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Seabirds play critical roles on islands. By catalysing terrestrial and marine productivity through guano nutrient input, seabirds support natural island functioning. In the Indo-Pacific, atolls comprise one-third of all islands but only ~0.02% of island area. The importance of atolls as seabird nesting grounds has been historically neglected except on a few key atolls. We compiled a global dataset of seabird surveys on atolls and modelled seabird distribution and nutrient deposition on all Indo-Pacific atolls. We found that atolls are breeding sites for 37 species, ranging from a few dozen to more than 3 million individuals per atoll. In total, an estimated 31.2 million seabirds nest on atolls, or ~25% of the tropical seabirds of the world. For 14 species, more than half of their global populations nest on atolls. Seabirds forage more than 10,000-100,000 km² around an atoll and deposit, on average, 65,000 kg N and 11,000 kg P per atoll per year, thus acting as major nutrient pumps within the tropical Indo-Pacific. Our findings reveal the global importance of atolls for tropical seabirds. Given global change, conservation will have to leverage atoll protection and restoration to preserve a relevant fraction of the tropical seabirds of the world., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: Understanding disease transmission is a fundamental challenge in ecology. We used transmission potential networks to investigate whether a gastrointestinal protozoan (Blastocystis spp.) is spread through social, environmental, and/or zoonotic pathways in rural northeast Madagascar., Materials and Methods: We obtained survey data, household GPS coordinates, and fecal samples from 804 participants. Surveys inquired about social contacts, agricultural activity, and sociodemographic characteristics. Fecal samples were screened for Blastocystis using DNA metabarcoding. We also tested 133 domesticated animals for Blastocystis. We used network autocorrelation models and permutation tests (network k-test) to determine whether networks reflecting different transmission pathways predicted infection., Results: We identified six distinct Blastocystis subtypes among study participants and their domesticated animals. Among the 804 human participants, 74% (n = 598) were positive for at least one Blastocystis subtype. Close proximity to infected households was the most informative predictor of infection with any subtype (model averaged OR [95% CI]: 1.56 [1.33-1.82]), and spending free time with infected participants was not an informative predictor of infection (model averaged OR [95% CI]: 0.95 [0.82-1.10]). No human participant was infected with the same subtype as the domesticated animals they owned., Discussion: Our findings suggest that Blastocystis is most likely spread through environmental pathways within villages, rather than through social or animal contact. The most likely mechanisms involve fecal contamination of the environment by infected individuals or shared food and water sources. These findings shed new light on human-pathogen ecology and mechanisms for reducing disease transmission in rural, low-income settings., (© 2024 Wiley Periodicals LLC.)

Advancements in space-based ocean observation and computational data processing techniques have demonstrated transformative value for managing living resources, biodiversity, and ecosystems of the ocean. We synthesize advancements in leveraging satellite-derived insights to better understand and manage fishing, an emerging revolution of marine industrialization, ocean hazards, sea surface dynamics, benthic ecosystems, wildlife via electronic tracking, and direct observations of ocean megafauna. We consider how diverse space-based data sources can be better coupled to modernize and improve ocean management. We also highlight examples of how data from space can be developed into tools that can aid marine decision-makers managing subjects from whales to algae. Thoughtful and prospective engagement with such technologies from those inside and outside the marine remote sensing community is, however, essential to ensure that these tools meet their full potential to strengthen the effectiveness of ocean management.

Background: Patients with psoriasis are less physically active compared to age-matched controls, due to psoriasis-specific barriers, which significantly limits their ability to benefit from health-promoting levels of physical activity (PA). In addition, long-term health outcomes for people with psoriasis are poor and include depression, metabolic syndrome and cardiovascular disease (CVD); presenting a significant challenge to healthcare services., Objectives: We designed a PA intervention in partnership with patients with psoriasis hypothesising this may have therapeutic utility in the management of psoriasis., Methods: Participants with chronic plaque psoriasis were recruited to a single-centre, 20-week, prospective cohort study. A wrist-worn accelerometer (GENEActiv Original; Activinsights Ltd) and a hip-worn pedometer (Onwalk 900; Decathlon Group) were used objectively measure levels of PA. Our 10-week PA intervention comprised twice weekly 60-min walks within three different greenspaces in Greater Manchester, each led by a Sports and Exercise Scientist to deliver a pre-specified volume/dose of activity. During weeks-11-20 of the study, participants followed independent activities. Clinical evaluation, including assessment of psoriasis severity, cardiometabolic parameters, psychological wellbeing and functional capacity was made at baseline, week-10 and -20., Results: Sixteen patients with psoriasis completed the study. We observed significantly reduced Psoriasis Area and Severity Index at week-10 ( p  = 0.01) and -20 ( p  = 0.001) compared to baseline, with 50% of participants achieving PASI-50 at week-20. Dermatology Life Quality Index (DLQI) was significantly reduced at week-20 ( p  = 0.04), compared to baseline. Significant reduction in blood pressure at week-10 (systolic: -7.4 mmHg, p  = 0.002; diastolic: -4.2 mmHg, p  = 0.03) and -20 (systolic: -8.8 mmHg, p  = 0.001; diastolic: 4.1 mmHg, p  = 0.008) was observed and pulse wave velocity was significantly reduced by week-20 ( p  = 0.02), suggesting improvement in cardiovascular health. Despite high prevalence of anxiety and depression at baseline, we documented a significant improvement in wellbeing and psychological health. Functional capacity was significantly enhanced following completion of the study., Conclusion: Increasing PA constitutes a promising therapeutic intervention in the management of psoriasis. Evaluation of our intervention in a clinical trial would help determine clinical utility and establish PA guidelines for patients with psoriasis., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

The reversible association of transmembrane helices is a fundamental mechanism in how living cells convey information and respond to physiological events. The cardiac calcium transport regulator phospholamban (PLN) is an example of a single-span transmembrane protein that populates a variety of reversible and competing oligomeric states. PLN primarily forms monomers and pentamers in the membrane, where the PLN pentamer is a storage form and the PLN monomer forms a hetero-dimeric inhibitory complex with SERCA. The binding affinity and free-energy of formation of the SERCA-PLN complex in a membrane have not been determined. As is the case for most transmembrane protein interactions, measuring these quantities experimentally is extremely challenging. In this study, we estimated binding affinities by employing in silico alchemical free-energy calculations for all PLN transmembrane alanine substitutions in a membrane bilayer. The binding affinities were calculated separately for the SERCA-PLN complex, a PLN monomer, and a PLN pentamer and compared to in vitro functional measurements of SERCA regulation by the PLN alanine substitutions. Initially, the changes in SERCA inhibition by PLN alanine substitutions were compared to the changes in free energy for the SERCA-PLN complex formed from the PLN monomer. However, the functional data for the PLN alanine substitutions were better explained by the formation of the SERCA-PLN complex directly from the PLN pentamer. This finding points to an inhibitory mechanism favoring conformational selection of SERCA and the interaction of a PLN pentamer with SERCA for 'delivery' of a PLN monomer to the inhibitory site. The implications of these findings suggest that the energetics of helix exchange between homo- and hetero-oligomeric signaling complexes is favored over an intermediate involving a free monomeric helix in the membrane bilayer., Competing Interests: The authors declare that they have no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Ibuzatrelvir (1) was recently disclosed and patented by Pfizer for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has received fast-track status from the USA Food and Drug Administration (FDA) and has entered phase III clinical trials as a possible replacement for Paxlovid. Like nirmatrelvir (2) in Paxlovid, this orally active drug candidate is designed to target viral main proteases (M pro ) through reversible covalent interaction of its nitrile warhead with the active site thiol of the chymotrypsin-like cysteine protease (3CL protease). Inhibition of M pro hinders the processing of the proteins essential for viral replication in vivo . However, ibuzatrelvir apparently does not require ritonavir (3), which is coadministered in Paxlovid to block human oxidative metabolism of nirmatrelvir. Here, we report the crystal structure of the complex of ibuzatrelvir with the active site of SARS-CoV-2 M pro at 2.0 Å resolution. In addition, we show that ibuzatrelvir also potently inhibits the M pro of Middle East respiratory syndrome-related coronavirus (MERS-CoV), which is fortunately not widespread but can be dangerously lethal (∼36% mortality). Co-crystal structures show that the binding mode of the drug to both active sites is similar and that the trifluoromethyl group of the inhibitor fits precisely into a critical S2 substrate binding pocket of the main proteases. However, our results also provide a rationale for the differences in potency of ibuzatrelvir for these two proteases due to minor differences in the substrate preferences leading to a weaker H-bond network in MERS-CoV M pro . In addition, we examined the reversibility of compound binding to both proteases, which is an important parameter in reducing off-target effects as well as the potential immunogenicity. The crystal structures of the ibuzatrelvir complexes with M pro of SARS-CoV-2 and of MERS-CoV will further assist drug design for coronaviral infections in humans and animals., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Direct exploitation through fishing is driving dramatic declines of wildlife populations in ocean environments, particularly for predatory and large-bodied taxa. Despite wide recognition of this pattern and well-established consequences of such trophic downgrading on ecosystem function, there have been few empirical studies examining the effects of fishing on whole system trophic architecture. Understanding these kinds of structural impacts is especially important in coral reef ecosystems-often heavily fished and facing multiple stressors. Given the often high dietary flexibility and numerous functional redundancies in diverse ecosystems such as coral reefs, it is important to establish whether web architecture is strongly impacted by fishing pressure or whether it might be resilient, at least to moderate-intensity pressure. To examine this question, we used a combination of bulk and compound-specific stable isotope analyses measured across a range of predatory and low-trophic-level consumers between two coral reef ecosystems that differed with respect to fishing pressure but otherwise remained largely similar. We found that even in a high-diversity system with relatively modest fishing pressure, there were strong reductions in the trophic position (TP) of the three highest TP consumers examined in the fished system but no effects on the TP of lower-level consumers. We saw no evidence that this shortening of the affected food webs was being driven by changes in basal resource consumption, for example, through changes in the spatial location of foraging by consumers. Instead, this likely reflected internal changes in food web architecture, suggesting that even in diverse systems and with relatively modest pressure, human harvest causes significant compressions in food chain length. This observed shortening of these food webs may have many important emergent ecological consequences for the functioning of ecosystems impacted by fishing or hunting. Such important structural shifts may be widespread but unnoticed by traditional surveys. This insight may also be useful for applied ecosystem managers grappling with choices about the relative importance of protection for remote and pristine areas and the value of strict no-take areas to protect not just the raw constituents of systems affected by fishing and hunting but also the health and functionality of whole systems., (© 2024 The Ecological Society of America.)

Conservation areas encompassing elevation gradients are biodiversity hotspots because they contain a wide range of habitat types in a relatively small space. Studies of biodiversity patterns along elevation gradients, mostly on small mammal or bird species, have documented a peak in diversity at mid elevations. Here, we report on a field study of medium and large mammals to examine the impact of elevation, habitat type, and gross primary productivity on community structure. Species richness was observed using a camera trap transect with 219 sites situated across different habitat types from 2329 to 4657 m above the sea level on the western slope of Mt Kenya, the second highest mountain in Africa. We found that the lowest elevation natural habitats had the highest species richness and relative abundance and that both metrics decreased steadily as elevation increased, paralleling changes in gross primary productivity, and supporting the energy richness hypothesis. We found no evidence for the mid-domain effect on species diversity. The lowest elevation degraded Agro-Forestry lands adjacent to the National Park had high activity of domestic animals and reduced diversity and abundance of native species. The biggest difference in community structure was between protected and unprotected areas, followed by more subtle stepwise differences between habitats at different elevations. Large carnivore species remained relatively consistent but dominant herbivore species shifted along the elevation gradient. There was some habitat specialization and turnover in species, such that the elevation gradient predicts a high diversity of species, demonstrating the high conservation return for protecting mountain ecosystems for biodiversity conservation., Competing Interests: No conflicts of interest are known between any co‐author and outside entities regarding fiscal, board membership, consultancy, or any other overlap., (© 2024 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

As the genetic landscape of cardiomyopathies continues to expand, the identification of missense variants in disease-associated genes frequently leads to a classification of variant of uncertain significance (VUS). For the proper reclassification of such variants, functional characterization is an important contributor to the proper assessment of pathogenic potential. Several missense variants in the calcium transport regulatory protein phospholamban have been associated with dilated cardiomyopathy. However, >40 missense variants in this transmembrane peptide are currently known and most remain classified as VUS with little clinical information. Similarly, missense variants in cardiac myosin binding protein have been associated with hypertrophic cardiomyopathy. However, hundreds of variants are known and many have low penetrance and are often found in control populations. Herein, we focused on novel missense variants in phospholamban, an Ala 15 -Thr variant found in a 4-year-old female and a Pro 21 -Thr variant found in a 60-year-old female, both with a family history and clinical diagnosis of dilated cardiomyopathy. The patients also harbored a Val 896 -Met variant in cardiac myosin binding protein. The phospholamban variants caused defects in the function, phosphorylation, and dephosphorylation of this calcium transport regulatory peptide, and we classified these variants as potentially pathogenic. The variant in cardiac myosin binding protein alters the structure of the protein. While this variant has been classified as benign, it has the potential to be a low-risk susceptibility variant because of the structural change in cardiac myosin binding protein. Our studies provide new biochemical evidence for missense variants previously classified as benign or VUS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Atoll islands are often perceived as inevitably lost due to rising sea levels. However, unlike other islands, atoll islands are dynamic landforms that have evolved, at least historically, to vertically accrete at a pace commensurate with changing sea levels. Rather than atoll islands' low elevation per se, the impairment of natural accretion processes is jeopardising their persistence. While global marine impacts are deteriorating coral reefs, local impacts also significantly affect accretion, together potentially tipping the scales toward atoll island erosion. Maintaining atoll island accretion requires intact sediment generation on coral reefs, unobstructed sediment transport from reef to island, and available vegetated deposition sites on the island. Ensuring the persistence of atoll islands must include global greenhouse gas emission reduction and local restoration of accretion processes., Competing Interests: Declaration of interests The authors have no interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Myoregulin (MLN) is a protein that regulates the activity of the sarcoplasmic reticulum Ca 2+ -ATPase (SERCA) without affecting its affinity for Ca 2+ . MLN's residue Lys27 is located at a site where other SERCA regulators control Ca 2+ affinity. Therefore, we conducted atomistic simulations and ATPase activity experiments to determine whether replacing Lys27 with asparagine, a conserved residue found in various muscle SERCA regulators, would enable MLN to modulate both the Ca 2+ affinity and catalytic activity of SERCA. Our findings indicate that replacing Lys27 with Asn significantly enhances the inhibitory potency of MLN, but it does not affect SERCA's affinity for Ca 2+ . We suggest that the SERCA site modulating Ca 2+ affinity also acts as a catalytic activity switch. Therefore, this site is a key element contributing to the functional divergence among homologous SERCA regulators. This study paves the way for future investigations to explore how biological function diverges during the evolution of the SERCA regulator family., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This study explores the relationship between structural alterations of nirmatrelvir, such as homologation and deuteration, and metabolic stability of newly synthesized derivatives. We developed a reliable synthetic protocol toward dideutero-nirmatrelvir and its homologated analogues with high isotopic incorporation. Deuteration of the primary metabolic site of nirmatrelvir provides a 3-fold improvement of its human microsomal stability but is accompanied by an increased metabolism rate at secondary sites. Homologation of the lactam ring allows the capping group modification to decrease and delocalize the molecule's lipophilicity, reducing the metabolic rate at secondary sites. The effect of deuteration was less pronounced for the 6-membered lactam than for its 5-membered analogue in human microsomes, but the trend is reversed in the case of mouse microsomes. X-ray data revealed that the homologation of the lactam ring favors the orientation of the drug's nitrile warhead for interaction with the catalytic sulfur of the SARS-CoV-2 M pro , improving its binding. Comparable potency against SARS-CoV-2 M pro from several variants of concern and selectivity over human cysteine proteases cathepsin B, L, and S was observed for the novel deuterated/homologated derivative and nirmatrelvir. Synthesized compounds displayed a large interspecies variability in hamster, rat, and human hepatocyte stability assays. Overall, we aimed to apply a rational approach in changing the physicochemical properties of the drug to refine its biochemical and biological parameters., Competing Interests: The authors declare the following competing financial interest(s): The Governors of the University of Alberta has filed a patent application that also contains a few of the molecules in this manuscript and currently some authors are listed as inventors., (© 2023 The Authors. Published by American Chemical Society.)

Background: Vascular Endothelial Growth Factor (VEGF)-A-mediated angiogenesis participates in the pathogenesis of psoriasis, thus inviting the hypothesis that anti-VEGF-A therapy could be beneficial in psoriasis. While anti-angiogenic agents are used in oncology and ophthalmology, these therapeutic strategies remain unexplored for the management of psoriasis., Objective: Our objective was to investigate ex vivo how VEGF-A blockade impacts blood vessels, epidermis and immune cells in organ-cultured plaque and non-lesional skin from patients with psoriasis., Methods: Skin biopsies from patients with psoriasis ( n  = 6; plaque and non-lesional skin) and healthy controls ( n  = 6) were incubated with anti-VEGF-A monoclonal antibody (bevacizumab, Avastin®) or a human IgG 1 isotype control for 72-h in serum-free organ culture. CD31/LYVE-1, Ki-67, and mast cell tryptase expression were assessed by quantitative immunohistomorphometry. VEGF-A levels in plasma, PBMCs and skin culture supernatants were measured., Results: Inhibition of VEGF-A blocked all free VEGF-A ex vivo, reduced blood vessel area and the number of blood vessel endothelial cells in plaques of psoriasis (* p  < 0.05). The treatment effect correlated significantly with levels of VEGF-A in organ culture supernatants ( r  = 0.94; * p  < 0.05) from plaque skin and with plasma levels of VEGF-A from patients with psoriasis ( r  = 0.943; * p  = 0.017)., Conclusions: These ex vivo data are the first studies to objectively investigate the potential of VEGF-A inhibition as a novel adjuvant treatment strategy for psoriasis. Taken together, our data encourage further investigation by clinical trial to explore whether downregulating pathological angiogenesis has clinical utility, especially in patients with severe psoriasis or those with elevated levels of VEGF-A in plasma and/or skin., Competing Interests: The authors state no conflict of interest., (© 2023 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Myoregulin (MLN) is a member of the regulin family, a group of homologous membrane proteins that bind to and regulate the activity of the sarcoplasmic reticulum Ca 2+ -ATPase (SERCA). MLN, which is expressed in skeletal muscle, contains an acidic residue in its transmembrane domain. The location of this residue, Asp35, is unusual because the relative occurrence of aspartate is very rare (<0.2%) within the transmembrane helix regions. Therefore, we used atomistic simulations and ATPase activity assays of protein co-reconstitutions to probe the functional role of MLN residue Asp35. These structural and functional studies showed Asp35 has no effects on SERCA's affinity for Ca 2+ or the structural integrity of MLN in the lipid bilayer. Instead, Asp35 controls SERCA inhibition by populating a bound-like orientation of MLN. We propose Asp35 provides a functional advantage over other members of the regulin family by populating preexisting MLN conformations required for MLN-specific regulation of SERCA. Overall, this study provides new clues about the evolution and functional divergence of the regulin family and offers novel insights into the functional role of acidic residues in transmembrane protein domains.

The main protease of SARS-CoV-2 (M pro ) is the most promising drug target against coronaviruses due to its essential role in virus replication. With newly emerging variants there is a concern that mutations in M pro may alter the structural and functional properties of protease and subsequently the potency of existing and potential antivirals. We explored the effect of 31 mutations belonging to 5 variants of concern (VOCs) on catalytic parameters and substrate specificity, which revealed changes in substrate binding and the rate of cleavage of a viral peptide. Crystal structures of 11 M pro mutants provided structural insight into their altered functionality. Additionally, we show M pro mutations influence proteolysis of an immunomodulatory host protein Galectin-8 (Gal-8) and a subsequent significant decrease in cytokine secretion, providing evidence for alterations in the escape of host-antiviral mechanisms. Accordingly, mutations associated with the Gamma VOC and highly virulent Delta VOC resulted in a significant increase in Gal-8 cleavage. Importantly, IC50s of nirmatrelvir (Pfizer) and our irreversible inhibitor AVI-8053 demonstrated no changes in potency for both drugs for all mutants, suggesting M pro will remain a high-priority antiviral drug candidate as SARS-CoV-2 evolves., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background: Vascular dysfunction is a significant contributor to the pathophysiology of psoriasis. Some individuals have variation within the gene for vascular endothelial growth factor-A (VEGF-A), which confers an increased risk of developing psoriasis and having a severe disease phenotype, and may determine responsiveness to treatment., Aim: To determine whether patients with psoriasis have alterations in cutaneous microvascular anatomy and physiology due to expression of VEGF and whether laser Doppler imaging has utility in the assessment of this., Methods: Twelve adult volunteers with Type 1 chronic plaque psoriasis underwent laser Doppler imaging of plaque and uninvolved skin. Skin biopsies were taken from the areas imaged for immunohistochemistry, including blood and lymphatic vessel markers, and VEGF-A isotype analysis (VEGF-A121, VEGF-A165 and VEGF-D). Venous blood was collected for DNA extraction, VEGF-A genotyping and peripheral blood mononuclear cell culture., Results: Mean blood vessel area (P < 0·01), number of blood vessels (P < 0·001), number of lymphatic vessels (P < 0·001) and blood flow (P < 0·001) was significantly increased in psoriasis plaques, as was expression of VEGF-A121 (P < 0·01), VEGF-A165 (P < 0·04) and VEGF-D (P < 0·01). Blood flow within psoriasis plaques was independent of their increased vascularity (P < 0·01) and may be associated with baseline productivity of VEGF. The number of blood vessels within uninvolved skin in patients with psoriasis was associated with the VEGF-A (rs833061) genotype (P = 0·01), in a relationship suggesting an allele dosing effect., Conclusion: Noninvasive imaging of blood flow may help determine the cutaneous vascular signature for individual patients. This may be a useful prognostic indicator of psoriasis susceptibility and severity, and thus support selection of treatments., Competing Interests: Conflict of interest: The authors declare that they have no conflict of interest. AK-A was a work-experience student., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Patients with psoriasis do not exercise to the extent recommended for cardiovascular health, which may contribute to the increased risk of cardiovascular disease (CVD) and metabolic syndrome observed in this patient group. We previously identified that patients with psoriasis have significant disease-specific barriers to exercise. Others have reported that individuals with psoriasis develop higher heart rates and systolic blood pressure during bouts of exercise, followed by a slower recovery than healthy control subjects., Aims: We hypothesized that a bespoke, evidenced-based, exercise programme could be developed for patients with psoriasis., Methods: We convened a multidisciplinary Working Group comprising key stakeholders, including patients with psoriasis, along with sports scientists and clinicians, to develop the programme., Results: To allow for different levels of fitness, lifestyle and motivation a 10-week intervention comprising two group walking sessions per week each of 1 h duration [led by a sports scientist (RS)] was designed using the Mapometer website. Walking distance was validated by a Walkmeter application, which uses global positioning system technology. The volume of exercise per session was calculated so that participants could incrementally progress to heart-healthy levels of exercise over the course of the programme. Maps of 20 unique walking routes were developed. A GENEactiv Original accelerometer and Newfeel Onwalk 900 pedometer were selected as wearable devices., Conclusion: We developed an exercise programme which specifically removed barriers to exercise for those with psoriasis, in partnership with patients. Regular exercise may offer significant health benefits for patients with psoriasis, including reduced CVD risk and increased psychosocial functioning, and this programme merits further investigation., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Variation in behavior within marine and terrestrial species can influence the functioning of the ecosystems they inhabit. However, the contribution of social behavior to ecosystem function remains underexplored. Many coral reef fish species provide potentially insightful models for exploring how social behavior shapes ecological function because they exhibit radical intraspecific variation in sociality within a shared habitat. Here, we provide an empirical exploration on how the ecological function of a shoaling surgeonfish ( Acanthurus triostegus ) may differ from that of solitary conspecifics on two Pacific coral reefs combining insight from behavioral observations, stable isotope analysis, and macronutrient analysis of gut and fecal matter. We detected important differences in how the social mode of A. triostegus affected its spatial and feeding ecology, as well as that of other reef fish species. Specifically, we found increased distance traveled and area covered by shoaling fish relative to solitary A. triostegus . Additionally, shoaling A. triostegus primarily grazed within territories of other herbivorous fish and had piscivorous and nonpiscivorous heterospecific fish associated with the shoal, while solitary A. triostegus grazed largely grazed outside of any territories and did not have any such interactions with heterospecific fish. Results from stable isotope analysis show a difference in δ15N isotopes between shoaling and solitary fish, which suggests that these different social modes are persistent. Further, we found a strong interaction between social behavior and site and carbohydrate and protein percentages in the macronutrient analysis, indicating that these differences in sociality are associated with measurable differences in both the feeding ecology and nutrient excretion patterns. Our study suggests that the social behavior of individuals may play an important and underappreciated role in mediating their ecological function., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

The physiology and pathology of the skin are influenced by daily oscillations driven by a master clock located in the brain, and peripheral clocks in individual cells. The pathogenesis of psoriasis is circadian-rhythmic, with flares of disease and symptoms such as itch typically being worse in the evening/night-time. Patients with psoriasis have changes in circadian oscillations of blood pressure and heart rate, supporting wider circadian disruption. In addition, shift work, a circadian misalignment challenge, is associated with psoriasis. These features may be due to underlying circadian control of key effector elements known to be relevant in psoriasis such as cell cycle, proliferation, apoptosis and inflammation. Indeed, peripheral clock pathology may lead to hyperproliferation of keratinocytes in the basal layers, insufficient apoptosis of differentiating keratinocytes in psoriatic epidermis, dysregulation of skin-resident and migratory immune cells and modulation of angiogenesis through circadian oscillation of vascular endothelial growth factor A (VEGF-A) in epidermal keratinocytes. Chronotherapeutic effects of topical steroids and topical vitamin D analogues have been reported, suggesting that knowledge of circadian phase may improve the efficacy, and therapeutic index of treatments for psoriasis. In this viewpoint essay, we review the current literature on circadian disruption in psoriasis. We explore the hypothesis that psoriasis is circadian-driven. We also suggest that investigation of the circadian components specific to psoriasis and that the in vitro investigation of circadian regulation of psoriasis will contribute to the development of a novel chronotherapeutic treatment strategy for personalised psoriasis management. We also propose that circadian oscillations of VEGF-A offer an opportunity to enhance the efficacy and tolerability of a novel anti-VEGF-A therapeutic approach, through the timed delivery of anti-VEGF-A drugs., (© 2022 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Predator-prey interactions shape ecosystem stability and are influenced by changes in ecosystem productivity. However, because multiple biotic and abiotic drivers shape the trophic responses of predators to productivity, we often observe patterns, but not mechanisms, by which productivity drives food web structure. One way to capture mechanisms shaping trophic responses is to quantify trophic interactions among multiple trophic groups and by using complementary metrics of trophic ecology. In this study, we combine two diet-tracing methods: diet DNA and stable isotopes, for two trophic groups (top predators and intermediate predators) in both low- and high-productivity habitats to elucidate where in the food chain trophic structure shifts in response to changes in underlying ecosystem productivity. We demonstrate that while top predators show increases in isotopic trophic position ( δ 15 N) with productivity, neither their isotopic niche size nor their DNA diet composition changes. Conversely, intermediate predators show clear turnover in DNA diet composition towards a more predatory prey base in high-productivity habitats. Taking this multi-trophic approach highlights how predator identity shapes responses in predator-prey interactions across environments with different underlying productivity, building predictive power for understanding the outcomes of ongoing anthropogenic change.

Intracellular calcium signaling is essential for all kingdoms of life. An important part of this process is the sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA), which maintains the low cytosolic calcium levels required for intracellular calcium homeostasis. In higher organisms, SERCA is regulated by a series of tissue-specific transmembrane subunits such as phospholamban in cardiac muscles and sarcolipin in skeletal muscles. These regulatory axes are so important for muscle contractility that SERCA, phospholamban, and sarcolipin are practically invariant across mammalian species. With the recent discovery of the arthropod sarcolambans, the family of calcium pump regulatory subunits appears to span more than 550 million years of evolutionary divergence from arthropods to humans. This evolutionary divergence is reflected in the peptide sequences, which vary enormously from one another and only vaguely resemble phospholamban and sarcolipin. The discovery of the sarcolambans allowed us to address two questions. How much sequence variation is tolerated in the regulation of mammalian SERCA activity by the transmembrane peptides? Do divergent peptide sequences mimic phospholamban or sarcolipin in their regulatory activities despite limited sequence similarity? We expressed and purified recombinant sarcolamban peptides from three different arthropods. The peptides were coreconstituted into proteoliposomes with mammalian SERCA1a and the effect of each peptide on the apparent calcium affinity and maximal activity of SERCA was measured. All three peptides were superinhibitors of SERCA, exhibiting either phospholamban-like or sarcolipin-like characteristics. Molecular modeling, protein-protein docking, and molecular dynamics simulations revealed novel features of the divergent peptides and their SERCA regulatory properties.

Wildfire dynamics are changing around the world and understanding their effects on ecological communities and landscapes is urgent and important. We report detailed food webs for unburned, low-to-moderate and high severity burned habitats three years post-fire in the Eldorado National Forest, California. The cumulative cross-habitat food web contains 3,084 ontogenetic stages (nodes) or plant parts comprising 849 species (including 107 primary producers, 634 invertebrates, 94 vertebrates). There were 178,655 trophic interactions between these nodes. We provide information on taxonomy, body size, biomass density and trophic interactions under each of the three burn conditions. We detail 19 sampling methods deployed across 27 sites (nine in each burn condition) used to estimate the richness, body size, abundance and biomass density estimates in the node lists. We provide the R code and raw data to estimate summarized node densities and assign trophic links., (© 2022. The Author(s).)

The frequency of large, high-severity "mega-fires" has increased in recent decades, with numerous consequences for forest ecosystems. In particular, small mammal communities are vulnerable to post-fire shifts in resource availability and play critical roles in forest ecosystems. Inconsistencies in previous observations of small mammal community responses to fire severity underscore the importance of examining mechanisms regulating the effects of fire severity on post-fire recovery of small mammal communities. We compared small mammal abundance, diversity, and community structure among habitats that burned at different severities, and used vegetation characteristics and small mammal functional traits to predict community responses to fire severity three years after one mega-fire in the Sierra Nevada, California. Using a model-based fourth-corner analysis, we examined how interactions between vegetation variables and small mammal traits associated with their resource use were associated with post-fire small mammal community structure among fire severity categories. Small mammal abundance was similar across fire severity categories, but diversity decreased and community structure shifted as fire severity increased. Differences in small mammal communities were large only between unburned and high-severity sites. Three highly correlated fire-dependent vegetation variables affected by fire and the volume of soft coarse woody debris were associated with small mammal community structures. Furthermore, we found that interactions between vegetation variables and three small mammal traits (feeding guild, primary foraging mode, and primary nesting habit) predicted community structure across fire severity categories. We concluded that resource use was important in regulating small mammal recovery after the fire because vegetation provided required resources to small mammals as determined by their functional traits. Given the mechanistic nature of our analyses, these results may be applicable to other fire-prone forest systems, although it will be important to conduct studies across large biogeographic regions and over long post-fire time periods to assess generality., (© 2022 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Amidst global shifts in the distribution and abundance of wildlife and livestock, we have only a rudimentary understanding of ungulate parasite communities and parasite-sharing patterns. We used qPCR and DNA metabarcoding of fecal samples to characterize gastrointestinal nematode (Strongylida) community composition and sharing among 17 sympatric species of wild and domestic large mammalian herbivore in central Kenya. We tested a suite of hypothesis-driven predictions about the role of host traits and phylogenetic relatedness in describing parasite infections. Host species identity explained 27-53% of individual variation in parasite prevalence, richness, community composition and phylogenetic diversity. Host and parasite phylogenies were congruent, host gut morphology predicted parasite community composition and prevalence, and hosts with low evolutionary distinctiveness were centrally positioned in the parasite-sharing network. We found no evidence that host body size, social-group size or feeding height were correlated with parasite composition. Our results highlight the interwoven evolutionary and ecological histories of large herbivores and their gastrointestinal nematodes and suggest that host identity, phylogeny and gut architecture-a phylogenetically conserved trait related to parasite habitat-are the overriding influences on parasite communities. These findings have implications for wildlife management and conservation as wild herbivores are increasingly replaced by livestock.

Chronic plaque psoriasis is an inflammatory skin disease in which genetic predisposition along with environmental factors lead to the development of the disease, which affects 2% of the UK's population and is associated with extracutaneous morbidities and a reduced quality of life. A complex crosstalk between innate and adaptive immunity, the epithelia and the vasculature maintain the inflammatory milieu in psoriasis. Despite the development of promising treatment strategies, mostly targeting the immune system, treatments fail to fulfil every patient's goals. Vascular endothelial growth factor-A (VEGF-A) mediates angiogenesis and is upregulated in the plaques and plasma of patients with psoriasis. Transgenic expression of VEGF-A in experimental models led to the development of skin lesions that share many psoriasis features. Targeting VEGF-A in in vivo models of psoriasis-like inflammation resulted in disease clearance. Anti-angiogenesis treatments are widely used for cancer and eye disease and there are clinical reports of patients treated with VEGF-A inhibitors who have experienced Psoriasis Area and Severity Index improvement. Existing psoriasis treatments downregulate VEGF-A and angiogenesis as part of their therapeutic effect. Pharmacogenetics studies suggest the existence of different genetic signatures within patients with psoriasis that correspond with different treatment responsiveness and disease severity. There is a subset of patients with psoriasis with an increased predisposition to produce high levels of VEGF-A, who may be most likely to benefit from anti-VEGF-A therapy, offering an opportunity to personalize treatment in psoriasis. Anti-VEGF-A therapies may offer an alternative to existing anticytokine strategies or be complementary to standard treatments for the management of psoriasis., (© 2022 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Coronaviruses infect a variety of hosts in the animal kingdom, and while each virus is taxonomically different, they all infect their host via the same mechanism. The coronavirus main protease (M pro , also called 3CL pro ), is an attractive target for drug development due to its essential role in mediating viral replication and transcription. An M pro inhibitor, GC376, has been shown to treat feline infectious peritonitis (FIP), a fatal infection in cats caused by internal mutations in the feline enteric coronavirus (FECV). Recently, our lab demonstrated that the feline drug, GC373, and prodrug, GC376, are potent inhibitors of SARS-CoV-2 M pro and solved the structures in complex with the drugs; however, no crystal structures of the FIP virus (FIPV) M pro with the feline drugs have been published so far. Here, we present crystal structures of FIPV M pro -GC373/GC376 complexes, revealing the inhibitors covalently bound to Cys144 in the active site, similar to SARS-CoV-2 M pro . Additionally, GC376 has a higher affinity for FIPV M pro with lower nanomolar K i values compared to SARS-CoV and SARS-CoV-2 M pro . We also show that improved derivatives of GC376 have higher potency for FIPV M pro . Since GC373 and GC376 represent strong starting points for structure-guided drug design, determining the crystal structures of FIPV M pro with these inhibitors are important steps in drug optimization and structure-based broad-spectrum antiviral drug discovery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lu, Chen, Khan, Brassard, Arutyunova, Lamer, Vuong, Fischer, Young, Vederas and Lemieux.)

Recurring coronavirus outbreaks, such as the current COVID-19 pandemic, establish a necessity to develop direct-acting antivirals that can be readily administered and are active against a broad spectrum of coronaviruses. Described in this Article are novel α-acyloxymethylketone warhead peptidomimetic compounds with a six-membered lactam glutamine mimic in P1. Compounds with potent SARS-CoV-2 3CL protease and in vitro viral replication inhibition were identified with low cytotoxicity and good plasma and glutathione stability. Compounds 15e , 15h , and 15l displayed selectivity for SARS-CoV-2 3CL protease over CatB and CatS and superior in vitro SARS-CoV-2 antiviral replication inhibition compared with the reported peptidomimetic inhibitors with other warheads. The cocrystallization of 15l with SARS-CoV-2 3CL protease confirmed the formation of a covalent adduct. α-Acyloxymethylketone compounds also exhibited antiviral activity against an alphacoronavirus and non-SARS betacoronavirus strains with similar potency and a better selectivity index than remdesivir. These findings demonstrate the potential of the substituted heteroaromatic and aliphatic α-acyloxymethylketone warheads as coronavirus inhibitors, and the described results provide a basis for further optimization.

Background: Patients with psoriasis have a level of physical activity below that recommended for cardiovascular health, which is significantly limited by disease severity and other psoriasis-specific barriers. We hypothesized that physical activity is important for cardiovascular health in patients with psoriasis and that its objective measurement could have clinical utility., Aim: To explore whether physical activity influences the risk of cardiovascular disease (CVD) in patients with psoriasis., Methods: In total, 242 patients with chronic plaque psoriasis were recruited. History, examination and physical activity were assessed and arteriography, the noninvasive measurement of arterial function, was performed for each participant., Results: We observed a significant relationship between volume of physical activity and the likelihood of future CVD as measured by pulse wave velocity (PWV; P < 0.02). We identified a significant relationship between the diastolic reflection area (DRA) and health-promoting levels of physical activity (P < 0.001), in addition to a significant correlation between DRA and the likelihood of future CVD (P < 0.001). The DRA is a complex, dimensionless variable that describes the intensity of diastolic wave reflection and the duration of diastole, which are key determinants of the blood supply to the left ventricle. Our data suggest that DRA may represent a surrogate marker for cardiorespiratory fitness., Conclusion: Our study describes a significant relationship between exercise, cardiorespiratory fitness and PWV, a preclinical indicator of future CVD risk, in patients with psoriasis. The DRA offers a noninvasive, objective measurement of exercise adherence, which could have clinical utility in the future., (© 2021 The Authors. Clinical and Experimental Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

The sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) hydrolyzes ATP to transport Ca 2+ from the cytoplasm to the sarcoplasmic reticulum (SR) lumen, thereby inducing muscle relaxation. Dysfunctional SERCA has been related to various diseases. The identification of small-molecule drugs that can activate SERCA may offer a therapeutic approach to treat pathologies connected with SERCA malfunction. Herein, we propose a method to study the mechanism of interaction between SERCA and novel SERCA activators, i. e. CDN1163, using a solid supported membrane (SSM) biosensing approach. Native SR vesicles or reconstituted proteoliposomes containing SERCA were adsorbed on the SSM and activated by ATP concentration jumps. We observed that CDN1163 reversibly interacts with SERCA and enhances ATP-dependent Ca 2+ translocation. The concentration dependence of the CDN1163 effect provided an EC 50 =6.0±0.3 μM. CDN1163 was shown to act directly on SERCA and to exert its stimulatory effect under physiological Ca 2+ concentrations. These results suggest that CDN1163 interaction with SERCA can promote a protein conformational state that favors Ca 2+ release into the SR lumen., (© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Replication of SARS-CoV-2, the coronavirus causing COVID-19, requires a main protease (M pro ) to cleave viral proteins. Consequently, M pro is a target for antiviral agents. We and others previously demonstrated that GC376, a bisulfite prodrug with efficacy as an anti-coronaviral agent in animals, is an effective inhibitor of M pro in SARS-CoV-2. Here, we report structure-activity studies of improved GC376 derivatives with nanomolar affinities and therapeutic indices >200. Crystallographic structures of inhibitor-M pro complexes reveal that an alternative binding pocket in M pro , S4, accommodates the P3 position. Alternative binding is induced by polar P3 groups or a nearby methyl. NMR and solubility studies with GC376 show that it exists as a mixture of stereoisomers and forms colloids in aqueous media at higher concentrations, a property not previously reported. Replacement of its Na + counter ion with choline greatly increases solubility. The physical, biochemical, crystallographic, and cellular data reveal new avenues for M pro inhibitor design., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Water sources in arid and semiarid ecosystems support humans, wildlife, and domestic animals, forming nodes of activity that sculpt surrounding plant communities and impact critical grazing and soil systems. However, global aridification and changing surface water supply threaten to disrupt these water resources, with strong implications for conservation and management of these ecosystems. To understand how effects of herbivore aggregation at water impact plant communities across contexts, we measured herbivore activity, plant height, cover (trees, grasses, forbs, and bare ground), diversity, and composition at 17 paired water sources and matrix sites across a range of abiotic factors in a semiarid savanna in Kenya. The effects of proximity to surface water and herbivore aggregation on plant communities varied substantially depending on soil and rainfall. In arid areas with nutrient-poor sandy soils, forb and tree cover were 50% lower at water sources compared to neighboring matrix sites, bare ground was 20% higher, species richness was 15% lower, and a single globally important grazing grass (Cynodon dactylon) dominated 60% of transects. However, in mesic areas with nutrient-rich finely textured soils, species richness was 25% higher, despite a 40% increase in bare ground, concurrent with the decline of a dominant tall grass (Themeda triandra) and increase in C. dactylon and other grass species near water sources. Recent rainfall was important for grasses; cover was higher relative to matrix sites only during wet periods, a potential indication of compensatory grazing. These findings suggest that effects of herbivore aggregation on vegetation diversity and composition will vary in magnitude, and in some cases direction, depending on other factors at the site. Where moisture and nutrient resources are high and promote the dominance of few plant species, herbivore aggregations may maintain diversity by promoting grazing lawns and increasing nondominant species cover. However, in arid conditions and sites with low nutrient availability, diversity can be substantially reduced by these aggregations. Our results highlight the importance of considering abiotic conditions when managing for effects of herbivore aggregations near water. This will be particularly important for future managers in light of growing global aridification and surface water changes., (© 2021 by the Ecological Society of America.)

Anthropogenic disturbance impacts the phylogenetic composition and diversity of ecological communities. While changes in diversity are known to dramatically change species interactions and alter disease dynamics, the effects of phylogenetic changes in host and vector communities on disease have been relatively poorly studied. Using a theoretical model, we investigated how phylogeny and extinction influence network structural characteristics relevant to disease transmission in disturbed environments. We modelled a multi-host, multi-vector community as a bipartite ecological network, where nodes represent host and vector species and edges represent connections among them through vector feeding, and we simulated vector preferences and threat status on host and parasite phylogenies. We then simulated loss of hosts, including phylogenetically clustered losses, to investigate how extinction influences network structure. We compared effects of phylogeny and extinction to those of host specificity, which we predicted to strongly increase network modularity and reduce disease prevalence. The simulations revealed that extinction often increased modularity, with higher modularity as species loss increased, although not as much as increasing host specificity did. These results suggest that extinction itself, all else being equal, may reduce disease prevalence in disturbed communities. However, in real communities, systematic patterns in species loss (e.g. favoring high competence species) or changes in abundance may counteract these effects. Unexpectedly, we found that effects of phylogenetic signal in host and vector traits were relatively weak, and only important when phylogenetic signal of host and vector traits were similar, or when these traits both varied., Competing Interests: The authors have declared that no competing interests exist.

Tragically, the death toll from the COVID-19 pandemic continues to rise, and with variants being observed around the globe new therapeutics, particularly direct-acting antivirals that are easily administered, are desperately needed. Studies targeting the SARS-CoV-2 3CL protease, which is critical for viral replication, with different peptidomimetics and warheads is an active area of research for development of potential drugs. To date, however, only a few publications have evaluated the nitrile warhead as a viral 3CL protease inhibitor, with only modest activity reported. This article describes our investigation of P3 4-methoxyindole peptidomimetic analogs with select P1 and P2 groups with a nitrile warhead that are potent inhibitors of SARS-CoV-2 3CL protease and demonstrate in vitro SARS-CoV-2 antiviral activity. A selectivity for SARS-CoV-2 3CL protease over human cathepsins B, S and L was also observed with the nitrile warhead, which was superior to that with the aldehyde warhead. A co-crystal structure with SARS-CoV-2 3CL protease and a reversibility study indicate that a reversible, thioimidate adduct is formed when the catalytic sulfur forms a covalent bond with the carbon of the nitrile. This effort also identified efflux as a property limiting antiviral activity of these compounds, and together with the positive attributes described these results provide insight for further drug development of novel nitrile peptidomimetics targeting SARS-CoV-2 3CL protease., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The sarco-endoplasmic reticulum calcium ATPase (SERCA) is responsible for maintaining calcium homeostasis in all eukaryotic cells by actively transporting calcium from the cytosol into the sarco-endoplasmic reticulum (SR/ER) lumen. Calcium is an important signaling ion, and the activity of SERCA is critical for a variety of cellular processes such as muscle contraction, neuronal activity, and energy metabolism. SERCA is regulated by several small transmembrane peptide subunits that are collectively known as the "regulins". Phospholamban (PLN) and sarcolipin (SLN) are the original and most extensively studied members of the regulin family. PLN and SLN inhibit the calcium transport properties of SERCA and they are required for the proper functioning of cardiac and skeletal muscles, respectively. Myoregulin (MLN), dwarf open reading frame (DWORF), endoregulin (ELN), and another-regulin (ALN) are newly discovered tissue-specific regulators of SERCA. Herein, we compare the functional properties of the regulin family of SERCA transmembrane peptide subunits and consider their regulatory mechanisms in the context of the physiological and pathophysiological roles of these peptides. We present new functional data for human MLN, ELN, and ALN, demonstrating that they are inhibitors of SERCA with distinct functional consequences. Molecular modeling and molecular dynamics simulations of SERCA in complex with the transmembrane domains of MLN and ALN provide insights into how differential binding to the so-called inhibitory groove of SERCA-formed by transmembrane helices M2, M6, and M9-can result in distinct functional outcomes.

DNA metabarcoding is an emerging tool used to quantify diet in environments and consumer groups where traditional approaches are unviable, including small-bodied invertebrate taxa. However, metabarcoding of small taxa often requires DNA extraction from full body parts (without dissection), and it is unclear whether surface contamination from body parts alters presumed diet presence or diversity.We examined four different measures of diet (presence, rarefied read abundance, richness, and species composition) for a terrestrial invertebrate consumer (the spider Heteropoda venatoria ) both collected in its natural environment and fed an offered diet item in contained feeding trials using DNA metabarcoding of full body parts (opisthosomas). We compared diet from consumer individuals surface sterilized to remove contaminants in 10% commercial bleach solution followed by deionized water with a set of unsterilized individuals.We found that surface sterilization did not significantly alter any measure of diet for consumers in either a natural environment or feeding trials. The best-fitting model predicting diet detection in feeding trial consumers included surface sterilization, but this term was not statistically significant ( β  = -2.3, p -value = .07).Our results suggest that surface contamination does not seem to be a significant concern in this DNA diet metabarcoding study for consumers in either a natural terrestrial environment or feeding trials. As the field of diet DNA metabarcoding continues to progress into new environmental contexts with various molecular approaches, we suggest ongoing context-specific consideration of the possibility of surface contamination., Competing Interests: None declared., (© 2021 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

The main protease (M pro , also known as 3CL protease) of SARS-CoV-2 is a high priority drug target in the development of antivirals to combat COVID-19 infections. A feline coronavirus antiviral drug, GC376, has been shown to be effective in inhibiting the SARS-CoV-2 main protease and live virus growth. As this drug moves into clinical trials, further characterization of GC376 with the main protease of coronaviruses is required to gain insight into the drug's properties, such as reversibility and broad specificity. Reversibility is an important factor for therapeutic proteolytic inhibitors to prevent toxicity due to off-target effects. Here we demonstrate that GC376 has nanomolar K i values with the M pro from both SARS-CoV-2 and SARS-CoV strains. Restoring enzymatic activity after inhibition by GC376 demonstrates reversible binding with both proteases. In addition, the stability and thermodynamic parameters of both proteases were studied to shed light on physical chemical properties of these viral enzymes, revealing higher stability for SARS-CoV-2 M pro . The comparison of a new X-ray crystal structure of M pro from SARS-CoV complexed with GC376 reveals similar molecular mechanism of inhibition compared to SARS-CoV-2 M pro , and gives insight into the broad specificity properties of this drug. In both structures, we observe domain swapping of the N-termini in the dimer of the M pro , which facilitates coordination of the drug's P1 position. These results validate that GC376 is a drug with an off-rate suitable for clinical trials., Competing Interests: Competing interests The authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The sarco-plasmic reticulum calcium pump (SERCA) plays a critical role in the contraction-relaxation cycle of muscle. In cardiac muscle, SERCA is regulated by the inhibitor phospholamban. A new regulator, dwarf open reading frame (DWORF), has been reported to displace phospholamban from SERCA. Here, we show that DWORF is a direct activator of SERCA, increasing its turnover rate in the absence of phospholamban. Measurement of in-cell calcium dynamics supports this observation and demonstrates that DWORF increases SERCA-dependent calcium reuptake. These functional observations reveal opposing effects of DWORF activation and phospholamban inhibition of SERCA. To gain mechanistic insight into SERCA activation, fluorescence resonance energy transfer experiments revealed that DWORF has a higher affinity for SERCA in the presence of calcium. Molecular modeling and molecular dynamics simulations provide a model for DWORF activation of SERCA, where DWORF modulates the membrane bilayer and stabilizes the conformations of SERCA that predominate during elevated cytosolic calcium., Competing Interests: MF, EB, RA, EC, MP, MD, NR, LE, SR, AZ, HY No competing interests declared, ML Reviewing editor, eLife, (© 2021, Fisher et al.)

Bovine spongiform encephalopathy (BSE) is a prion disease of cattle that is caused by the misfolding of the cellular prion protein (PrPC) into an infectious conformation (PrPSc). PrPC is a predominantly α-helical membrane protein that misfolds into a β-sheet rich, infectious state, which has a high propensity to self-assemble into amyloid fibrils. Three strains of BSE prions can cause prion disease in cattle, including classical BSE (C-type) and two atypical strains, named L-type and H-type BSE. To date, there is no detailed information available about the structure of any of the infectious BSE prion strains. In this study, we purified L-type BSE prions from transgenic mouse brains and investigated their biochemical and ultrastructural characteristics using electron microscopy, image processing, and immunogold labeling techniques. By using phosphotungstate anions (PTA) to precipitate PrPSc combined with sucrose gradient centrifugation, a high yield of proteinase K-resistant BSE amyloid fibrils was obtained. A morphological examination using electron microscopy, two-dimensional class averages, and three-dimensional reconstructions revealed two structural classes of L-type BSE amyloid fibrils; fibrils that consisted of two protofilaments with a central gap and an average width of 22.5 nm and one-protofilament fibrils that were 10.6 nm wide. The one-protofilament fibrils were found to be more abundant compared to the thicker two-protofilament fibrils. Both fibrillar assemblies were successfully decorated with monoclonal antibodies against N- and C-terminal epitopes of PrP using immunogold-labeling techniques, confirming the presence of polypeptides that span residues 100-110 to 227-237. The fact that the one-protofilament fibrils contain both N- and C-terminal PrP epitopes constrains molecular models for the structure of the infectious conformer in favour of a compact four-rung β-solenoid fold., Competing Interests: The authors have declared that no competing interests exist.

Background: Junior doctors are required to make career decisions at an early stage in their postgraduate training. Trainees also feel inadequately prepared for the transition to consultant roles., Aim: To explore the key factors influencing the choice of dermatology as a postgraduate medical career and to identify the training needs required for transition from trainee to consultant., Methods: An online questionnaire was designed to identify (i) why trainees chose a postgraduate medical career in dermatology, and (ii) the training required for transition from trainee to consultant., Results: In total, 46 responses were received from trainees in their first to final years (ST3-6), of whom 89% had undertaken an undergraduate dermatology placement, with a median duration of 2 weeks. Dermatology was considered as a career during medical school by 61% of trainees, and 41% confirmed their decision to pursue a career in dermatology during foundation training. The most influential factors involved in speciality selection were first, enjoyment of the work, second, postgraduate experience and equal third, the variety of the speciality and the regularity of working hours (P < 0.05). Mentoring was pivotal to career decision-making. Significant numbers of trainees expressed a need for training in medical leadership, such as running an outpatient clinic and supervising clinical multidisciplinary teams. Although larger numbers of trainees had training in management of dermatology services, such as service improvement (52%) and local governance/National Health Service structures (43%), significant numbers of trainees had no training in writing job plans (89%) or business plans (85%). Training was significantly deficient for personal management and self-awareness., Conclusion: Our study highlights important considerations in career decision-making for trainees. Training in medical leadership, management and self-awareness could be enhanced to ensure that trainees feel adequately equipped for consultant roles., (© 2020 The Authors. Clinical and Experimental Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Vector-borne diseases (VBDs) are embedded within complex socio-ecological systems. While research has traditionally focused on the direct effects of VBDs on human morbidity and mortality, it is increasingly clear that their impacts are much more pervasive. VBDs are dynamically linked to feedbacks between environmental conditions, vector ecology, disease burden, and societal responses that drive transmission. As a result, VBDs have had profound influence on human history. Mechanisms include: (1) killing or debilitating large numbers of people, with demographic and population-level impacts; (2) differentially affecting populations based on prior history of disease exposure, immunity, and resistance; (3) being weaponised to promote or justify hierarchies of power, colonialism, racism, classism and sexism; (4) catalysing changes in ideas, institutions, infrastructure, technologies and social practices in efforts to control disease outbreaks; and (5) changing human relationships with the land and environment. We use historical and archaeological evidence interpreted through an ecological lens to illustrate how VBDs have shaped society and culture, focusing on case studies from four pertinent VBDs: plague, malaria, yellow fever and trypanosomiasis. By comparing across diseases, time periods and geographies, we highlight the enormous scope and variety of mechanisms by which VBDs have influenced human history., (© 2021 John Wiley & Sons Ltd.)

Background: The epidermal barrier is important for water conservation, failure of which is evident in dry-skin conditions. Barrier function is fulfilled by the stratum corneum, tight junctions (TJs, which control extracellular water) and keratinocyte mechanisms, such as organic osmolyte transport, which regulate intracellular water homeostasis. Organic osmolyte transport by keratinocytes is largely unexplored and nothing is known regarding how cellular and extracellular mechanisms of water conservation may interact., Objectives: We aimed to characterize osmolyte transporters in skin and keratinocytes, and, using transporter inhibitors, to investigate whether osmolytes can modify TJs. Such modification would suggest a possible link between intracellular and extracellular mechanisms of water regulation in skin., Methods: Immunostaining and quantitative polymerase chain reaction of organic osmolyte-treated organ-cultured skin were used to identify changes to organic osmolyte transporters, and TJ protein and gene expression. TJ functional assays were performed on organic osmolyte-treated primary human keratinocytes in culture., Results: Immunostaining demonstrated the expression of transporters for betaine, taurine and myo-inositol in transporter-specific patterns. Treatment of human skin with either betaine or taurine increased the expression of claudin-1, claudin-4 and occludin. Osmolyte transporter inhibition abolished this response. Betaine and taurine increased TJ function in primary human keratinocytes in vitro., Conclusions: Treatment of skin with organic osmolytes modulates TJ structure and function, which could contribute to the epidermal barrier. This emphasizes a role for organic osmolytes beyond the maintenance of intracellular osmolarity. This could be harnessed to enhance topical therapies for diseases characterized by skin barrier dysfunction., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Psoriasis impacts the health and psychosocial functioning of patients, conferring a significant economic burden on healthcare systems. There remain unmet needs in psoriasis care, which if addressed by research, could improve clinical outcomes., Aim: To research priorities and identify a health service delivery model from the UK Psoriasis Priority Setting Partnership (PsPSP)., Methods: Between July 2017 and November 2018, we invited people with lived experience of psoriasis and healthcare professionals to (i) identify unmet needs, and (ii) prioritize the order in which these should be addressed by research. We collaborated with the Psoriasis Association and used methodology established by the James Lind Alliance, which pioneers the joint setting of research priorities by patients and clinicians worldwide., Results: In our initial harvesting survey (Survey 1), 2133 questions were submitted by 805 individuals. Submissions that had not been answered by research (true uncertainties) were supplemented with evidence gaps from systematic reviews/guidelines published in the previous 5 years and refined to produce 55 indicative questions. Voting in Survey 2, by 1154 individuals, enabled a shortlist of questions, which were prioritized during the final workshop to produce a top 20 list of research questions. Submissions on health service delivery (5.8% of the total submissions), which were analysed separately, described a blueprint for psoriasis care., Conclusions: The PsPSP will inform the translational research agenda, ensuring that future research is relevant for the needs of people with psoriasis and those who manage the disease. Submissions on health service delivery describe a model of holistic, patient-focused care providing high-quality, effective management for patients with psoriasis., (© 2020 The Authors. Clinical and Experimental Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Medical students at The University of Manchester have the option of research intercalation on the Master of Research programme. There is a paucity of evidence for the benefits of research intercalation. However, we hypothesised that research intercalation would accelerate post-graduate career progression and aimed to objectively measure the career enhancing impact, quantify the benefits and determine the alumni perception of research intercalation., Methods: Data was collected retrospectively by electronic questionnaire (in 2018) from those commencing research intercalation between 2005 and 2012., Results: Participants (n=52) returned questionnaires (68% response), demonstrating that the cohort had completed 67 postgraduate qualifications, published 304 manuscripts (median 3 publications per person (PP); range: 0-53) and made 430 presentations (median 7 PP; range: 0-37). Alumni had been awarded 49 research grants; funding disclosed on 43% totalled £823,000. Career progression of 73% of alumni had taken the minimum number of years; 27% took longer due to time spent working abroad or to gain additional experience prior to specialty training. Fifty-five publications and 71 presentations were directly related to MRes projects., Conclusion: Research intercalation provides graduates with an opportunity to learn valuable transferrable skills, contribute to translational research, and objectively enhances medical career progression.

The rhomboid protease PARL is a critical regulator of mitochondrial homeostasis through its cleavage of substrates such as PINK1, PGAM5, and Smac/Diablo, which have crucial roles in mitochondrial quality control and apoptosis. However, the catalytic properties of PARL, including the effect of lipids on the protease, have never been characterized in vitro. To address this, we isolated human PARL expressed in yeast and used FRET-based kinetic assays to measure proteolytic activity in vitro. We show that PARL activity in detergent is enhanced by cardiolipin, a lipid enriched in the mitochondrial inner membrane. Significantly higher turnover rates were observed for PARL reconstituted in proteoliposomes, with Smac/Diablo being cleaved most rapidly at a rate of 1 min -1 . In contrast, PGAM5 is cleaved with the highest efficiency (k cat /K M ) compared with PINK1 and Smac/Diablo. In proteoliposomes, a truncated β-cleavage form of PARL, a physiological form known to affect mitochondrial fragmentation, is more active than the full-length enzyme for hydrolysis of PINK1, PGAM5, and Smac/Diablo. Multiplex profiling of 228 peptides reveals that PARL prefers substrates with a bulky side chain such as Phe in P1, which is distinct from the preference for small side chain residues typically found with bacterial rhomboid proteases. This study using recombinant PARL provides fundamental insights into its catalytic activity and substrate preferences that enhance our understanding of its role in mitochondrial function and has implications for specific inhibitor design., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Helical assemblies of proteins, which consist of a two-dimensional lattice of identical subunits arranged with helical symmetry, are a common structural motif in nature. For membrane proteins, crystallization protocols can induce helical arrangements and take advantage of the symmetry found in these assemblies for the structural determination of target proteins. Modern advances in the field of electron cryo-microscopy (cryo-EM), in particular the advent of direct electron detectors, have opened the potential for structure determination of membrane proteins in such assemblies at high resolution. The nature of the symmetry in helical crystals of membrane proteins means that a single image potentially contains enough information for three-dimensional structural determination. With the current direct electron detectors, we have never been closer to making this a reality. Here, we present a protocol detailing the preparation of helical crystals, with an emphasis on further cryo-EM analysis and structural determination of the sarco(endo)plasmic reticulum Ca 2+ -ATPase in the presence of regulatory subunits such as phospholamban.

A large part of ecosystem function in woodland systems depends on soil fungal communities. However, global climate change has the potential to fundamentally alter these communities as fungal species are filtered with changing environmental conditions. In this study, we examined the potential effects of climate on host-associated (i.e. tree-associated) soil fungal communities at climatically distinct sites in the Tehachapi Mountains in California, where more arid conditions represent likely regional climate futures. We found that soil fungal community composition changes strongly across sites, with species richness and diversity being highest at the most arid site. However, host association may buffer the effects of climate on community composition, as host-associated fungal communities are more similar to each other across climatically distinct sites than the whole fungal community. Lastly, an examination of functional traits for ectomycorrhizal fungi, a well-studied guild of fungal mutualist species, showed that stress-tolerant traits were more abundant at arid sites than mesic sites, providing a mechanistic understanding of these community patterns. Taken together, our results indicate that fungal community composition will likely shift with future climate change but that host association may buffer these effects, with shifts in functional traits having implications for future ecosystem function., (© The Author(s) 2020. Published by Oxford University Press on behalf of FEMS.)

Background: Psoriasis is associated with an increased risk of cardiovascular disease. Despite recommendation that exercise is important for cardiorespiratory fitness, patients with psoriasis avoid participation in physical activities for reasons that are, as yet, unclear., Objectives: This study investigated the relationship between psoriasis-specific experiences and self-reported patterns of exercise, hypothesizing that individuals with psoriasis are less likely to engage in physical activity for reasons that are related to their psoriasis., Methods: In total 404 patients with chronic plaque psoriasis were recruited. History, examination and physical activity were assessed for each participant., Results: Overall, 52·8% (n = 188) of patients with psoriasis aged 18-65 years and 66% (n = 37) of those aged > 65 years engaged in less than the recommended amount of physical activity for cardiorespiratory fitness. As the severity and psychosocial impact of psoriasis increased, the participation in exercise (of all intensities) decreased. There was a significant negative correlation between Psoriasis Area and Severity Index and total activity in women aged 18-65 years (r = -0·19, 95% confidence interval -0·36 to 0; P = 0·04) and a significant negative correlation between physical activity and Dermatology Life Quality Index (DLQI) in all participants (r = -0·11, 95% confidence interval -0·21 to 0; P = 0·04). Individual components of the DLQI identified barriers to physical activity including skin sensitivity and reluctance to participate in leisure activities., Conclusions: Psoriasis-specific factors - severity, skin sensitivity, clothing choice, participation in social/leisure activities, and treatments - contribute to exercise avoidance and may augment the increased risk of cardiovascular disease in patients with psoriasis., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: As biosimilars have become available in various parts of the world, the International Psoriasis Council has reviewed aspects of their use., Objective: To provide consensus statements from the Biosimilar Working Group about the use of biosimilars in patients with psoriasis., Methods: A semiqualitative structured process was employed to approve the consensus statements on biosimilars using the nominal group technique. The final statements were validated by a survey of the paricipants. The approval of the consensus statements was predefined as >80% positive opinions., Results: A consensus was reached in 36/38 statements regarding regulatory considerations, extrapolation of indication, interchangeability, substitution at the pharmacy level, pharmacovigilance, traceability, naming, biosimilar policy, education, and cost of biosimilars. Example statements include "Switching a stable patient from a reference product to a biosimilar product is appropriate if the patient and physician agree to do so" and "Patients and patients' organisations should be involved in all decision making and policy development about the use of biosimilars.", Conclusion: The International Psoriasis Council Biosimilar Working Group provides consensus statements for the use of biosimilars in the treatment of patients with psoriasis. We suggest that these statements provide global guidance to clinicians, healthcare organizations, pharmaceutical companies, regulators, and patients regarding the development and use of biosimilars in patients with psoriasis., (© 2020 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)