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COVID-19 is a systemic disease involving multiple organs. We previously established a platform to derive organoids and cells from human pluripotent stem cells to model SARS-CoV-2 infection and perform drug screens1,2. This provided insight into cellular tropism and the host response, yet the molecular mechanisms regulating SARS-CoV-2 infection remain poorly defined. Here we systematically examined changes in transcript profiles caused by SARS-CoV-2 infection at different multiplicities of infection for lung airway organoids, lung alveolar organoids and cardiomyocytes, and identified several genes that are generally implicated in controlling SARS-CoV-2 infection, including CIART, the circadian-associated repressor of transcription. Lung airway organoids, lung alveolar organoids and cardiomyocytes derived from isogenic CIART−/− human pluripotent stem cells were significantly resistant to SARS-CoV-2 infection, independently of viral entry. Single-cell RNA-sequencing analysis further validated the decreased levels of SARS-CoV-2 infection in ciliated-like cells of lung airway organoids. CUT&RUN, ATAC-seq and RNA-sequencing analyses showed that CIART controls SARS-CoV-2 infection at least in part through the regulation of NR4A1, a gene also identified from the multi-organoid analysis. Finally, transcriptional profiling and pharmacological inhibition led to the discovery that the Retinoid X Receptor pathway regulates SARS-CoV-2 infection downstream of CIART and NR4A1. The multi-organoid platform identified the role of circadian-clock regulation in SARS-CoV-2 infection, which provides potential therapeutic targets for protection against COVID-19 across organ systems.

The SARS-CoV-2 pandemic is an ongoing threat to global health, and the continuing emergence of contagious variants highlights the urgent need for additional antiviral therapy to attenuate COVID-19 disease. The SARS-CoV-2 main protease (3CL

ATP-independent molecular chaperones are important for maintaining cellular fitness but the molecular determinants for preventing aggregation of partly unfolded protein substrates remain unclear, particularly regarding assembly state and basis for substrate recognition. The BRICHOS domain can perform small heat shock (sHSP)-like chaperone functions to widely different degrees depending on its assembly state and sequence. Here, we observed three hydrophobic sequence motifs in chaperone-active domains, and found that they get surface-exposed when the BRICHOS domain assembles into larger oligomers. Studies of loop-swap variants and site-specific mutants further revealed that the biological hydrophobicities of the three short motifs linearly correlate with the efficiency to prevent amorphous protein aggregation. At the same time, they do not at all correlate with the ability to prevent ordered amyloid fibril formation. The linear correlations also accurately predict activities of chimeras containing short hydrophobic sequence motifs from a sHSP that is unrelated to BRICHOS. Our data indicate that short, exposed hydrophobic motifs brought together by oligomerisation are sufficient and necessary for efficient chaperone activity against amorphous protein aggregation.

STUDY QUESTION Does previous bariatric surgery (BS) in women affect cumulative live birth rate in IVF? SUMMARY ANSWER Women having had BS seem to have the same cumulative live birth rate as non-operated women of the same BMI at IVF treatment. WHAT IS KNOWN ALREADY Because of the perinatal risks of obesity to mother and infant as well as impaired outcomes of IVF, obese women are advised to reduce their weight, but it is not clear whether previous BS could affect IVF results. STUDY DESIGN, SIZE, DURATION This national register-based case–control study included all cases of BS (n = 30 436) undergoing IVF (n = 153) from 2007 until 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS Swedish women between 18 and 45 years operated with BS, with at least one first started cycle of IVF after surgery, were included. For each woman having IVF after BS (n = 153), up to five non-operated control women (n = 744) starting their first IVF cycle during the study period were matched for age, parity and BMI at treatment. The primary outcome in this study was the cumulative live birth rate (CLBR) after the first IVF cycle, defined as all live births after the first cycle including fresh and frozen embryo transfers. MAIN RESULTS AND THE ROLE OF CHANCE There was no significant difference in CLBR between the BS group and the matched controls (29.4% compared to 33.1%), even though the number of retrieved oocytes (7.6 vs 8.9, P = 0.005) and frozen embryos (1.0 vs 1.5, P = 0.041) were significantly fewer in the BS group. There was no association between cumulative live birth and BS, adjusted odds ratio 1.04, 95% CI (0.73, 1.51). However, the birth weight was significantly lower in the children born to mothers with previous BS, mean (SD) 3190 (690) vs 3478 (729) g, P = 0.037. LIMITATIONS, REASONS FOR CAUTION Confounders such as age, BMI and previous childbirth were accounted for by the matching design of the study, but there were no data on indication for IVF, anti-Müllerian hormone, smoking or previous comorbidities. The study was exploratory and did not reach sufficient power to detect potential smaller differences in live birth rates. WIDER IMPLICATIONS OF THE FINDINGS The findings concur with those in previously published smaller studies and provide somewhat reassuring results considering IVF outcomes after BS with a CLBR comparable to that of controls, despite a lower mean birth weight. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by grants from the Southern Health Care Region of Sweden. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER N/A.

Background: Increasing evidence suggests that cardiac arrhythmias are frequent clinical features of coronavirus disease 2019 (COVID-19). Sinus node damage may lead to bradycardia. However, it is challenging to explore human sinoatrial node (SAN) pathophysiology due to difficulty in isolating and culturing human SAN cells. Embryonic stem cells (ESCs) can be a source to derive human SAN-like pacemaker cells for disease modeling. Methods: We used both a hamster model and human ESC (hESC)–derived SAN-like pacemaker cells to explore the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pacemaker cells of the heart. In the hamster model, quantitative real-time polymerase chain reaction and immunostaining were used to detect viral RNA and protein, respectively. We then created a dual knock-in SHOX2:GFP;MYH6:mCherry hESC reporter line to establish a highly efficient strategy to derive functional human SAN-like pacemaker cells, which was further characterized by single-cell RNA sequencing. Following exposure to SARS-CoV-2, quantitative real-time polymerase chain reaction, immunostaining, and RNA sequencing were used to confirm infection and determine the host response of hESC-SAN–like pacemaker cells. Finally, a high content chemical screen was performed to identify drugs that can inhibit SARS-CoV-2 infection, and block SARS-CoV-2–induced ferroptosis. Results: Viral RNA and spike protein were detected in SAN cells in the hearts of infected hamsters. We established an efficient strategy to derive from hESCs functional human SAN-like pacemaker cells, which express pacemaker markers and display SAN-like action potentials. Furthermore, SARS-CoV-2 infection causes dysfunction of human SAN-like pacemaker cells and induces ferroptosis. Two drug candidates, deferoxamine and imatinib, were identified from the high content screen, able to block SARS-CoV-2 infection and infection-associated ferroptosis. Conclusions: Using a hamster model, we showed that primary pacemaker cells in the heart can be infected by SARS-CoV-2. Infection of hESC-derived functional SAN-like pacemaker cells demonstrates ferroptosis as a potential mechanism for causing cardiac arrhythmias in patients with COVID-19. Finally, we identified candidate drugs that can protect the SAN cells from SARS-CoV-2 infection.

Many studies in affective neuroscience rely on statistical procedures designed to estimate population averages and base their main conclusions on group averages. However, the obvious unit of analysis in affective neuroscience is the individual, not the group, because emotions are individual phenomena that typically vary across individuals. Conclusions based on group averages may therefore be misleading or wrong, if interpreted as statements about emotions of an individual, or meaningless, if interpreted as statements about the group, which has no emotions. We therefore advocate the Single-N design as the default strategy in research on emotions, testing one or several individuals extensively with the primary purpose of obtaining results at the individual level. In neuroscience, the equivalent to the Single-N design is deep imaging, the emerging trend of extensive measurements of activity in single brains. Apart from the fact that individuals react differently to emotional stimuli, they also vary in shape and size of their brains. Group-based analysis of brain imaging data therefore refers to an “average brain” that was activated in a way that may not be representative of the physiology of any of the tested individual brains, nor of how these brains responded to the experimental stimuli. Deep imaging avoids such group-averaging artifacts by simply focusing on the individual brain. This methodological shift toward individual analysis has already opened new research areas in fields like vision science. Inspired by this, we call for a corresponding shift in affective neuroscience, away from group averages, and toward experimental designs targeting the individual.

Polycystic ovary syndrome’s (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders in women. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead to changes in protein levels and biological function. To advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry. Adipose tissue and skeletal muscle were collected at baseline from 10 women with and without PCOS, and in women with PCOS after 5 weeks of treatment with electrical stimulation. Perilipin-1, a protein that typically coats the surface of lipid droplets in adipocytes, was increased whereas proteins involved in muscle contraction and type I muscle fiber function were downregulated in PCOS muscle. Proteins in the thick and thin filaments had many altered phosphorylation sites, indicating differences in protein activity and function. The upregulated proteins in muscle post treatment were enriched in pathways involved in extracellular matrix organization and wound healing, which may reflect a protective adaptation to repeated contractions and tissue damage due to needling. A similar, albeit less pronounced, upregulation in extracellular matrix organization pathways was also seen in adipose tissue. Our results suggest that hyperandrogenic women with PCOS have higher levels of extramyocellular lipids, fewer oxidative and insulin-sensitive type I muscle fibers. These could be key factors leading insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective.

The Svalbard Archipelago has experienced a rapid increase in tourism-related activities over the past few decades. The Norwegian Government’s ambition to develop the Archipelago’s tourism industry offers multiple socio-economic opportunities. The development and scope of these tourism activities is affected by a complex governance system that entails strict environmental regulation and preparedness considerations. To understand the balance of goals across the national and international policy levels, we have mapped, reviewed, and analyzed the national and international regulations and agreements that affect tourism activities on Svalbard. The document analysis reveals the framework of natural and environmental consideration, access to areas and passage, requirements for organized outdoor activities, and regulatory tools. We discovered conflicts and internal inconsistencies in the way that Svalbard tourism has developed. It has been shaped by both economic growth and environmental preservation, without any specific business development objectives and goals or acceptable limits of environmental and social change in place. For tourism stakeholders, this might complicate any rational assessment of the balance between economic development and environmental status. The challenges we have identified are specific to Svalbard, but are likely to be similar in many other Arctic locations involved in tourism. Svalbard, regulations, environment, sustainability, tourism, cruise, governance, Arctic

The Teacher Social Justice Advocacy Scale was developed to measure teachers' social justice advocacy orientation. Six hundred and seven K-12 teachers participated in the study. Results support a 22-item scale with three distinct factors: teacher advocacy orientation, social justice awareness, and student empowerment. Bivariate correlations demonstrated positive relationships between the TSJAS, a measure of general social advocacy, and political involvement, and a negative relationship with a measure of just world ideology. TSJAS scores also evidenced adequate internal consistency reliability.

Genetics (i.e., mutations) has been assumed to be the major factor in rheumatoid arthritis (RA) etiology, but accounts for a minority of the variance in disease risk for RA. In contrast to genetics, the environment can have dramatic impacts on epigenetics that associate with disease etiology. The current study used buccal cells and purified blood monocytes from two different clinical cohorts involving Caucasian or African American female populations with or without arthritis. The differential DNA methylation regions (DMRs) between the control and RA populations were identified with an epigenome-wide association study. The DMRs (i.e., epimutations) identified in the buccal cells and monocytes were found to be distinct. The DMR associated genes were identified and many have previously been shown to be associated with arthritis. Observations demonstrate DNA methylation epimutation RA biomarkers are cell type specific and similar findings were observed with the two racial background populations. Rheumatoid arthritis susceptibility epigenetic diagnosis appears feasible and may improve the clinical management of RA and allowpreventative medicine considerations.

Just over two decades ago, Bob Boutilier published a much-cited Review in this journal on the mechanisms of cell survival in hypoxia and hypothermia. Here, we celebrate this important Review by describing how our knowledge of the mechanisms behind anoxia tolerance have progressed since 2001, including new key roles of mitochondria, something Boutilier had started exploring. Evidence now suggests that, in anoxia-tolerant brains, mitochondria initiate responses aimed at suppressing electrical activity and energy use. These responses are largely dependent on gamma-aminobutyric acid (GABA) release. Animals that survive anoxia must also tolerate reoxygenation – a major challenge that could cause a massive production of damaging reactive oxygen species (ROS). Here, the handling of succinate, which builds up during anoxia, is critical. Interestingly, there are clear species differences in succinate handling among anoxia-tolerant vertebrates (Trachemys and Chrysemys turtles and crucian carp, Carassius carassius). Trachemys turtles suppress succinate build-up during anoxia, presumably to limit ROS production during reoxygenation. By contrast, in crucian carp, reduction of fumarate to succinate during anoxia appears to be essential for keeping their mitochondria charged and viable. Consequently, during anoxia, crucian carp accumulate much more succinate than Trachemys turtles. Moreover, during anoxia, succinate is apparently transported from crucian carp brain and heart to the liver, which handles succinate upon reoxygenation. This is one example of the striking physiological diversity among vertebrates that survive long-term anoxia. More examples are given, and we argue that -omics approaches are, and will be, helpful in providing new insight and moving the field forward.

Edible insects are worldwide promoted as an alternative protein, trace mineral and lipid source in animal feed and human food. The house cricket (Acheta domesticus) is already being reared at an industrial scale, yet current mass-rearing practices and facility design may still leave room for improvement. Behavioral tests have been suggested as an important assessment tool at the whole-organism level that can be used to find optimal housing conditions (e.g. density, diet, temperature). Here, we adapt the widely used open field test to the house cricket. We tested 16 male and 16 female house crickets four times under two different light intensities. Videos were analysed with Ethovision™ tracking software and variables distance moved, velocity, and duration and frequency in zone were extracted. Results showed that house crickets, like vertebrate model species, spent most time close to the walls of the arena, and crossed the center zone with high velocity. Brighter illumination was associated with increased velocity, in particular in the center zone during the first test occasion, suggesting avoidance of this zone. Male crickets had higher locomotory activity than females. Consistency repeatabilities and intraclass correlation coefficients (ICCs) were moderate to high, and the correlation between subsequent occasions became stronger over the four occasions at day 1, 2, 3 and 7. The first test occasion differed from subsequent occasions, therefore repeated testing may be necessary when analysing experimental manipulations of small effect size. Overall, the results are promising for use of the open field test as a precise phenotyping tool.

Background Management of pancreaticobiliary malignancy is complex and multi-disciplinary. Decompression of malignant biliary obstruction (MBO) is preferentially achieved with endoscopic retrograde cholangiopancreatography (ERCP) and biliary stent placement. This may improve the quality of life for patients with unresectable disease and improve outcomes in resectable/borderline-resectable disease. Purpose To assess quality outcomes in patients undergoing biliary stenting for MBO. Method This is a retrospective chart audit of patients referred to the University of Alberta Hospital (UAH) for suspected or confirmed MBO. The primary outcome was clinical success (reduction in bilirubin of >50% at 30 days). Secondary outcomes were technical success, type of stent used, need for re-intervention, adverse events (AEs), time from stent placement to surgery or cancer centre assessment, and survival. Result(s) Between January 2020 and June 2022, 222 patients (102 female, 46%) with a mean age of 70±1 years (range 34-93 years) underwent 290 ERCPs. The cause of MBO was pancreatic cancer in 130 (59%), cholangiocarcinoma in 32 (14%), ampullary cancer in 9 (4%), and others in 51 (23%). Technical success for stent insertion on first ERCP was achieved in 180/222 patients (81%) with only brushings performed in 2. Of the 40 patients (18%) with unsuccessful ERCP, further success was achieved by repeat ERCP (8), percutaneous transhepatic drainage (PTC, 15), PTC with rendezvous ERCP (1), surgical decompression (3), and endoscopic ultrasound-guided biliary drainage (1). No biliary drainage was performed in 12 patients. Overall, ERCP with stent insertion was technically successful in 188/222 patients (85%). A total of 233 biliary stents were inserted (38 plastic, 195 metal). Clinical success was achieved in 20/38 patients (53%) with plastic stents and 151/181 patients (83%) with metal stents (Χ2 17.4 p Adverse events were encountered in 33 patients (11%) with stent migration occurring in 8 (3%), cholangitis in 7 (2%), post-ERCP pancreatitis in 7 (2%), post-sphincterotomy bleeding in 4 (1%), and death in 2 (1%). Re-intervention was required in 36 patients (20%) after initial ERCP with successful stent placement. The re-intervention rate was significantly higher with plastic stents (14/27, 52%) than with metal stents (22/153, 14%) after initial ERCP (Χ2 20.1 p The overall survival was a mean of 249±16 days (5-967) for patients with plastic stents and 248± 16 days (1-959) for those with metal stents. Survival was significantly worse in patients with unresectable disease vs resectable/borderline-resectable disease (Log rank 38.89, p Image Conclusion(s) In MBO, metal stents appear to provide significantly better biliary drainage, with less need for re-intervention, but do not appear to be associated with any survival benefit over plastic stents. We hope that this quality assurance project will help in the development of a regional management pathway for optimizing the care of patients presenting with MBO. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Light is a key factor in poultry production; however, there is still a lack of knowledge as to describing the light quality, how to measure the light environment as perceived by birds, and how artificial light compares with the light in the natural forest habitats of their wild ancestors. The aim of this study was to describe the light environment in broiler breeder houses with three different light sources, using two different methods of light assessment. We also aimed to compare an artificial light environment with the light in a range of relevant natural forest habitats. A total of 9 commercial broiler breeder houses with one of three different light sources—Lumilux 830 CFL (n = 3), Biolux 965 CFL (n = 3) or LED Evolys with UVA (n = 3) were visited. Assessments of the light environment in the breeder houses were conducted using both a spectrometer and the environmental light field (ELF) method. ELF measurements from three forest types in south India (Kerala) were also included. We found that most aspects of the light environment were similar between the nine breeder houses and were not dependent on the type of light sources. The only clear difference related to the light source was the spectral balance, wherein 830 CFL had the most red-dominated light, 965 CFL had the most blue-dominated light and Evolys was intermediate but with more UV than the latter two. Plumage color had minimal effect on the light environment. Both the spectrometer and the ELF method provided valuable information. The spectrometer gave detailed values about certain aspects of the light environment, while the ELF described the light more in line with human and avian visual perception. We also found that the light environment in the investigated broiler breeder houses differs dramatically in all measured aspects from the natural light habitats of wild junglefowl, suggesting improvement possibilities in artificial lighting systems.

Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.

Lung-infiltrating macrophages create a marked inflammatory milieu in a subset of patients with COVID-19 by producing a cytokine storm, which correlates with increased lethality. However, these macrophages are largely not infected by SARS-CoV-2, so the mechanism underlying their activation in the lung is unclear. Type I interferons (IFN-I) contribute to protecting the host against SARS-CoV-2 but may also have some deleterious effect, and the source of IFN-I in the lungs of infected patients is not well defined. Plasmacytoid dendritic cells (pDCs), a key cell type involved in antiviral responses, can produce IFN-I in response to SARS-CoV-2. We observed the infiltration of pDCs in the lungs of SARS-CoV-2–infected patients, which correlated with strong IFN-I signaling in lung macrophages. In patients with severe COVID-19, lung macrophages expressed a robust inflammatory signature, which correlated with persistent IFN-I signaling at the single-cell level. Hence, we observed the uncoupling in the kinetics of the infiltration of pDCs in the lungs and the associated IFN-I signature, with the cytokine storm in macrophages. We observed that pDCs were the dominant IFN-α–producing cells in response to the virus in the blood, whereas macrophages produced IFN-α only when in physical contact with infected epithelial cells. We also showed that IFN-α produced by pDCs, after the sensing of SARS-CoV-2 by TLR7, mediated changes in macrophages at both transcriptional and epigenetic levels, which favored their hyperactivation by environmental stimuli. Together, these data indicate that the priming of macrophages can result from the response by pDCs to SARS-CoV-2, leading to macrophage activation in patients with severe COVID-19.

An epigenome-wide association study (EWAS) was performed on buccal cells from monozygotic-twins (MZ) reared together as children, but who live apart as adults. Cohorts of twin pairs were used to investigate associations between neighborhood walkability and objectively measured physical activity (PA) levels. Due to dramatic cellular epigenetic sex differences, male and female MZ twin pairs were analyzed separately to identify differential DNA methylation regions (DMRs). A priori comparisons were made on MZ twin pairs discordant on body mass index (BMI), PA levels, and neighborhood walkability. In addition to direct comparative analysis to identify specific DMRs, a weighted genome coexpression network analysis (WGCNA) was performed to identify DNA methylation sites associated with the physiological traits of interest. The pairs discordant in PA levels had epigenetic alterations that correlated with reduced metabolic parameters (i.e., BMI and waist circumference). The DNA methylation sites are associated with over fifty genes previously found to be specific to vigorous PA, metabolic risk factors, and sex. Combined observations demonstrate that behavioral factors, such as physical activity, appear to promote systemic epigenetic alterations that impact metabolic risk factors. The epigenetic DNA methylation sites and associated genes identified provide insight into PA impacts on metabolic parameters and the etiology of obesity.

Rationale: While respiratory failure is a frequent and clinically significant outcome of coronavirus disease 2019 (COVID-19), cardiac complications are a common feature in hospitalized COVID-19 patients and are associated with worse patient outcomes. The cause of cardiac injury in COVID-19 patients is not yet known. Case reports of COVID-19 autopsy heart samples have demonstrated abnormal inflammatory infiltration of macrophages in heart tissues. Objective: Generate an immunocardiac coculture platform to model macrophage-mediated hyperinflammation in COVID-19 hearts and screen for drugs that can block the macrophage-mediated inflammation. Methods and Results: We systematically compared autopsy samples from non–COVID-19 donors and COVID-19 patients using RNA sequencing and immunohistochemistry. We observed strikingly increased expression levels of CCL2 (C-C motif chemokine ligand 2) and macrophage infiltration in heart tissues of COVID-19 patients. We generated an immunocardiac coculture platform containing human pluripotent stem cell–derived cardiomyocytes and macrophages. We found that macrophages induce increased reactive oxygen species and apoptosis in cardiomyocytes by secreting IL (interleukin)-6 and TNF-α (tumor necrosis factor alpha) after Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. Using this immunocardiac coculture platform, we performed a high content screen and identified ranolazine and tofacitinib as compounds that protect cardiomyocytes from macrophage-induced cardiotoxicity. Conclusions: We established an immuno-host coculture system to study macrophage-induced host cell damage following SARS-CoV-2 infection and identified Food and Drug Administration–approved drug candidates that alleviate the macrophage-mediated hyperinflammation and cellular injury.

The rapid repurposing of antivirals is particularly pressing during pandemics. However, rapid assays for assessing candidate drugs typically involve in vitro screens and cell lines that do not recapitulate human physiology at the tissue and organ levels. Here, we show that a microfluidic bronchial-airway-on-a-chip lined by highly differentiated human bronchial-airway epithelium and pulmonary endothelium can model viral infection, strain-dependent virulence, cytokine production, and the recruitment of circulating immune cells. In airway chips infected with influenza A, the co-administration of nafamostat with oseltamivir doubled the treatment-time window for oseltamivir. In chips infected with pseudotyped SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), clinically relevant doses of the antimalarial drug amodiaquine inhibited infection, but clinical doses of hydroxychloroquine and other antiviral drugs that inhibit the entry of pseudotyped SARS-CoV-2 in cell lines under static conditions did not. We also show that amodiaquine showed substantial prophylactic and therapeutic activities in hamsters challenged with native SARS-CoV-2. The human airway-on-a-chip may accelerate the identification of therapeutics and prophylactics with repurposing potential., One-sentence editorial summary: A microfluidic bronchial-airway-on-a-chip lined by human bronchial-airway epithelium and pulmonary endothelium can be used to rapidly identify antiviral therapeutics and prophylactics with repurposing potential.

Connectivity of coral reef fish populations relies on successful dispersal of a pelagic larval phase. Pelagic larvae must exhibit high swimming abilities to overcome ocean and reef currents, but once settling onto the reef, larvae transition to endure habitats that become hypoxic at night. Therefore, coral reef fish larvae must rapidly and dramatically shift their physiology over a short period of time. Taking an integrative, physiological approach, using swimming respirometry, and examining hypoxia tolerance and transcriptomics, we show that larvae of cinnamon anemonefish (Amphiprion melanopus) rapidly transition between “physiological extremes” at the end of their larval phase. Daily measurements of swimming larval anemonefish over their entire early development show that they initially have very high mass-specific oxygen uptake rates. However, oxygen uptake rates decrease midway through the larval phase. This occurs in conjunction with a switch in haemoglobin gene expression and increased expression of myoglobin, cytoglobin, and neuroglobin, which may all contribute to the observed increase in hypoxia tolerance. Our findings indicate that critical ontogenetic changes in the gene expression of oxygen-binding proteins may underpin the physiological mechanisms needed for successful larval recruitment to reefs.

One of the most important developing cell types in any biological system is the gamete (sperm and egg). The transmission of phenotypes and optimally adapted physiology to subsequent generations is in large part controlled by gametogenesis. In contrast to genetics, the environment actively regulates epigenetics to impact the physiology and phenotype of cellular and biological systems. The integration of epigenetics and genetics is critical for all developmental biology systems at the cellular and organism level. The current review is focused on the role of epigenetics during gametogenesis for both the spermatogenesis system in the male and oogenesis system in the female. The developmental stages from the initial primordial germ cell through gametogenesis to the mature sperm and egg are presented. How environmental factors can influence the epigenetics of gametogenesis to impact the epigenetic transgenerational inheritance of phenotypic and physiological change in subsequent generations is reviewed., How environmental factors can influence the epigenetics of gametogenesis to impact the epigenetic transgenerational inheritance of phenotypic and physiological change in subsequent generations is reviewed.

Echolocation is the ability to gather information from sound reflections. Most previous studies have focused on the ability to detect sound reflections, others on the ability to localize sound reflections, but no previous study has compared the two abilities in the same individuals. Our study compared echo-detection (reflecting object present or not?) and echo-localization (reflecting object to the left or right?) in 10 inexperienced sighted participants across 10 distances (1–4.25 m) to the reflecting object, using an automated system for studying human echolocation. There were substantial individual differences, particularly in the performance on the echo-localization task. However, most participants performed better on the detection than the localization task, in particular at the closest distances (1 and 1.7 m), illustrating that it sometimes may be hard to perceive whether an audible reflection came from the left or right.

The goal of this qualitative study was to examine the strengths and posttraumatic growth experiences of a community of female refugees from Burma resettled in a Midwestern city of the United States. Based on data gathered from eleven participants, consensual qualitative research analysis yielded a thematic overview of two domains: (a) coping and resilience, and (b) experiences of posttraumatic growth. The results provided contextual evidence to the preresettlement and postresettlement stressors experienced by Burmese refugee women in resettlement. Findings also highlight the strengths, protective factors, and resources of Burmese refugee women, whose narratives of positive growth and change seem to coexist with memories and experiences of trauma, suffering, and hardship. Implications for research and clinical practice as well as future directions are discussed.

According to 2019 data, there are 26 million refugees and 3.5 million asylum seekers around the globe, representing a major humanitarian crisis. This Major Contribution provides information on the experiences of refugees resettled in the United States via the presentation of five manuscripts. In this introductory article, we address the current refugee crisis, refugee policies, and resettlement processes in the United States, as well as the American Psychological Association’s response to the crisis and the role of counseling psychology in serving refugees. Next follows three empirical articles, addressing aspects of the resettlement experiences of three groups of refugees: Somali, Burmese, and Syrian. The final article provides an overview of a culturally responsive intervention model to use when working with refugees.

More than 100,000 Somali refugees have resettled in the United States, creating a need for additional research about mental health needs and premigration experiences that precede resettlement. The purpose of this study was to learn more about premigration traumatic experiences, the process of acculturation following resettlement, and the relationship between premigration trauma, acculturation, and mental health. Eighty Somali refugees from two mid-sized Midwestern cities participated. It was hypothesized that acculturation would mediate the relationship between premigration trauma and mental health symptoms. The results partially supported this hypothesis, dependent upon the dimension of acculturation included in the path analysis. Unexpected relationships among the various acculturation dimensions in the model (American cultural identity, English language competency, and American cultural competency) occurred with traumatic experiences, mental health symptoms, and time in the United States. We discuss implications and directions for future research, practice, advocacy, and training.

Jet fuel hydrocarbons is the generic name for aviation fuels used in gas-turbine engine powered aircraft. The Deepwater Horizon oil rig explosion created the largest environmental disaster in U.S. history, and the second largest oil spill in human history with over 800 million liters of hydrocarbons released into the Gulf of Mexico over a period of 3 months. Due to the widespread use of jet fuel hydrocarbons, this compound mixture has been recognized as the single largest chemical exposure for military personnel. Previous animal studies have demonstrated the ability of jet fuel (JP-8) exposure to promote the epigenetic transgenerational inheritance of disease susceptibility in subsequent generations. The diseases observed include late puberty, kidney, obesity and multiple disease pathologies. The current study is distinct and was designed to identify potential sperm DNA methylation biomarkers for specific transgenerational diseases. Observations show disease specific differential DNA methylation regions (DMRs) called epimutations in the transgenerational F3 generation great-grand-offspring male rats ancestrally exposed to jet fuel. The potential epigenetic DMR biomarkers were identified for late puberty, kidney, obesity, and multiple diseases, and found to be predominantly disease specific. These disease specific DMRs have associated genes that were previously shown to be linked with each of these specific diseases. Therefore, the germline (i.e. sperm) has environmentally induced ancestrally derived epimutations that have the potential to transgenerationally transmit disease susceptibilities to subsequent generations. Epigenetic biomarkers for specific diseases could be developed as medical diagnostics to facilitate clinical management of disease, and allow preventative medicine therapeutics.

[Extract:] In their study, Clark et al. suggest that previous studies on the effects of elevated levels of CO2 on the behaviour of coral reef fishes are not repeatable and that ocean acidification does not impair the behaviour of coral reef fishes, even though six significant behavioural effects were detected in their study, each of which was dismissed for a different reason. They then compare the means and variances of six previous ocean acidification studies in fish with a data distribution that is derived from a multi-species compilation of their own data to conclude that the results of previous studies are statistically improbable. However, Clark et al. did not closely repeat previous studies, as they did not replicate key species, used different life stages and ecological histories and changed methods in important ways that reduce the likelihood of detecting the effects of ocean acidification.

In this paper, we provide guidance on how standard safety analyses and reporting of clinical trial safety data may need to be modified, given the potential impact of the COVID-19 pandemic. The impact could include missed visits, alternative methods for assessments (such as virtual visits), alternative locations for assessments (such as local labs), and study drug interruptions. We focus on safety planning for Phase 2-4 clinical trials and integrated summaries for submissions. Starting from the recommended safety analyses proposed in white papers and a workshop, created as part of an FDA/PHUSE collaboration (PHUSE 2013, 2015, 2017, 2019), we assess what modifications might be needed. Impact from COVID-19 will likely affect treatment arms equally, so analyses of adverse events from controlled data can, to a large extent, remain unchanged. However, interpretation of summaries from uncontrolled data (summaries that include open-label extension data) will require even more caution than usual. Special consideration will be needed for safety topics of interest, especially events expected to have a higher incidence due to a COVID-19 infection or due to quarantine or travel restrictions (e.g., depression). Analyses of laboratory measurements may need to be modified to account for the combination of measurements from local and central laboratories., Comment: 21 pages, 0 figures, submitted to Statistics in Biopharmaceutical Research

Most animals are visually oriented, and their eyes provide their 'window to the world'. Eye size correlates positively with visual performance, because larger eyes can house larger pupils that increase photon catch and contrast discrimination, particularly under dim light, which have positive effects on behaviours that enhance fitness, including predator avoidance and foraging. Recent studies have linked predation risk to selection for larger eyes and pupils, and such changes should be of importance for the majority of teleost fishes as they have a pupil that is fixed in size (eyes lack a pupillary sphincter muscle) and, hence, do not respond to changes in light conditions. Here, we quantify eye and pupil size of individual crucian carp, a common freshwater fish, following controlled manipulations of perceived predation risk (presence/absence). We also tested if crucian carp responded to increased predation risk by shifts in diel activity patterns. We found that crucian carp show phenotypic plasticity with regards to pupil size, but not eye size, as pupil size increased when exposed to predators (pike). Predator-exposed crucian carp also shifted from diurnal to nocturnal activity. Using a modelling exercise, we moreover show that the plastically enlarged pupils significantly increase visual range, especially for small objects under dim light conditions. Overall, our results provide compelling evidence for predator-induced pupil enlargement resulting in enhanced visual capabilities in a teleost fish. Pupil size plasticity in combination with the observed shift towards nocturnal activity may allow for efficient foraging also under dark conditions when predation risk from diurnal and visually oriented predators is reduced. The data highlight the powerful role of predation risk for eye development and evolution.