survival rate in previous studies. In this study, the team found that the deletion of super-enhancer of ANLN could reduce the protein expression and tumour cell growth. "These findings demonstrate the power of leveraging epigenetic landscape to identify novel players in TNBC, paving the way to discover more effective therapeutic targets for this aggressive form of breast cancer," Dr Chin said.

Breast cancer is the most common type of cancer in women, with about 4,600 new cases of breast cancer being diagnosed in Hong Kong each year. Among all breast cancers, TNBC accounts for about 10-15%. Different from other types of breast cancer, TNBC does not express hormone receptors (namely estrogen receptors and progesterone receptors) and a protein called Her2, and that's where its name "triple-negative breast cancer" comes from. So TNBC is quite "invisible", and it is also difficult to heal as the scientists have not found an effective "target" on the TNBC cancer cell for the drugs to attack.

TNBC usually develops between the ages of 40-50, younger than the average breast cancer patients. Also, the time for TNBC metastasis is shorter. Patients typically relapse within 5 years of treatment, and is considered to have a poorer prognosis than other breast cancer forms.

"We hope our findings can contribute to the development of effective drugs for TNBC patients to improve their chance of survival," said Dr Chin.

More than 30 years ago, wilderness areas - natural areas that have not been considerably modified by humans - were identified as priorities of conservation and protection actions. Only recently has there been a push to define how to measure wilderness, with a focus on intact habitats. The integrity of natural ecosystems has also been recognized by the UN Convention on Biological Diversity as an important goal in the post-2020 global biodiversity framework. "We know intact habitat is increasingly being lost and the values of intact habitat have been demonstrated for both biodiversity and people," says Dr Andrew Plumptre from the Key Biodiversity Areas Secretariat in Cambridge, lead author of the study, "but this study found that much of what we consider as intact habitat is missing species that have been hunted by people, or lost because of invasive species or disease."

Defining intactness

Currently, there is no common definition of intactness. Past assessments, which focused on mapping human influence on habitat intactness, created maps of anthropogenic impact that independently estimated that between 20% and 40% of the planet's terrestrial surface remains free from major human disturbance (such as human settlements, roads, and light and noise pollution).

In the new study, Plumptre and colleagues took a different approach. Instead of focusing on human impact, they made a scoping of Key Biodiversity Areas (KBA) Criterion C sites, which states that an intact ecological community has the full complement of species known to occur in a particular site in their natural abundances (ie no known loss of animals in that area), relative to a regionally appropriate benchmark. As a benchmark, the authors chose the year 1500 CE, as this is the baseline date for assessing species extinctions within the IUCN Red List of Threatened Species. In addition to habitat intactness, the authors also assessed faunal intactness (ie, without any loss of animal species) and functional intactness (no loss of animal densities below a level that would affect the healthy functioning of an ecosystem).

Restoring intact habitats

The authors explored how applying these 3 measures of intactness reduces the number of sites that might qualify under KBA Criterion C. They found that only between 2% an 3% of Earth's terrestrial surface qualifies if Criterion C is defined as sites which are functionally intact, 10 times lower than previously estimated. Worryingly, only 11% of the measured sites are covered by protected areas. Many of the identified areas coincide with territories managed by indigenous communities, who play a crucial role in maintaining them. "Areas identified as functionally intact included east Siberia and northern Canada for boreal and tundra biomes, parts of the Amazon and Congo basin tropical forests, and the Sahara Desert," according to the authors.

However, there is hope. The authors say that up to 20% of the planet's land surface could be restored to faunal intactness through reintroductions of only a few species into remaining intact habitat. Plumptre says: "The results show that it might be possible to increase the area with ecological intactness back to up to 20% through the targeted reintroductions of species that have been lost in areas where human impact is still low, provided the threats to their survival can be addressed and numbers rebuilt to a level where they fulfil their functional role."

In the future, identifying areas under KBA Criterion C can help focus attention on these sites for conservation and restoration, according to Plumptre, "It has been shown that intact habitat has important benefits for both wildlife and people and as a result needs to be a critical target of the ongoing negotiations of the Convention on Biological Diversity post-2020 global biodiversity framework. Recognition of these special places within intact habitat, where you have full functional intactness, is needed and plans to focus restoration in areas where ecological integrity might be recovered."

A new study in SLEEP, published by Oxford University Press, demonstrates the significant benefits of later school start times for middle and high school students' sleep schedules.

Sleep is essential to a student's overall health, social development, and academic achievement, yet lack of sleep is common among children and adolescents. Biological changes to sleep cycles during puberty make falling asleep early difficult for adolescents. This, coupled with early school start times, means that students often end up with insufficient sleep.

Approximately 28,000 elementary, middle, and high school students and parents completed surveys annually, before changes to school start times and for two years afterward. Participating elementary schools started 60 minutes earlier, middle, 40-60 minutes later, and high school started 70 minutes later. Student and parent surveys separately asked about students' typical bedtime and wake time on both weekdays and weekends. The surveys also asked respondents to report on students' quality of sleep and their experience of daytime sleepiness.

Researchers found that the greatest improvements in these measures occurred for high school students, who obtained an extra 3.8 hours of sleep per week after the later start time was implemented. More than one in ten high school students reported improved sleep quality and one in five reported less daytime sleepiness. The average "weekend oversleep," or additional sleep on weekends, amongst high schoolers dropped from just over two hours to 1.2 hours, suggesting that with enough weekday sleep, students are no longer clinically sleep deprived and no longer feel compelled to "catch up" on weekends. Likewise, middle school students obtained 2.4 additional hours of sleep per week with a later school start time. Researchers saw a 12% decrease in middle schoolers reporting daytime sleepiness. The percent of elementary school students reporting sufficient sleep duration, poor sleep quality, or daytime sleepiness did not change over the course of the study.

The benefits of later start times were similar across racial and socioeconomic groups, but survey results indicated differences in weekday bedtimes. The authors encourage steps to be taken to "identify and ameliorate systemic factors that contribute to these differences," recommending education programs developed in partnership with families to ensure that guidance for adjusting bedtimes and increasing sleep opportunities are sensitive to sociocultural and environmental factors.

Previous studies have not concurrently considered the impact of changing start times on sleep for students from Kindergarten through 12th grade, a key factor in policy outcomes due to the need for school districts to stagger start times to accommodate transportation schedules.

"This study is remarkable due to the large sample size, the inclusion of elementary and middle school students, the two-year follow-up, and both student and parent report. It also provides the strongest evidence to date that moving elementary school start times to 8:00 am caused no significant negative effect on student sleep or daytime sleepiness. As students return to in-person learning, it is important for districts to consider healthy start times for all students."

As females age, their bodies typically undergo two significant changes that generally occur during adolescence and middle age. The first, known as menarche, is the time during puberty when a girl begins having monthly menstruation cycles, which often tends to range from 8-13 years of age. She enters the second change, known as menopause, 12 months following her last menstruation cycle when her ovarian function ceases, usually sometime in her 40s or 50s.

The time after menarche and prior to menopause is known as a woman's reproduction life span and marks the years when she is most able to bear children. For many women, these events occur naturally. However, women can enter menopause earlier than expected due to other issues. Women that undergo radiation therapy for cancer typically stop menstruating, as do women who undergo surgical menopause procedures such as having their ovaries removed.

Because each woman experiences these life stages at different times, one woman's reproductive life span is generally shorter or longer than that of another, sometimes significantly so. Duke Appiah, Ph.D., from the Texas Tech University Health Sciences Center (TTUHSC) Graduate School of Biomedical Sciences, said those differences can affect much more than a woman's reproductive health.

For instance, Appiah said, researchers have known a link exists between the duration of a woman's reproductive life span and her overall metabolic health, but they haven't known why. Part of that link, he opined, could be caused by a woman being naturally exposed to estrogen and various estrogen compounds. Estrogens can be beneficial because they can help protect or delay the onset of certain health issues. However, they also have been associated with some diseases, and women that normally have less estrogen and remain that way through menopause are more likely to develop heart disease or osteoporosis.

"If the reproductive life span is longer, then that means they still have exposure to the natural estrogens, which will also help delay some diseases like cardiovascular disease and osteoporosis, and to some extent, even cancer," Appiah said.

But why do some women who have longer reproductive life spans, and therefore longer exposure to estrogens, still develop metabolic issues?

It's a question Appiah and a group of collaborators set out to address in a research letter to the Journal of the American Medical Association (JAMA). The letter, "Trends in Age at Natural Menopause and Reproductive Life Span Among U.S. Women, 1959-2018," was published in JAMA's April 8 issue. Appiah's collaborators included Chike C. Nwabuo, M.D., MPH, from Johns Hopkins University; Imo A. Ebong, M.D., M.S., from the University of California, Davis; Melissa F. Wellons, M.D., MHS, from Vanderbilt University Medical Center; and Stephen J. Winters, M.D., from the University of Louisville.

Appiah, an assistant professor of public health at the TTUHSC and director of the university's master's program in public health, said women who enter menopause at age 40-45 years have a higher risk of developing cardiovascular disease, whereas those who become menopausal after the age of 50 experience a higher risk of breast cancer.

"These characteristics have clinical significance, but we wanted to see in the United States over the past 60 years, if there have been any changes in age at menopause, reproductive life span and to age at menarche," Appiah explained. "If it was changing, we wanted to find out what factors are possibly associated with these changes. Not many studies have been done in the U.S. to look at trends in age at menopause. If we can see some of the factors which are associated with or are driving having natural menopause at an earlier age, perhaps we can intervene."

Appiah said many of the previous studies are outdated and used data from shorter time periods such as 1910-1950. None of these studies investigate the link between age at menopause and the development of metabolic health issues. They also failed to address factors that may cause a woman to enter menopause earlier in her life.

To collect data for his study, Appiah used successive surveys spanning the 1959-1962 National Health Examination Survey I (NHES I) through the National Health and Nutrition Examination Survey (NHANES) for 2017-2018. The NHANES is a biennial survey conducted by the Centers of Disease Control and Prevention to generally evaluate the health of children and adults in the U.S. In addition to providing a significantly larger sample size, the NHANES provides a cross-sectional sample of the non-institutionalized U.S. adult population. It includes a detailed demographic and behavioral questionnaire, a physical examination, laboratory testing and a list of all prescription medications used by the respondent.

Using this data, Appiah was able to analyze 7,773 women aged 40 to 74 years at the time of the survey and who had reached natural menopause. From the 1959-1962 NHES I to the 2015-2018 NHANES, the mean age at which women reached natural menopause increased from 48.4 years to 49.9 years and the mean age at menarche fell from 13.5 years to 12.7 years. This resulted in an increase of the mean reproductive life span from 35.0 years to 37.1 years.

In multivariable adjusted models Appiah saw that race and ethnicity (Black and Hispanic), poverty, current and former smoking status and hormone therapy use were associated with earlier age at natural menopause and a shorter reproductive life span. Factors such as more years of education and use of oral contraceptives were associated with women who reached natural menopause at a later age and had longer reproductive life span.

Appiah said other factors not assessed in their study such as lifestyle and behavior factors, improved access to health care, nutrition, obesity and environmental factors may be related to the increasing trends in age at natural menopause and reproductive life span.

In past research, Appiah has shown that menopause is associated with metabolic conditions, which also influence the development of certain diseases. More importantly, he said, his work has shown that researchers tend to be more concerned about the age at which women reach menopause when they actually need to identify factors that are causing women to reach menopause at an earlier age because those factors tend to be more important.

"This study was to give some empirical evidence to some of my past studies, but then for future studies, I'm still looking at how age and menopause is associated with cardiac structure and function, for instance, how the heart beats, how the heart becomes bigger with age," Appiah said. "This paper has given perspective to some of my past work, and it's also given some direction to my future work, whereby I'll look at whether age at natural menopause and length of reproductive life span is a marker for overall health in women."

Little is known about azhdarchid pterosaurs, gigantic flying reptiles with impressive wingspans of up to 12 meters. Cousins of dinosaurs and the largest animals ever to fly, they first appeared in the fossil record in the Late Triassic about 225 million years ago and disappeared again at the end of the Cretaceous period about 66 million years ago. One of their most notable features for such a large flighted animal was a neck longer than that of a giraffe. Now, researchers report an unexpected discovery in the journal iScience on April 14: their thin neck vertebrae got their strength from an intricate internal structure unlike anything that's been seen before.

"One of our most important findings is the arrangement of cross-struts within the vertebral centrum," says Dave Martill of the University of Portsmouth, UK. "It is unlike anything seen previously in a vertebra of any animal. The neural tube is placed centrally within the vertebra and is connected to the external wall via a number of thin rod-like trabeculae, radially arranged like the spokes of a bicycle wheel and helically arranged along the length of the vertebra. They even cross over like the spokes of a bicycle wheel. Evolution shaped these creatures into awesome, breathtakingly efficient flyers."

Scientists previously thought the pterosaur's neck had a simpler tube-within-a-tube structure, he explains. But it raised an important question: how could their thin-walled bones, needed to reduce weight in the flying reptiles, still support their bodies and allow them to capture and eat heavy prey animals?

Cariad Williams, the study's first author, hadn't set out to answer that question. She wanted to examine the degree of movement between each vertebra of the pterosaur's neck.

"These animals have ridiculously long necks," Williams says, adding that, in some species, the fifth vertebra of the neck from the head end is as long as the animal's body. "It makes a giraffe look perfectly normal. We wanted to know a bit about how this incredibly long neck functioned, as it seems to have very little mobility between each vertebra."

While the Moroccan pterosaur bones they study are well preserved in three dimensions, the researchers still hadn't expected the scans to offer such a clear view of the vertebra's intricate internal structure.

"We did not originally CT scan it to learn about the inside; we wanted a very detailed image of the outside surface," Martill says. "We could have got this by ordinary surface scanning, but we had an opportunity to put some specimens in a CT scanner, and it seemed churlish to turn the offer down. We were simply trying to model the degree of movement between all the vertebrae to see how the neck might perform in life."

He adds, "What was utterly remarkable was that the internal structure was perfectly preserved--so too was the microhistology when we made some petrographic sections through the bone. As soon as we saw the intricate pattern of radial trabeculae, we realized there was something special going on. As we looked closer, we could see that they were arranged in a helix traveling up and down the vertebral tube and crossing each other like bicycle wheel spokes."

His team realized immediately that they needed to bring in engineers to understand how the biomechanics of this unusual neck would have worked. Those analyses suggest that as few as 50 of the spoke-like trabeculae increased the amount of weight their necks could carry without buckling by 90%. Together with the basic tube-within-a-tube structure, it explains how the relatively light-weight animals could capture and carry heavy prey items without breaking their necks.

"It appears that this structure of extremely thin cervical vertebrae and added helically arranged cross-struts resolved many concerns about the biomechanics of how these creatures were able to support massive heads--longer than 1.5 meters--on necks longer than the modern-day giraffe, all whilst retaining the ability of powered flight," Martill says.

While pterosaurs are sometimes thought of as evolutionary dead ends, Martill and colleagues say the new findings reveal them as "fantastically complex and sophisticated." Their bones and skeletons were marvels of biology--extremely light yet strong and durable.

The researchers say there's still much to learn in future work about pterosaurs, including seemingly basic questions about their flight abilities and feeding ecology.