Culture

Scientists from the lab of Franz Klein from the Department of Chromosome Biology at the Max Perutz Labs, a joint venture of the University of Vienna and the Medical University of Vienna, have now discovered that cells sometimes liberate DNA fragments at sites of paired, or double, DSBs. Whilst this presents an obvious risk of germline mutations as a consequence of erroneous repair or of integration of fragments from elsewhere at break sites, it may also be a source of evolutionary diversity. The study is published as a research article in Nature.

Genetic information in humans is encoded in 23 chromosome pairs, where one pair consists of two slightly different copies or homologs. One is inherited from the father and one from the mother. Human gametes, however, are haploid - they start out with only half the number of chromosomes. When gametes fuse during sexual reproduction they create an organism with the full set of chromosomes. The random assortment of parental chromosomes together with the exchange of genetic material between homologous chromosomes during early meiosis, account for genetic diversity in the offspring.

Meiosis begins with controlled self-harm

Each human gamete contains one of billions of possible combinations of the genetic information they inherit from their parental cells. Sexually reproducing organisms take a high risk to achieve this diversity. To initiate meiotic recombination, cells introduce hundreds of dangerous DNA DSBs in chromosomes with an enzyme called Spo11-complex. By using the homologous copy as a template, the breaks are repaired and genetic information is exchanged between chromosomes. "Cells have been observed to keep double strand breaks far apart from one another", explains group leader Franz Klein. "However, rather surprisingly, we have now discovered that approximately 20% of breaks correspond to closely positioned pairs of DSBs, that punch out entire pieces of the chromosome. These gaps can also initiate recombination, something that has not been considered before."

Spo11 recognizes physical strain of DNA

The team led by molecular biologist Dr. Silvia Prieler and bioinformatician Dr. Doris Chen mapped the liberated fragments across the entire yeast genome with single nucleotide precision, better than DSBs had ever been mapped before. This precision led to several new observations, for instance that DNA may have to be bent during the cleavage reaction. They also found that sites where DNA is frequently under high topological stress are cleaved more efficiently. During transcription, the two DNA strands are separated to allow RNA production. This causes the DNA-strands on both sides of the transcription-bubble to be over- or underwound and generates considerable physical strain. This kind of topological strain is resolved by so-called topoisomerases, to which the Spo11-complex is closely related. A key question, therefore, is why a topoisomerase-relative initiates meiotic recombination, given that the cell has dedicated nucleases that could cleave the DNA. "The goal in meiosis is to provide chances for novel genetic combination on as many sites as possible, to combine even closely spaced parental alleles", says Franz Klein. "Our study provides a hint as to why Spo11 may be so suitable to initiate meiotic recombination: instead of recognizing specific DNA sequences, which would recombine chromosomes always at predetermined positions, it recognizes stressed DNA, something that can occur at any sequence that is frequently used."

High risk - high potential

Why cells undergo the risk to punch out chromosome pieces is still unclear. The gaps and their corresponding fragments pose an enhanced risk for mutations, caused by deletions or by the insertion of fragments in irregular positions. The scientists show that although these pairs of double strand breaks are spread across the genome, they often correspond with promoter regions that are especially prone to topological stress. Promoters are genetic elements that regulate the level of transcription. "Evolutionarily, it would be great to be able to exchange functional regulatory elements between different sites in the genome. This raises the intriguing possibility that meiotic gaps at double DSBs could stimulate the evolution of control elements in the genome", concludes Franz Klein. A risky business for a single cell, no doubt, but perhaps worth the risk for the species.

Language is one of our species' most important skills, as it has enabled us to occupy nearly every corner of the planet. Among other things, language allows indigenous societies to use the biodiversity that surrounds them as a "living pharmacy" and to describe the medicinal properties of plants. Linguists estimate that there are nearly 7,400 languages in the world today.

Most of these languages, however, are not recorded in writing, and many languages are not being passed on to the next generation. This has led linguists to estimate that 30 percent of all languages will disappear by the end of the 21st century. For indigenous cultures who mostly transmit knowledge orally, this high risk of language extinction also threatens their knowledge of medicinal plants.

Threatened languages support most of unique knowledge

Researchers from the University of Zurich have now assessed the degree to which indigenous knowledge of medicinal plants is linked to individual languages. Senior researcher Rodrigo Cámara-Leret and Jordi Bascompte, professor of ecology, analyzed 3,597 medicinal species and 12,495 medicinal applications associated with 236 indigenous languages in North America, northwest Amazonia and New Guinea. "We found that more than 75 percent of all medicinal plant services are linguistically-unique and therefore only known to one language," Cámara-Leret points out.

To quantify how much of this linguistically-unique knowledge may vanish as languages or plants go extinct, the researchers turned to the Glottolog catalogue of the world's languages and the IUCN Red List of Threatened Species to gain information on the threat to languages and medicinal plant species, respectively. They found that threatened languages support over 86 percent of all unique knowledge in North America and Amazonia, and 31 percent of all unique knowledge in New Guinea. By contrast, less than 5 percent of medicinal plant species were threatened.

International Decade of Indigenous Languages

The findings of this study indicate that each indigenous language provides unique insights into the medicinal applications associated with biodiversity. Unfortunately, the study suggests that language loss will be even more critical to the extinction of medicinal knowledge than biodiversity loss. The study coincides with the United Nations proclaiming the next 10 years as the International Decade of Indigenous Languages to raise global awareness of the critical situation of many indigenous languages. "The next steps, in line with the vision of the UN, will require mobilizing resources for the preservation, revitalization and promotion of these threatened languages," Bascompte says. Additionally, launching large-scale community-based participatory efforts will be crucial to document endangered medicinal knowledge before it vanishes.

Researchers at the University of Geneva (UNIGE) demonstrate that innovative projects spearheaded by United Nations (UN) country offices are remodeling the institution and expanding its role. Digital initiatives, particularly those scaled through headquarters, were shown to have the strongest impact, changing ways of working, embedding new skills, and restructuring teams across the UN. These findings, published in the Journal of Management Studies, highlight that fostering even single innovative projects could lead to fundamental transformations in the UN.

How do International Organizations build innovation capabilities through intrapreneurship and entrepreneurial behavior? To answer this question, researchers Tina Ambos and Katherine Tatarinov of the Geneva School of Economics and Management (GSEM) at the UNIGE looked at how innovative projects, particularly those born in country offices, are changing the institutional system in a sustainable way.

The role of digital technology

In one of the case studies conducted for this research, a refugee cash transfer initiative using blockchain widened the responsible UN body's role from 'ending poverty and hunger' to that more closely resembling a fintech company or development bank. By providing a platform for aid delivery, the organization is now helping its partners bypass unstable third-parties and save on transaction costs. "Such new activities often stretch the original mission of the organization", explains Tina Ambos, professor of international management at GSEM and director of the i2i Hub for Innovation and Cross-Sector Partnerships. "The use of blockchain could spread across the entire UN system, changing the ways of working and increasing transparency."

Sensitive data on vulnerable groups held by the UN often means that digital innovation cannot be outsourced. This results in the organization upgrading its institutional knowledge and creating new teams to manage digital projects, which were found to have the biggest impact on how the UN operates overall. "Other skills have also been internalized, such as technical skills and human-centered design approaches", says co-author and PhD student Katherine Tatarinov. "After learning in one context, the UN was able to test different technologies in its sites of operation according to local needs without depending on external experts."

Innovation units were found to be key in helping the UN scale initiatives by driving forward dynamic solutions. Such units nurture initiatives through boot camps, cross-sectoral connections, helping teams overcome internal barriers, and broadcasting new learnings to the entire organization. The UN also involves local people to ensure sustainability and maximize social impact. End-users, such as refugees, are often active members of development teams, helping ensure that projects 'do no harm.'

The power of bottom-up innovation

Innovations often start life in UN country offices, where staff need to respond quickly to unfolding crises. To circumvent slow central procedures, in-country innovators may decide not to involve the headquarters. Good ideas then spread from country to country, such as an anonymous SMS polling tool designed to gauge opinions on taboo topics in remote communities. "The idea grew organically, as other country offices could see the value of access to data on taboo topics", says Tina Ambos. Such country-level innovations can achieve scale and have been shown to change the organization's culture when digital technology is involved.

Innovation champions at the country level are willing to employ workarounds to avoid head office bureaucracy, because they are motivated to solve an urgent problem - rather than by internal rewards or recognition. They are therefore able to access funds and forge partnerships which may have been disregarded by the large, centralized machinery of the UN, but which nevertheless align with broader organizational values.

"Strict hierarchies, risk-averse donors, and lengthy sign-off processes can stifle ideas, yet international organizations need to innovate to stay relevant", says co-author Katherine Tatarinov. "Greater public scrutiny, funding challenges, and the push towards digital means that bodies like the UN need to reinvent themselves - their culture, identity, and management styles. By becoming more responsive and fostering innovative ideas, they can better achieve their missions and our shared global goals." The study findings show that the seed from one good idea can grow throughout a complex organization like the UN, changing it from the inside, and creating new space for enterprising ideas to flourish.

Scientists from the University of Melbourne and University of Queensland have revealed the mystery behind the unique reproductive parts of the much-loved echidna.

In the paper, "The Unique Penile Morphology of the Short-Beaked Echidna, Tachyglossus aculeatus", the team detail how the male monotreme's testes never descend, have no scrotum, and when not in use, their penis is stored internally.

They also detail how the echidna penis has four heads, which are actually rosette-like glans at the end. Just two of the four glans ever become functional during erection and which glans are functional appears to alternate between subsequent erections.

Led by Professor Andreas Hartmann, from the University of Freiburg (Germany), the researchers analyzed the presence of several pollutants in water from many karst aquifers of Europe, North Africa, and the Middle East, relating fast infiltration processes to an increased concentration of these substances. The findings of this research are published in the scientific journal Proceedings of the National Academy of Sciences (PNAS).

This way, they warn that during rainfall events -when aquifers recharge, especially during autumn rainfall- the concentration of pollutants and pathogenic microorganisms can significantly exceed the safe levels, causing serious consequences for human consumption.

"About one quarter of the world's population obtains water from karst aquifers, which are especially vulnerable to contamination due to their functioning. Groundwater usually flows fast in this type of environment, which favors the infiltration of pollutants", explains the Professor of External Geodynamics from the UMA Bartolomé Andreo, Director of CEHIUMA.

The risks of fertilizers

The researchers considered the degradable pesticide named glyphosate, a widely used agricultural herbicide, as an example to demonstrate their findings. The simulations performed show that rapid transport of glyphosate to the groundwater may cause this pesticide to exceed by 19 times the maximum values permitted by law. "The highest risk of groundwater contamination occurs in regions where agriculture depends on degradable fertilizers and pesticides", they assure.

In this regard, the researcher from the UMA Matías Mudarra, another author of this study, stresses that the risk from degradable pollutants like pesticides, pharmacological products or pathogens must be considered in the studies, as it is significantly higher than expected and has a direct impact on the water quality, "a critical aspect for its potential use for water supply", he says.

At the heart of almost every sufficiently massive galaxy there is a black hole whose gravitational field, although very intense, affects only a small region around the centre of the galaxy. Even though these objects are thousands of millions of times smaller than their host galaxies our current view is that the Universe can be understood only if the evolution of galaxies is regulated by the activity of these black holes, because without them the observed properties of the galaxies cannot be explained.

Theoretical predictions suggest that as these black holes grow they generate sufficient energy to heat up and drive out the gas within galaxies to great distances. Observing and describing the mechanism by which this energy interacts with galaxies and modifies their evolution is therefore a basic question in present day Astrophysics.

With this aim in mind, a study led by Ignacio Martín Navarro, a researcher at the Instituto de Astrofísica de Canarias (IAC), has gone a step further and has tried to see whether the matter and energy emitted from around these black holes can alter the evolution, not only of the host galaxy, but also of the satellite galaxies around it, at even greater distances. To do this, the team has used the Sloan Digital Sky Survey, which allowed them to analyse the properties of the galaxies in thousands of groups and clusters. The conclusions of this study, started during Ignacio's stay at the Max Planck Institute for Astrophysics, are published today in Nature magazine.

"Surprisingly we found that the satellite galaxies formed more or fewer stars depending on their orientation with respect to the central galaxy", explains Annalisa Pillepich, researcher at the Max Planck Institute for Astronomy (MPIA, Germany) and co-author of the article. To try to explain this geometrical effect on the properties of the satellite galaxies the researchers used a cosmological simulation of the Universe called Illustris-TNG whose code contains a specific way of handling the interaction between central black holes and their host galaxies. "Just as with the observations, the Illustris-TNG simulation shows a clear modulation of the star formation rate in satellite galaxies depending on their position with respect to the central galaxy", she adds.

This result is doubly important because it gives observational support for the idea that central black holes play an important role in regulating the evolution of galaxies, which is a basic feature of our current understanding of the Universe. Nevertheless, this hypothesis is continually questioned, given the difficulty of measuring the possible effect of the black holes in real galaxies, rather than considering only theoretical implications.

These results suggest, then, that there is a particular coupling between the black holes and their galaxies, by which they can expel matter to great distances from the galactic centres, and can even affect the evolution of other nearby galaxies. "So not only can we observe the effects of central black holes on the evolution of galaxies, but our analysis opens the way to understand the details of the interaction", explains Ignacio Martín Navarro, who is the first author of the article.

"This work has been possible due to collaboration between two communities: the observers and the theorists which, in the field of extragalactic Astrophysics, are finding that cosmological simulations are a useful tool to understand how the Universe behaves", he concludes.

Homocysteine (HCY) is a sulfur-containing aminoacid, which attract more and more attention as the increase of homocysteine level associates with a number of pathological conditions. Hyperhomocysteinemia (hHCY) is an elevation of HCY level in plasma and develops due to genetic mutations of enzymes involved in regulation of HCY metabolism, nutritional deficiencies of vitamins B12, B6 and folate; chronic renal failure; alcoholism, smoking, excess coffee consumption, hypothyroidism; taking a number of medications like antiepileptic drugs and LDOPA; and aging. hHcy is a well-known independent risk factor for cardio-vascular diseases, neurodegenerative disorders, and associated with common pregnancy complications such as preeclampsia, and adverse pregnancy outcomes. High level of oxidative stress was shown in brain tissues of rodents in the model of hHCY.

Population studies suggested a link between migraine and HCY level, especially migraine with aura; however, there is no evidence of this link in animal studies. Migraine is a disabling neurovascular disorder, characterized mainly by unilateral pulsating headache and several neurological symptoms, including hypersensitivity to light known as photophobia, which is one of the leading symptoms of migraine. Moreover, migraine sufferers often acquire various autonomic, cognitive and emotional dysfunctions, including depression and anxiety. About a third of migraine patients complain of transient aura symptoms starting from minutes to hours before the headache or during the headache phase. Cortical spreading depression is a slowly propagating wave of transient neuronal and glial depolarization - an electrical phenomenon of the brain underlies the migraine with aura. In this study, the team used the model of prenatal hHCY to evaluate the sensitivity of rats to cortical spreading depression and behavioral features of migraine. Electrophysiological data indicated that rats with an elevated plasma level of HCY have a higher susceptibility to the development of the cortical spreading depression. Moreover, in the behavioral tests, the authors revealed typical migraine related symptoms in rats with hHCY, such as mechanical allodynia, photophobia and higher anxiety. Taken together, the findings support a link between HCY and migraine with aura; this suggests that timely correction of the elevated HCY level in persons from higher risk groups may be beneficial for treatment.

The study is part of a project related to the investigation of the etiology of migraine. Using experimental animal models, one can reveal mechanisms underlying the excitability of the brain cortex and peripheral afferents innervating the meninges, which triggers migraine attacks. Moreover, the search for endogenous factors provoking migraines will help to develop strategies for the correction of pathological conditions.

The researchers plan to analyze sensitivity of rats with hHCY in nitroglycerine-induced hyperalgesia, photophobia and anxiety, which is widely used to imitate migraine symptoms in rodents. To reveal the molecular mechanisms underlying the higher susceptibility of rats with hHCY to migraine-like symptoms, they will assess the excitability of the peripheral part of the trigeminal system, including recordings of the electrical activity of trigeminal nerve and the membrane properties of isolated trigeminal neurons. Finally, the authors will develop and test strategies for correcting high homocysteine levels, such as administrating vitamins of the B group or antioxidants.

A joint research project based in Kumamoto University, Japan has developed a new, highly sensitive analytical method that can detect degraded β-lactam antibacterial agents used in the treatment of bacterial infections. With this method, researchers found that reactive sulfur species produced by bacteria degrade and inactivate β-lactam antibiotics.

Bacteria are different from animal cells in that their outer layer is covered with a rigid structure called a cell wall. β-lactam antimicrobial agents interfere with the processes that form the cell wall. This results in bacteria no longer being able to withstand their own internal pressure so they rupture and die. β-lactam antimicrobial agents are very potent because they selectively inhibit bacterial cell wall synthesis and have few side effects on hosts such as humans. These antimicrobial agents have a common structure called the β-lactam ring that is essential for inhibiting cell wall development. If this ring is degraded, the antimicrobial effect disappears.

Previous studies have reported that hydrogen sulfide (H2S), which bacteria produce during sulfur metabolism, reduces their susceptibility to antimicrobial agents leading to resistance. However, the detailed mechanism causing this are not yet understood. Researchers at Kumamoto University previously showed that the molecule cysteine persulfide, a combination of H2S and the amino acid cysteine, has an extremely potent antioxidant effect that is not found in H2S or cysteine alone.

In this study, researchers examined how this reactive sulfur species is involved in the acquisition of resistance to β-lactam antibiotics. They discovered that β-lactam antibiotics such as penicillin G, ampicillin, and meropenem (carbapenem antibiotics) rapidly lose bactericidal activity when exposed to cysteine persulfide but not with hydrogen sulfide. A detailed study of the reaction between β-lactam antimicrobial agents and cysteine persulfide revealed that the β-lactam ring, which is essential for bactericidal action, decomposes and a sulfur atom is inserted into part of the ring creating carbothioic acid. The production of carbothioic acid from a β-lactam antimicrobial agent appears to be a novel degradation metabolite.

Researchers thus developed a highly sensitive analytical method to detect and quantify carbothioic acid using mass spectrometry, and then analyzed carbothioic acid production from bacteria that were exposed to β-lactam antimicrobials. They found that bacteria can absorb antimicrobial agents and use cysteine persulfide to degrade the agents into carbothioic acid which is then discharged. This is believed to be a previously undescribed inactivation and degradation mechanism of β-lactam antimicrobial agents into carbothioic acid by cysteine persulfide.

"Our newly developed analytical method makes it possible to quantify the amount of carbothioic acid discharged from bacteria with high sensitivity," said Professor Tomohiro Sawa, who led the study. "We believe it will be possible to screen for compounds that inhibit bacterial synthesis of cysteine persulfide by using carbothioic acid as a biomarker. Such a cysteine persulfide synthesis inhibitor in combination with β-lactam antibiotics is expected to inhibit antibiotic degradation and result in successful treatments with a lower concentration of β-lactam antibiotics. This should also help to reduce the emergence of new resistant bacteria."

KINSHASA, Democratic Republic of Congo (June 9, 2021) - A new study led by the Wildlife Conservation Society (WCS) has updated the global population estimate for the Critically Endangered Grauer's gorillas (Gorilla beringei graueri) - the world's largest gorilla subspecies- to 6,800 individuals from a previous global estimate of 3,800 individuals. This revised estimate comes from recent field surveys conducted in one of this animal's largest remaining strongholds, in areas that were previously inaccessible for surveys. However, these gorillas continue to be heavily impacted by ongoing insecurity, and by human incursion into their remaining habitat in eastern Democratic Republic of Congo.

Publishing in the American Journal of Primatology, the authors found a total of 3815 Grauer's gorillas remaining in Kahuzi-Biega National Park and the contiguous Oku community forests These two areas hold almost 60 percent of the global population.

A previous peer-reviewed paper led by WCS in 2016 showed a decline of almost 80 percent in the population of these gorillas since the last range-wide survey carried out in the mid-1990s. However, due to insecurity, the 2016 estimate did not include data from all areas of the Grauer's gorilla range. The 2021 population estimate includes new field surveys in the Oku forests conducted over the past four years and provide the most up to date assessment of the subspecies to date. These new findings still maintain Grauer's gorillas as Critically Endangered, but suggest declines were not as great as previously feared. The findings also provide hope for the conservation of Grauer's gorilla in this challenging area. Gorilla populations in the Oku forests and the highland sectors of the Kahuzi-Biega National Park have remained relatively stable over the past 20 years, highlighting the importance of these areas for the future of this subspecies.

"This is one of the most extensive surveys ever of this great ape, carried out under very difficult circumstances. It is a tribute to the courage and dedication of the Congolese biologists who took part, often at great risk from the ongoing insecurity." said the study's lead author Dr. Andrew Plumptre, Key Biodiversity Area Secretariat hosted by Birdlife International, who conducted the research while with WCS. "We show that gorillas and chimpanzees are avoiding areas where people are extracting minerals, an occupation that contributes to the insecurity in the region"

Additionally, there is good news for chimpanzee populations, which have also held steady over the past twenty years. Many other primates have declined however, likely due to bushmeat hunting, especially the Endangered Ulindi River Red Colobus (Piliocolobus lulindicus).

Grauer's gorillas are a subspecies of eastern gorilla found only in the eastern Democratic Republic of Congo and can weigh over 450 pounds (204 kilograms).

The authors say that the results of the study underscore the importance of good forest protection in the region. They note that the Oku community forests probably has more Grauer's gorillas than any other site across its range, and together with the Kahuzi?Biega National Park is the last stronghold for this ape. In 2018, three local community forest concessions comprising a total area of 1,465 square kilometers (565 square miles) were created and attributed to community management in Oku. Additionally, WCS is working with these communities, the Government's Nature Conservation Agency, ICCN, and the local NGO Reserve des Gorilles de Punia (RGPu), to create an additional Wildlife Reserve in the Oku forests to secure up to 3,000 square kilometers (1,158 square miles) of forest for gorillas and other flora and fauna in this area.

Said Deo Kujirakwinja, co-author and WCS DRC Technical Director: "Without good protection and forest management, Grauer's gorillas would be on the brink of extinction. They face growing pressure from habitat destruction from mining and poaching for food. We must secure these forests to safeguard Grauer's gorillas and other primates."

The civil war in DRC and continued presence of armed rebel groups have made conservation exceedingly difficult. Furthermore, expansion of mining in the area brings further pressures on gorilla habitat and from hunting of gorillas for food to feed the burgeoning mining towns. More than 80 percent of the world's supply of coltan - used in many electronic devices and electric cars - is found in the DRC, including much of the Grauer's gorilla habitat. The focus of conservation efforts must now be on supporting local community management of the Oku forests to protect gorillas and their habitats from outside threats.

Researchers at Vanderbilt University Medical Center (VUMC) have identified a common mechanism underlying a spectrum of epilepsy syndromes and neurodevelopmental disorders, including autism, that are caused by variations in a gene encoding a vital transporter protein in the brain.

Their findings, reported last month in the journal Brain, suggest that boosting transporter function via genetic or pharmacological means could be beneficial in treating brain disorders linked to these genetic variations.

"This points (to) a clear direction of treating a wide spectrum of neurodevelopmental disorders, from various epilepsy syndromes (and) autism to neurodevelopmental delay and intellectual disabilities, caused by the pathological variants in this gene," said Jing-Qiong (Katty) Kang, MD, PhD, associate professor of Neurology and Pharmacology, and the paper/s corresponding author.

"The disorders associated with the gene mutations are rare and there is no effective treatment available," Kang said. "If ... the clinical syndromes we see are the tip of an iceberg, we now know what is going on underneath, and we start to know how to correct the problems."

The gene, SLC6A1, encodes the GABA transporter 1 (GAT-1) at the axonal termini (ends) of neurons (nerve cells) and astrocytes (star-shaped glial cells that support and protect neurons). GAT-1 removes or "reuptakes" GABA, the major inhibitory neurotransmitter, from the synaptic cleft between two neurons.

GABA regulates nerve signals throughout the brain and plays a key role in normal brain development. Reuptake enables the brain to precisely regulate the supply of the neurotransmitter in concert with GABAA receptors, ion channels that bind it.

Kang and her colleagues have extensively studied GABAA receptors and are world
leaders in determining how disrupted GABA signaling can affect brain function and development.

SLC641 variants previously have been associated with a spectrum of epilepsy syndromes, autism and impaired cognition. But until now scientists did not know how these variants could cause such a broad range of brain disorders.

Using high-throughput assays such as flow cytometry and a radioactive labeling technique for measuring GABA reuptake by neurons and astrocytes, the VUMC researchers determined the impact of 22 different variants of SLC6A1 on GAT-1 function in several types of nerve cells derived from patients with neurodevelopmental disorders, epilepsy and autism.

The work was validated in patient-induced pluripotent stem cells that were "reprogrammed" to form neurons and astrocytes.

The researchers found that disease-causing variants were associated with misfoldings of the GAT-1 protein that led to its degradation and which reduced its expression on cell surfaces. Less GAT-1, in turn, lowered GABA reuptake by nerve cells and astrocytes and disrupted neurotransmitter function.

"This is the first large-scale study on SLC6A1 pathological variants," Kang said. "Our work indicates that SLC6A1-mediated disorders are good candidates for pharmacological as well as gene therapy that restore the functional transporter at the cell surface."

A compound identified at VUMC that corrects GAT-1 function in mouse models and cells from patients with urea cycle disorder is now being tested in a clinical trial. The inherited disease causes a buildup of ammonia in the bloodstream that can damage the brain and may be fatal.

Another potential approach is the use of antisense oligonucleotides, short, synthetic pieces of genetic material that may increase expression of the normal, "wild-type" GAT-1 protein.

Kang said the research could not have been done without the help of two "hero" mothers of children with rare genetic disorders: Amber Freed, founder and CEO of the Denver-based advocacy group SLC6A1 Connect; and Terry Jo Bichell, PhD, founder and director of Nashville-based COMBINEDBrain, which supports brain research.

"I have been very lucky and privileged to work with them," Kang said. "They have taught me so much along the way and inspired me to do meaningful research."

"She loves kids with SLC6A1 as her own and selflessly works to improve their lives with the urgency of a mother," Freed responded. "Throughout this journey, Katty has been a loving person, inquisitive scientist and pillar of strength."

"That empathy kept her discoveries progressing through the pandemic," Bichell added. "She would ride her bicycle to the lab and care for the mouse and cell models at night, on weekends and even holidays ... Dr. Kang is doing basic science that will translate to real treatments for real children she has met--and hugged."

Felicia Mermer and Sarah Poliquin are the paper's first authors. Other VUMC co-authors are Kathryn Rigsby, Anuj Rastogi, Wangzhen Shen, MD, Alejandra Romero-Morales, Gerald Nwosu and Vivian Gama, PhD.

A University of Oklahoma doctoral student, graduate and undergraduate research assistants, and an associate professor in the Homer L. Dodge Department of Physics and Astronomy in the University of Oklahoma College of Arts and Sciences are lead authors on a paper describing a "changing-look" blazar - a powerful active galactic nucleus powered by supermassive blackhole at the center of a galaxy. The paper is published in The Astrophysical Journal.

Hora D. Mishra, a Ph.D. student, and faculty member Xinyu Dai are lead authors of the paper, along with Christopher Kochanek and Kris Stanek at the Ohio State University and Ben Shappee at the University of Hawaii. The paper represents the findings of researchers from 12 different institutions who participated in a two-year collaborative project involving the collection of spectra or imaging data in different electromagnetic bands. The OU team led the effort in analyzing all the data collected from the collaboration and contributed primarily on the interpretation of the analysis results, assisted by OU graduate student Saloni Bhatiani and undergraduate students Cora DeFrancesco and John Cox who performed ancillary analyses to the project.

Blazars, explains Mishra, who also serves as president of Lunar Sooners, appear as parallel rays of light or particles, or jets, pointing to observers and radiating across all wavelengths of the electromagnetic spectrum. These jets span distances on the million light-year scales and are known to impact the evolution of the galaxy and galaxy cluster in which they reside via the radiation. These features make blazars ideal environments in which to study the physics of jets and their role in galaxy evolution.

"Blazars are a unique kind of AGN with very powerful jets," she said. "Jets are a radio mode of feedback and because of their scales, they penetrate the galaxy into their large-scale environment. The origin of these jets and processes driving the radiation are not well-known. Thus, studying blazars allows us to understand these jets better and how they are connected to other components of the AGN, like the accretion disk. These jets can heat up and displace gas in their environment affecting, for example, the star formation in the galaxy."

The team's paper highlights the results of a campaign to investigate the evolution of a blazar known as B2 1420+32. At the end of 2017, this blazar exhibited a huge optical flare, a phenomenon captured by the All Sky Automated Survey for SuperNovae telescope network.

"We followed this up by observing the evolution of its spectrum and light curve over the next two years and also retrieved archival data available for this object," Mishra said. "The campaign, with data spanning over a decade, has yielded some most exciting results. We see dramatic variability in the spectrum and multiple transformations between the two blazar sub-classes for the first time for a blazar, thus giving it the name 'changing-look' blazar."

The team concluded that this behavior is caused by the dramatic continuum flux changes, which confirm a long-proposed theory that separates blazars into two major categories.

"In addition, we see several very large multiband flares in the optical and gamma-ray bands on different timescales and new spectral features," Mishra said. "Such extreme variability and the spectral features demand dedicated searches for more such blazars, which will allow us to utilize the dramatic spectral changes observed to reveal AGN/jet physics, including how dust particles around supermassive black holes are destructed by the tremendous radiation from the central engine and how energy from a relativistic jet is transferred into the dust clouds, providing a new channel linking the evolution of the supermassive black hole with its host galaxy."

"We are very excited by the results of discovering a changing-look blazar that transforms itself not once, but three times, between its two sub-classes, from the dramatic changes in its continuum emission," she added. "In addition, we see new spectral features and optical variability that is unprecedented. These results open the door to more such studies of highly variable blazars and their importance in understanding AGN physics."

"It is really interesting to see the emergence of a forest of Iron emission lines, suggesting that nearby dust particles were evaporated by the strong radiation from the jet and released free Iron ions into the emitting clouds, a phenomenon predicted by theoretical models and confirmed in this blazar outburst," Dai said.

A new study identifies a novel biomarker indicating resilience to chronic stress. This biomarker is largely absent in people suffering from major depressive disorder, and this absence is further associated with pessimism in daily life, the study finds.

Nature Communications published the research by scientists at Emory University.

The researchers used brain imaging to identify differences in the neurotransmitter glutamate within the medial prefrontal cortex before and after study participants underwent stressful tasks. They then followed the participants for four weeks, using a survey protocol to regularly assess how participants rated their expected and experienced outcomes for daily activities.

"To our knowledge, this is the first work to show that glutamate in the human medial prefrontal cortex shows an adaptive habituation to a new stressful experience if someone has recently experienced a lot of stress," says Michael Treadway, senior author of the study and professor in Emory's Department of Psychology and Department of Psychiatry and Behavioral Science. "Importantly, this habituation is significantly altered in patients with depression. We believe this may be one of the first biological signals of its kind to be identified in relation to stress and people who are clinically depressed."

"Learning more about how acute stress and chronic stress affect the brain may help in the identification of treatment targets for depression," adds Jessica Cooper, first author of the study and a post-doctoral fellow in Treadway's Translational Research in Affective Disorders Laboratory.

The lab focuses on understanding the molecular and circuit-level mechanisms of psychiatric symptoms related to mood disorders, anxiety and decision-making.

It's long been known that stress is a major risk factor for depression, one of the most common and debilitating of mental illnesses. "In many ways, depression is a stress-linked disorder," Treadway says. "It's estimated that 80 percent of first-time depressive episodes are preceded by significant, chronic life stress."

Around 16 to 20 percent of the U.S. population will meet the criteria for a major depressive disorder during their lifetimes. Experts are predicting rates of depression to climb even further in the wake of the ongoing COVID-19 pandemic. During the pandemic, about four in 10 adults in the United States have reported symptoms of anxiety or depressive disorder, up from one in 10 who reported them in 2019, according to the Kaiser Family Foundation.

"The pandemic has created more isolation for many people, while also increasing the amount of severe stressors and existential threats they experience," Treadway says. "That combination puts a lot of people at high risk for becoming depressed."

Although the link between stress and depression is clearly established, the mechanisms underlying this relationship are not. Experiments with rodents have shown an association between the response of glutamate -- the major excitatory neurotransmitter in the mammalian brain -- and stress. The role of glutamate in humans with depression, however, has been less clear.

The 88 participants in the current study included people without a mental health disorder and unmedicated patients diagnosed with a major depressive disorder. Participants were surveyed about perceived recent stress in their lives before they underwent experiments using a brain scanning technique known as magnetic resonance spectroscopy.

While in the scanner, participants were required to alternate between performing two tasks that served as acute stressors: Putting their hand up to the wrist in ice water and counting down from the number 2,043 by steps of 17 while someone evaluated their accuracy.

Brain scans before and after the acute stressor measured glutamate in the medial prefrontal cortex, an area of the brain involved with thinking about one's state and forming expectations. Previous research has also found that this brain area is involved in regulating adaptive responses to stress.

Participants submitted saliva samples while in the scanner, allowing the researchers to confirm that the tasks elicited a stress response by measuring the amount of the stress hormone cortisol in the sample.

In healthy individuals, the brain scans revealed that glutamate change in response to stress in the medial prefrontal cortex was predicted by individual levels of recent perceived stress. Healthy participants with lower levels of stress showed increased glutamate in response to acute stress, while healthy participants with higher levels of stress showed a reduced glutamate response to acute stress. This adaptive response was comparatively absent in the patients diagnosed with depression.

"The decrease in the glutamate response over time appears to be a signal, or a marker, of a healthy adaptation to stress," Treadway says. "And if the levels remain high that appears to be a signal for maladaptive responses to stress."

The initial result was strong for the adaptation in healthy participants, but was in a modest sample size, so the researchers decided to see if they could replicate it. "Not only did we get a replication, it was an unusually strong replication," Treadway says.

The experiment also included a group of healthy controls who underwent scanning before and after performing tasks. Rather than stressful tasks, however, the controls were asked to place a hand into warm water or to simply count out loud consecutively. Their glutamate levels were not associated with perceived stress and they did not show a salivary cortisol response.

To expand their findings, the researchers followed participants for four weeks after scanning. Every other day, the participants reported on their expected and experienced outcomes for activities in their daily lives. The results showed that glutamate changes that were higher than expected based on an individual's level of perceived stress predicted an increased pessimistic outlook -- a hallmark for depression.

"We were able to show how a neural response to stress is meaningfully related to what people experience in their daily lives," Cooper says. "We now have a large, rich data set that gives us a tangible lead to build upon as we further investigate how stress contributes to depression."

Scientists have developed polypeptide-based materials that act as effective vectors for delivering gene therapies. The first-of-its-kind platform enables the vectors to be adapted to suit the specific gene therapy cargo.

The work, led by researchers from RCSI University of Medicine and Health Sciences and funded by Science Foundation Ireland, is published in Biomaterials Science.

A major challenge for gene therapies is preparing them in a way that can deliver the genetic information into the host cells. For the Covid-19 vaccines that use mRNA technology, the genetic information is delivered in a lipid nanoparticle to maintain its stability and deliver it into cells. The success of the COVID vaccines has established nanoparticles as key to the development of many advanced therapies.

The researchers developed a platform that produces bespoke star-shaped polypeptide nanoparticles, which effectively deliver a range of therapies, including gene therapies. Crucially, these polypeptides are more flexible and easier to handle than lipids. To demonstrate the potential of this material, the researchers used it to deliver a gene therapy that regenerated bone.

In preclinical work, the researchers loaded the material with DNA molecules that promote bones and blood vessels to regrow. They placed these nanomedicines in a scaffold that could be implanted into a defect site and deliver the genetic cargo into infiltrating host cells. The gene-loaded scaffold accelerated bone tissue regeneration, with a six-fold increase in new bone formation compared to a scaffold alone.

"With the success of the COVID-19 vaccines, the potential of gene therapies is becoming apparent, and advanced nanoparticle delivery systems are key to enabling their use clinically. We have shown that these nanoparticles have real potential to be a game changer in the delivery of gene therapies," said Professor Sally-Ann Cryan, the study's senior author and Professor of Drug Delivery, RCSI.

"While more testing is needed before these therapies can be used clinically, our platform allows us to design our polypeptides to meet a variety of delivery scenarios and provide tailored solutions to gene delivery challenges," added Professor Andreas Heise, project collaborator and Professor of Polymer Chemistry, RCSI.

"We are developing this patent-protected technology towards commercialisation, with support from an Enterprise Ireland Commercialisation Fund Award, and are seeking expressions of interest from industry partners and investors."

DARIEN, IL - A study of nearly 2,500 adults found that having trouble falling asleep, as compared to other patterns of insomnia, was the main insomnia symptom that predicted cognitive impairment 14 years later.

Results show that having trouble falling asleep in 2002 was associated with cognitive impairment in 2016. Specifically, more frequent trouble falling asleep predicted poorer episodic memory, executive function, language, processing speed, and visuospatial performance. Further analysis found that associations between sleep initiation and later cognition were partially explained by both depressive symptoms and vascular diseases in 2014 for all domains except episodic memory, which was only partially explained by depressive symptoms.

"While there is growing evidence for a link between insomnia and cognitive impairment in older adults, it has been difficult to interpret the nature of these associations given how differently both insomnia and cognitive impairment can present across individuals," said lead author Afsara Zaheed, a graduate student in clinical science within the department of psychology at the University of Michigan. "By investigating associations between specific insomnia complaints and cognition over time using strong measures of cognitive ability, we hoped to gain additional clarity on whether and how these different sleep problems may lead to poor cognitive outcomes."

Insomnia involves difficulty falling asleep or staying asleep, or regularly waking up earlier than desired, despite allowing enough time in bed for sleep. Daytime symptoms include fatigue or sleepiness; feeling dissatisfied with sleep; having trouble concentrating; feeling depressed, anxious, or irritable; and having low motivation or energy.

The study analyzed data from the Health and Retirement Study, which involved 2,496 adults who were at least 51 years of age. In 2002 they reported the frequency of experiencing insomnia symptoms. In 2016 the participants' cognition was assessed as part of the Harmonized Cognitive Assessment Protocol and operationalized with a comprehensive neuropsychological battery tapping episodic memory, executive function, language, visuoconstruction, and processing speed. Analyses controlled for sociodemographics and baseline global cognitive performance.

"These results are important given the lack of currently available treatments for late-life cognitive disorders, like Alzheimer's disease and other dementias," said Zaheed. "Sleep health and sleep behaviors are often modifiable. These results suggest that regular screening for insomnia symptoms may help with tracking and identifying people with trouble falling asleep in mid-to-late life who might be at risk for developing cognitive impairments later in life. Additional intervention research is needed to determine whether intervening on insomnia symptoms can help prevent or slow the progression of cognitive impairments in later life."

DARIEN, IL - A 15-year longitudinal study shows that childhood insomnia symptoms that persist into adulthood are strong determinants of mood and anxiety disorders in young adults.

Results show that insomnia symptoms persisting from childhood through adolescence and into adulthood were associated with a 2.8-fold increased risk of internalizing disorders. Insomnia symptoms that newly developed over the course of the study were associated with a 1.9-fold increased risk of internalizing disorders. No increased risk of internalizing disorders was found for those children in whom insomnia symptoms remitted during the study period.

"We found that about 40% of children do not outgrow their insomnia symptoms in the transition to adolescence and are at risk of developing mental health disorders later on during early adulthood," said lead author Julio Fernandez-Mendoza, who has a doctorate in psychobiology and is an associate professor at Penn State College of Medicine. He is a psychologist board certified in behavioral sleep medicine at Penn State Health Sleep Research and Treatment Center in Hershey, Pennsylvania.

Data were analyzed from the Penn State Child Cohort, a population-based sample of 700 children with a median age of 9 years. The researchers had followed up 8 years later with 421 participants when they were adolescents (median age of 16 years) and now 15 years later with 492 of them when they were young adults (median age of 24 years). Insomnia symptoms were defined as moderate-to-severe difficulties initiating or maintaining sleep.

The symptoms were parent-reported in childhood and self-reported in adolescence and young adulthood. The presence of internalizing disorders was defined as a self-report of a diagnosis or treatment for mood and/or anxiety disorders. Results were adjusted for sex, race/ethnicity, age, and any prior history of internalizing disorders or use of medications for mental health problems.

According to the authors, childhood insomnia symptoms have been shown to be associated with internalizing disorders, which include depressive disorders and anxiety disorders. "These new findings further indicate that early sleep interventions are warranted to prevent future mental health problems, as children whose insomnia symptoms improved over time were not at increased risk of having a mood or anxiety disorder as young adults," said Fernandez-Mendoza.