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Snake venom is produced, transported and delivered by the sophisticated venom delivery system (VDS). When snakes bite, the venom travels from the venom gland through the venom duct into needle‐like fangs that inject it into their prey. To counteract breakages, fangs are continuously replaced throughout life. Currently, the anatomy of the connection between the duct and the fang has not been described, and the mechanism by which the duct is reconnected to the replacement fang has not been identified. We examined the VDS in 3D in representative species from two families and one subfamily (Elapidae, Viperidae, Atractaspidinae) using contrast‐enhanced microCT (diceCT), followed by dissection and histology. We observed that the venom duct bifurcates immediately anterior to the fangs so that both the original and replacement fangs are separately connected and functional in delivering venom. When a fang is absent, the canal leading to the empty position is temporarily closed. We found that elapid snakes have a crescent‐shaped venom reservoir where venom likely pools before it enters the fang. These findings form the final piece of the puzzle of VDS anatomy in front‐fanged venomous snakes. Additionally, they provide further evidence for independent evolution of the VDS in these three snake taxa. [ABSTRACT FROM AUTHOR]

Aim: Pathophysiological differences between patients with heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction (EF) remain unclear. Therefore we used a phenomics approach, integrating selected proteomics data with patient characteristics and cardiac structural and functional parameters, to get insight into differential pathophysiological mechanisms and identify potential treatment targets. Methods and results: We report data from a representative subcohort of the prospective Singapore Heart Failure Outcomes and Phenotypes (SHOP), including patients with HFrEF (EF <40%, n = 217), HFpEF (EF ≥50%, n = 213), and age‐ and sex‐matched controls without HF (n = 216). We measured 92 biomarkers using a proximity extension assay and assessed cardiac structure and function in all participants using echocardiography. We used multi‐block projection to latent structure analysis to integrate clinical, echocardiographic, and biomarker variables. Candidate biomarker targets were cross‐referenced with small‐molecule and drug databases. The total cohort had a median age of 65 years (interquartile range 60–71), and 50% were women. Protein profiles strongly discriminated patients with HFrEF (area under the curve [AUC] = 0.89) and HFpEF (AUC = 0.94) from controls. Phenomics analyses identified unique druggable inflammatory markers in HFpEF from the tumour necrosis factor receptor superfamily (TNFRSF), which were positively associated with hypertension, diabetes, and increased posterior and relative wall thickness. In HFrEF, interleukin (IL)‐8 and IL‐6 were possible targets related to lower EF and worsening renal function. Conclusion: We identified pathophysiological mechanisms related to increased cardiac wall thickness parameters and potentially druggable inflammatory markers from the TNFRSF in HFpEF. [ABSTRACT FROM AUTHOR]

Secondary metabolites play an important role in plant adaptation, because they can mitigate biotic and abiotic environmental stresses. However, their production and allocation incur different costs and benefits, and are therefore subject to trade‐offs, which are less studied.To understand large‐scale geographic patterns of secondary metabolites, and their environmental drivers and trade‐offs, we studied 39 natural populations of the perennial herb Japanese knotweed (Reynoutria japonica) along a large latitudinal gradient in China. We measured the concentrations of six polyphenols in leaves and rhizomes of R. japonica, and associated the variation in these metabolites with biotic and abiotic environmental factors as well as with functional plant traits and putative costs of secondary metabolites.We found that climate was an important driver of variation in secondary metabolites, both above‐ and below‐ground. Remarkably, the patterns of association differed between leaves and rhizomes, as well as between putative low‐cost versus high‐cost compounds. While annual mean temperature was a stronger predictor of above‐ground metabolites, annual precipitation was more frequently associated with variation in below‐ground metabolites. Moreover, annual temperature was positively associated with high‐cost metabolites, but negatively with low‐cost metabolites. Above‐ground secondary metabolites were generally more strongly associated with functional traits (e.g. specific leaf area) than below‐ground metabolites, and in all cases the directions of correlation were opposite for low‐cost versus high‐cost metabolites above‐ground. The patterns of association also varied with latitude such that leaf concentrations of low‐cost metabolites (quercetin) increased but those of high‐cost metabolites (resveratrol, piceid and emodin) decreased at higher latitudes. In rhizomes, in contrast, the concentrations of high‐cost metabolites (piceid and emodin) increased with latitude.Synthesis. Our findings indicate that allocation strategies differ between above‐ and below‐ground tissues of Reynoutria japonica. As latitude increases, R. japonica invests relatively more into below‐ground metabolites. We propose that reduced high‐cost metabolites in the leaves at higher latitudes may help to conserve nutrients after defoliation, while maintaining high‐cost metabolites in rhizomes may be important for persistent allelopathic effects and resource conservation below‐ground. The divergent patterns of above‐ and below‐ground metabolite allocation thus likely reflect the multiple functions of metabolites and the plants' adaptation to different environments. [ABSTRACT FROM AUTHOR]

Background: Citizen science is a way to democratise science by involving groups of citizens in the research process. Clinical guidelines are used to improve practice, but their implementation can be limited. Involving patients and the public can enhance guideline implementation, but there is uncertainty about the best approaches to achieve this. Citizen science is a potential way to involve patients and the public in improving clinical guideline implementation. We aimed to explore the application of citizen science methods to involve patients and the public in the dissemination and implementation of clinical guidelines in oral health and dentistry. Methods: We developed GUIDE (GUideline Implementation in oral health and DEntistry), a citizen science online platform, using a participatory approach with researchers, oral health professionals, guideline developers and citizens. Recruitment was conducted exclusively online. The platform focused on prespecified challenges related to oral health assessment guidelines, and asked citizens to generate ideas, as well as vote and comment on other citizens' ideas to improve those challenges. Citizens also shared their views via surveys and two online synchronous group meetings. Data were collected on participant's demographics, platform engagement and experience of taking part. The most promising idea category was identified by an advisory group based on engagement, feasibility and relevance. We presented quantitative data using descriptive statistics and analysed qualitative data using inductive and deductive thematic analysis. Results: The platform was open for 6 months and we recruited 189 citizens, from which over 90 citizens actively engaged with the platform. Most citizens were over 34 years (64%), female (58%) and had a university degree (50%). They generated 128 ideas, 146 comments and 248 votes. The challenge that led to most engagement was related to prevention and oral health self‐care. To take this challenge forward, citizens generated a further 36 ideas to improve a pre‐existing National Health Service oral care prevention leaflet. Citizens discussed motivations to take part in the platform (understanding, values, self‐care), reasons to stay engaged (communication and feedback, outputs and impact, and relevance of topics discussed) and suggestions to improve future platforms. Conclusion: Citizen science is an effective approach to generate and prioritise ideas from a group of citizens to improve oral health and dental services. Prevention and oral health self‐care were of particular interest to citizens. More research is needed to ensure recruitment of a diverse group of citizens and to improve retention in citizen science projects. Patient or Public Contribution: This project was inherently conducted with the input of public partners (citizen scientists) in all key aspects of its conduct and interpretation. In addition, two public partners were part of the research team and contributed to the design of the project, as well as key decisions related to its conduct, analysis, interpretation and dissemination and are co‐authors of this manuscript. [ABSTRACT FROM AUTHOR]

Keywords: acoustic; amphibian; classification; detection; endangered; machine learning; monitoring; signal processing; acústico; anfibio; aprendizaje mecánico; clasificación; detección; en peligro; monitoreo; procesamiento de señal EN acoustic amphibian classification detection endangered machine learning monitoring signal processing acústico anfibio aprendizaje mecánico clasificación detección en peligro monitoreo procesamiento de señal 1659 1668 10 10/05/21 20211001 NES 211001 Introduction Globally, many anurans (frogs and toads) are in danger of extinction (Scheele et al. 2019). [Extracted from the article]

Plant-focused studies with a G × E framework generally test microbiome effects on plant performance or stress tolerance not only for one narrow type of experimental set-up but across a range of different environments and/or multiple plant genotypes (Figure 1B). Keywords: evolutionary ecology; G × E; genotype-by-environment interactions; microbial communities; multifactorial experiments; natural variation; pathogens; stress tolerance EN evolutionary ecology G × E genotype-by-environment interactions microbial communities multifactorial experiments natural variation pathogens stress tolerance 1820 1823 4 11/02/21 20211001 NES 211001 Plant microbiomes have become one of the hottest topics in plant biology. Understanding plant microbiomes requires a genotype × environment framework Microbiome-focused studies with a G × E character essentially treat the microbiome as an "extended phenotype" of the plant that is subject to the same complex influences as other plant phenotypes. [Extracted from the article]

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). For example, among healthy individuals, BNP concentrations average <=10 pg/mL; interestingly, while NT-proBNP concentrations are often much higher than BNP in the presence of prevalent HF, in healthy individuals NT-proBNP is often as very low as BNP. After the first proof of principle for B-type natriuretic peptide (BNP) as a diagnostic aid for acute heart failure (AHF) was reported by Davis I et al i . in 1994,1 the Breathing Not Properly (BNP) study, published in 2002, ushered in a new era for natriuretic peptides (NPs) as companion biomarkers for the diagnosis of heart failure (HF).2 More than just a clinical trial with novel and favourable results, it revolutionized a whole field and introduced biomarkers and the molecular phenotyping of the heart to algorithms in use for HF diagnosis and management. The "Peptide for Life" Initiative: a call for action to provide equal access to the use of natriuretic peptides in the diagnosis of acute heart failure across Europe. [Extracted from the article]

Objective: To quantify shared patient relationships between primary care physicians (PCPs) and cardiologists and oncologists and the degree to which those relationships were captured within insurance networks. Data Sources: Secondary analysis of Vericred data on physician networks, CareSet data on physicians' shared Medicare patients, and insurance plan attributes from Health Insurance Compare. Data validation exercises used data from Physician Compare and IQVIA. Study Design: Cross‐sectional study of the PCP‐to‐specialist in‐network shared patient percentage (primary outcome). We also categorized networks by insurance market segment (Medicare Advantage [MA], Medicaid managed care, small‐group or individually purchased), insurance plan type, and network breadth. Data Extraction: We analyzed data on 219,982 PCPs, 29,400 cardiologists, and 22,745 oncologists who, in 2021, accepted MA (n = 941 networks), Medicaid managed care (n = 293), and individually‐purchased (n = 332) and small‐group (n = 501) plans. Principal Findings: Networks captured, on average, 64.6% of PCP‐cardiology shared patient ties, and 61.8% of PCP‐oncologist ties. Less than half of in‐network ties (44.5% and 38.9%, respectively) were among physicians with a common organizational affiliation. After adjustment for network breadth, we found no evidence of differences in the shared patient percentage across insurance market segments or networks of different types (p‐value >0.05 for all comparisons). An exception was among national versus local and regional networks, where we found that national plans captured fewer shared patient ties, particularly among the narrowest networks (58.4% for national networksvs. 64.7% for local and regional networks for PCP‐cardiology). Conclusions: Given recent trends toward narrower networks, our findings underscore the importance of incorporating additional and nuanced measures of network composition to aid plan selection (for patients) and to guide regulatory oversight. [ABSTRACT FROM AUTHOR]

Wildlife managers often rely on population estimates, but estimates can be challenging to obtain for geographically widespread species. Spotlight surveys provide abundance data for many species and, when conducted over wide spatial scales, have potential to provide population estimates of geographically widespread species. The bare‐nosed wombat (Vombatus ursinus) has a broad geographical range and is subject to spotlight surveys. We used 19 years (2002–2020) of annual spotlight surveys to provide the first estimates of population abundance for two of the three extant bare‐nosed wombat subspecies: V. u. ursinus on Flinders Island; and V. u. tasmaniensis on the Tasmanian mainland. Using distance sampling methods, we estimated annual rates of change and 2020 population sizes for both subspecies. Tasmanian mainland surveys included habitat data, which allowed us to also look for evidence of habitat associations for V. u. tasmaniensis. The average wombat density estimate was higher on Flinders Island (0.42 ha−1, 95% CI = 0.25–0.79) than on the Tasmanian mainland (0.11 ha−1, CI = 0.07–0.19) and both wombat subspecies increased over the 19‐year survey period with an estimated annual growth rate of 2.90% (CI = −1.7 to 7.3) on Flinders Island and 1.20% (CI = −1.1 to 2.9) on mainland Tasmania. Habitat associations for V. u. tasmaniensis were weak, possibly owing to survey design; however, we detected regional variation in density for this subspecies. We estimated the population size of V. u. ursinus to be 71,826 (CI = 43,913–136,761) on Flinders Island, which when combined with a previously published estimate of 2599 (CI = 2254–2858) from Maria Island, where the subspecies was introduced, provides a total population estimate. We also estimated 840,665 (CI = 531,104–1,201,547) V. u. tasmaniensis on mainland Tasmania. These estimates may be conservative, owing to individual heterogeneity in when wombats emerge from burrows. Although these two subspecies are not currently threatened, our population estimates provide an important reference when assessing their population status in the future, and demonstrate how spotlight surveys can be valuable to inform management of geographically widespread species. [ABSTRACT FROM AUTHOR]

Post‐release mortality threatens shark populations already imperiled by overfishing, capture stress, and a changing climate. Few studies have quantified post‐release mortality for sharks captured in land‐based recreational fisheries. From 2018 to 2021, a land‐based shark post‐release mortality study was conducted and identified water temperature and species‐specific behavior as contributing factors to post‐release mortality. The purpose of this study was to estimate the effectiveness of disseminating the recommendation for best practices to recreational shark anglers and to determine if this information influenced angler behavior. Awareness of our post‐release mortality study influenced an angler's likely release behavior, with an increase in sharks landed in the water and corresponding decrease of sharks landed on dry sand. This study demonstrated direct evidence of conservation‐based changes in angler behavior following effective research communication and involvement of anglers in research. Outreach and engagement initiatives aimed at providing best handling practices to recreational anglers should be easily digestible, widely available, and an important component of future research. [ABSTRACT FROM AUTHOR]

Summary: Background: Magnetic resonance imaging‐proton density fat fraction (MRI‐PDFF) is an excellent biomarker for the non‐invasive quantification of hepatic steatosis. Aim: To examine clinical and histologic factors associated with discordance between steatosis grade determined by histology and MRI‐PDFF in patients with non‐alcoholic fatty liver disease (NAFLD) Methods: We included 728 patients with biopsy‐proven NAFLD from UC San Diego (n = 414) and Yokohama City University (n = 314) who underwent MRI‐PDFF and liver biopsy. Patients were stratified by steatosis, and matched with MRI‐PDFF cut‐points for each steatosis grade: 0 (MRI‐PDFF < 6.4%), 1 (MRI‐PDFF: 6.4%–17.4%), 2 (MRI‐PDFF: 17.4%–22.1%), 3 (MRI‐PDFF ≥ 22.1%). Primary outcome was major discordance defined as ≥2 steatosis grade difference determined by histology and MRI‐PDFF. Results: Mean (±SD) age and BMI were 55.3 (±13.8) years and 29.9 (±4.9) kg/m2, respectively. The distributions of histology and MRI‐PDFF‐determined steatosis were 5.5% grade 0 (n = 40), 44.8% 1 (n = 326, 44.8%), 33.9% 2 (n = 247), and 15.8% 3 (n = 115) vs. 23.5% grade 0 (n = 171), 49.7% 1 (n = 362), 12.9% 2 (n = 94), and 13.9% 3 (n = 101). Major discordance rate was 6.6% (n = 48). Most cases with major discordance had greater histology‐determined steatosis grade (n = 40, 88.3%), higher serum AST and liver stiffness, and greater likelihood of fibrosis ≥2, ballooning ≥1 and lobular inflammation ≥2 (all p < 0.05). Conclusion: Histology overestimates steatosis grade compared to MRI‐PDFF. Patients with advanced NASH are likely to be upgraded on steatosis grade by histology. These data have important implications for steatosis estimation and reporting on histology in clinical practice and trials, especially in patients with stage 2 fibrosis. [ABSTRACT FROM AUTHOR]

UFMylation involves the covalent modification of substrate proteins with UFM1 (Ubiquitin‐fold modifier 1) and is important for maintaining ER homeostasis. Stalled translation triggers the UFMylation of ER‐bound ribosomes and activates C53‐mediated autophagy to clear toxic polypeptides. C53 contains noncanonical shuffled ATG8‐interacting motifs (sAIMs) that are essential for ATG8 interaction and autophagy initiation. However, the mechanistic basis of sAIM‐mediated ATG8 interaction remains unknown. Here, we show that C53 and sAIMs are conserved across eukaryotes but secondarily lost in fungi and various algal lineages. Biochemical assays showed that the unicellular alga Chlamydomonas reinhardtii has a functional UFMylation pathway, refuting the assumption that UFMylation is linked to multicellularity. Comparative structural analyses revealed that both UFM1 and ATG8 bind sAIMs in C53, but in a distinct way. Conversion of sAIMs into canonical AIMs impaired binding of C53 to UFM1, while strengthening ATG8 binding. Increased ATG8 binding led to the autoactivation of the C53 pathway and sensitization of Arabidopsis thaliana to ER stress. Altogether, our findings reveal an ancestral role of sAIMs in UFMylation‐dependent fine‐tuning of C53‐mediated autophagy activation. Synopsis: Phylogenomic profiling has shown that UFMylation coevolves with the shuffled ATG8‐interacting motifs (sAIMs) in the ER‐phagy receptor C53. Further mechanistic analyses demonstrated that sAIMs regulate C53‐mediated autophagy by competitively binding UFM1 and ATG8.UFMylation and C53 autophagy pathways are conserved in eukaryotes, but secondarily lost in fungi and various parasitic and algal species.UFMylation is crucial for ER stress tolerance in the unicellular alga Chlamydomonas reinhardtii.Both UFM1 and ATG8 bind the shuffled AIM sequences within the intrinsically disordered domain of C53, yet their binding modes are different.Competitive binding of either UFM1 or ATG8 to C53 shuffled AIM sequences regulates C53‐mediated autophagy and ER stress tolerance. [ABSTRACT FROM AUTHOR]

Consistent individual differences in behavior, commonly termed animal personality, are a widespread phenomenon across taxa that have important consequences for fitness, natural selection, and trophic interactions. Animal personality research may prove useful in several conservation contexts, but which contexts remains to be determined. We conducted a structured literature review of 654 studies identified by combining search terms for animal personality and various conservation subfields. We scored the relevance of personality and conservation issues for each study to identify which studies meaningfully integrated the 2 fields as opposed to surface‐level connections or vague allusions. We found a taxonomic bias toward mammals (29% of all studies). Very few amphibian or reptile studies applied personality research to conservation issues (6% each). Climate change (21%), invasive species (15%), and captive breeding and reintroduction (13%) were the most abundant conservation subfields that occurred in our search, though a substantial proportion of these papers weakly integrated conservation and animal personality (climate change 54%, invasive species 51%, captive breeding and reintroduction 40%). Based on our results, we recommend that researchers strive for consistent and broadly applicable terminology when describing consistent behavioral differences to minimize confusion and improve the searchability of research. We identify several gaps in the literature that appear to be promising and fruitful avenues for future research, such as disease transmission as a function of sociability or exploration as a driver of space use in protected areas. Practitioners can begin informing future conservation efforts with knowledge gained from animal personality research. [ABSTRACT FROM AUTHOR]

Continuous subcutaneous (SubQ) treprostinil is an effective therapy for pediatric patients diagnosed with pulmonary hypertension (PH). To date, the clinical characteristics and factors associated with failure to tolerate this therapy have not been described. The purpose was to describe patient-reported factors contributing to SubQ treprostinil intolerance in pediatric patients with PH. A retrospective descriptive study was performed at 11 participating sites in the United States and Canada for patients younger than 21 years of age diagnosed with PH who failed treatment to tolerate SubQ treprostinil between January 1, 2009, and December 31, 2019. All data were summarized using descriptive statistics. Forty-one patients met the inclusion criteria. The average age at SQ treprostinil initiation, and length of treatment, was 8.6 years and 22.6 months, respectively. The average maximum dose, concentration, and rate were 95.8 ng/kg/min, 6.06 mg/mL, and 0.040 mL/h, respectively. The reasons for failure to tolerate SubQ treprostinil included intractable site pain (73.2%), frequent site changes (56.1%), severe site reactions (53.7%), infections (26.8%), and noncompliance/depression/anxiety (17.1%). Thirty-nine (95.1%) patients transitioned to a prostacyclin therapy with 23 patients transitioning to intravenous prostacyclin, 5 to inhaled prostacyclin, 5 to oral prostacyclin, and 7 to a prostacyclin receptor agonist. A subset of pediatric PH patients failed to tolerate SubQ treprostinil infusions despite advances in SubQ site maintenance and pain management strategies. Intractable site pain, frequent SubQ site changes, and severe localized skin reactions were the most common reasons for failure. [ABSTRACT FROM AUTHOR]

Key points: Collaboration between publishers and learned society partners can accelerate and amplify DEIA outcomes.97 HSS titles have adopted alt‐text publication workflows and this change has been welcomed by journal authors and editors.Efforts to promote global inclusivity do not always result in greater membership diversity, retention and growth.Top‐down, publisher‐led DEIA initiatives are effective when they are aligned strategically to pre‐existing society initiatives.Bottom‐up, member‐led DEIA initiatives benefit from publisher support to mitigate financial and time‐based barriers to active participation.To reliably track DEIA outcomes, publishers ought to adopt systematic data collection strategies through initiatives like C4 and the Joint Commitment. [ABSTRACT FROM AUTHOR]

Background: Approximately 10% of all bone fractures result in delayed fracture healing or non‐union; thus, the identification of biomarkers and prognostic factors is of great clinical interest. MicroRNAs (miRNAs) are known to be involved in the regulation of the bone healing process and may serve as functional markers for fracture healing. Aims and methods: This systematic review aimed to identify common miRNAs involved in fracture healing or non‐union fractures using a qualitative approach. A systematic literature search was performed with the keywords 'miRNA and fracture healing' and 'miRNA and non‐union fracture'. Any original article investigating miRNAs in fracture healing or non‐union fractures was screened. Eventually, 82 studies were included in the qualitative analysis for 'miRNA and fracture healing', while 19 were selected for the 'miRNA and fracture non‐union' category. Results and conclusions: Out of 151 miRNAs, miR‐21, miR‐140 and miR‐214 were the most investigated miRNAs in fracture healing in general. miR‐31‐5p, miR‐221 and miR‐451‐5p were identified to be regulated specifically in non‐union fractures. Large heterogeneity was detected between studies investigating the role of miRNAs in fracture healing or non‐union in terms of patient population, sample types and models used. Nonetheless, our approach identified some miRNAs with the potential to serve as biomarkers for non‐union fractures, including miR‐31‐5p, miR‐221 and miR‐451‐5p. We provide a discussion of involved pathways and suggest on alignment of future research in the field. [ABSTRACT FROM AUTHOR]

The approval of new heart failure (HF) therapies has slowed over the past two decades in part due to the high costs of conducting large randomized clinical trials that are needed to adequately power major clinical endpoint studies. Several biomarkers have been identified reflecting different elements of HF pathophysiology, with possible applications in diagnosis, risk stratification, treatment monitoring, and even in the design of clinical trials. Biomarkers could potentially be used to refine study inclusion criteria to enable enrolment of patients who are more likely to respond to a therapeutic intervention, despite being at sufficient risk to meet pre‐determined study endpoint rates. When there is a close relationship between biomarker levels and clinical endpoints, changes in biomarker levels after a given treatment can act as a surrogate endpoint, potentially reducing the duration and cost of a clinical trial. Natriuretic peptides have been widely used in clinical trials with a variable amount of added value, which such variation being probably due to the absence of a close pathophysiological connection to the study drug. Notable exceptions to this include sacubitril/valsartan and vericiguat. Future studies should seek to adopt unbiased approaches for discovery of true companion diagnostics; with ‐omics‐based tools, biomarkers might be more precisely selected for use in clinical trials to identify responses that closely reflect the biological effects of the drug under investigation. Finally, biomarkers associated with cardiac damage and remodelling, such as cardiac troponin, could be employed as safety endpoints provided that standardization between different assays is achieved. [ABSTRACT FROM AUTHOR]

Congestion is a cardinal sign of heart failure (HF). In the past, it was seen as a homogeneous epiphenomenon that identified patients with advanced HF. However, current evidence shows that congestion in HF varies in quantity and distribution. This updated view advocates for a congestive‐driven classification of HF according to onset (acute vs. chronic), regional distribution (systemic vs. pulmonary), compartment of distribution (intravascular vs. extravascular), and clinical vs. subclinical. Thus, this review will focus on the utility of circulating biomarkers for assessing and managing the different fluid overload phenotypes. This discussion focused on the clinical utility of the natriuretic peptides, carbohydrate antigen 125 (also called mucin 16), bio‐adrenomedullin and mid‐regional pro‐adrenomedullin, ST2 (also known as interleukin‐1 receptor‐like 1), cluster of differentiation 146, troponin, C‐terminal pro‐endothelin‐1, and parameters of haemoconcentration. The utility of circulation biomarkers on top of clinical evaluation, haemodynamics, and imaging needs to be better determined by dedicated studies. Some multiparametric frameworks in which these tools contribute to management are proposed. [ABSTRACT FROM AUTHOR]

Autophagy is essential for protein quality control and regulation of the functional proteome. Failure of autophagy pathways with age contributes to loss of proteostasis in aged organisms and accelerates the progression of age‐related diseases. In this work, we show that activity of endosomal microautophagy (eMI), a selective type of autophagy occurring in late endosomes, declines with age and identify the sub‐proteome affected by this loss of function. Proteomics of late endosomes from old mice revealed an aberrant glycation signature for Hsc70, the chaperone responsible for substrate targeting to eMI. Age‐related Hsc70 glycation reduces its stability in late endosomes by favoring its organization into high molecular weight protein complexes and promoting its internalization/degradation inside late endosomes. Reduction of eMI with age associates with an increase in protein secretion, as late endosomes can release protein‐loaded exosomes upon plasma membrane fusion. Our search for molecular mediators of the eMI/secretion switch identified the exocyst‐RalA complex, known for its role in exocytosis, as a novel physiological eMI inhibitor that interacts with Hsc70 and acts directly at the late endosome membrane. This inhibitory function along with the higher exocyst‐RalA complex levels detected in late endosomes from old mice could explain, at least in part, reduced eMI activity with age. Interaction of Hsc70 with components of the exocyst‐RalA complex places this chaperone in the switch from eMI to secretion. Reduced intracellular degradation in favor of extracellular release of undegraded material with age may be relevant to the spreading of proteotoxicity associated with aging and progression of proteinopathies. [ABSTRACT FROM AUTHOR]

Type 2‐high asthma is a chronic inflammatory disease of the airways which is increasingly prevalent in countries where helminth parasite infections are rare, and characterized by T helper 2 (Th2)‐dependent accumulation of eosinophils in the lungs. Regulatory cytokines such as TGF‐β can restrain inflammatory reactions, dampen allergic Th2 responses, and control eosinophil activation. The murine helminth parasite Heligmosomoides polygyrus releases a TGF‐β mimic (Hp‐TGM) that replicates the biological and functional properties of TGF‐β despite bearing no structural similarity to the mammalian protein. Here, we investigated if Hp‐TGM could alleviate allergic airway inflammation in mice exposed to Alternaria alternata allergen, house dust mite (HDM) extract or alum‐adjuvanted ovalbumin protein (OVA). Intranasal administration of Hp‐TGM during Alternaria exposure sharply reduced airway and lung tissue eosinophilia along with bronchoalveolar lavage fluid IL‐5 and lung IL‐33 cytokine levels at 24 h. The protective effect of Hp‐TGM on airway eosinophilia was also obtained in the longer T‐cell mediated models of HDM or OVA sensitisation with significant inhibition of eotaxin‐1, IL‐4 and IL‐13 responses depending on the model and time‐point. Hp‐TGM was also protective when administered parenterally either when given at the time of allergic sensitisation or during airway allergen challenge. This project has taken the first steps in identifying the role of Hp‐TGM in allergic asthma and highlighted its ability to control lung inflammation and allergic pathology. Future research will investigate the mode of action of Hp‐TGM against airway allergic eosinophilia, and further explore its potential to be developed as a biotherapeutic in allergic asthma. [ABSTRACT FROM AUTHOR]

Host species that can independently maintain a pathogen in a host community and contribute to infection in other species are important targets for disease management. However, the potential of host species to maintain a pathogen is not fixed over time, and an important challenge is understanding how within‐ and across‐season variability in host maintenance potential affects pathogen persistence over longer time scales relevant for disease management (e.g., years). Here, we sought to understand the causes and consequences of seasonal infection dynamics in leopard frogs (Rana sphenocephala and Rana pipiens) infected with the fungal pathogen Batrachochytrium dendrobatidis (Bd). We addressed three questions broadly applicable to seasonal host–parasite systems. First, to what degree are observed seasonal patterns in infection driven by temperature‐dependent infection processes compared to seasonal host demographic processes? Second, how does seasonal variation in maintenance potential affect long‐term pathogen persistence in multi‐host communities? Third, does high deterministic maintenance potential relate to the long‐term stochastic persistence of pathogens in host populations with seasonal infection dynamics? To answer these questions, we used field data collected over 3 years on >1400 amphibians across four geographic locations, laboratory and mesocosm experiments, and a novel mathematical model. We found that the mechanisms that drive seasonal prevalence were different from those driving seasonal infection intensity. Seasonal variation in Bd prevalence was driven primarily by changes in host contact rates associated with breeding migrations to and from aquatic habitat. In contrast, seasonal changes in infection intensity were driven by temperature‐induced changes in Bd growth rate. Using our model, we found that the maintenance potential of leopard frogs varied significantly throughout the year and that seasonal troughs in infection prevalence made it unlikely that leopard frogs were responsible for long‐term Bd persistence in these seasonal amphibian communities, highlighting the importance of alternative pathogen reservoirs for Bd persistence. Our results have broad implications for management in seasonal host–pathogen systems, showing that seasonal changes in host and pathogen vital rates, rather than the depletion of susceptible hosts, can lead to troughs in pathogen prevalence and stochastic pathogen extirpation. [ABSTRACT FROM AUTHOR]

Aim: Different associations between epicardial adipose tissue (EAT) and cardiac function have been suggested in patients with heart failure with preserved (HFpEF) versus reduced and mildly reduced ejection fraction (HFrEF/HFmrEF). However, few studies have directly compared the association between EAT and left atrial (LA) and left ventricular (LV) function in patients with HFpEF and HFrEF/HFmrEF. Methods and results: We studied EAT thickness using transthoracic echocardiography in a multicentre cohort of 149 community‐dwelling controls without heart failure, 99 patients with HFpEF, and 366 patients with HFrEF/HFmrEF. EAT thickness was averaged from parasternal long‐axis and short‐axis views, respectively, and off‐line speckle tracking analysis was performed to quantify LA and LV function. Data were validated in an independent cohort of 626 controls, 243 patients with HFpEF, and 180 patients with HFrEF/HFmrEF. For LV function, LV global longitudinal strain (GLS) was measured in both derivation and validation cohorts. For LA function, LAGLS at reservoir, contractile and conduit phase were measured in the derivation cohort, and only LAGLS at reservoir phase was measured in the validation cohort. In the derivation cohort, EAT thickness was lower in HFrEF/HFmrEF (7.3 ± 2.5 mm) compared to HFpEF (8.3 ± 2.6 mm, p < 0.05) and controls (7.9 ± 1.8 mm, p < 0.05). Greater EAT thickness was associated with better LV and contractile LA function in HFrEF/HFmrEF, but not in HFpEF (p for interaction <0.05). These findings were confirmed in the validation cohort, where EAT thickness was lower in HFrEF/HFmrEF (6.7 ± 1.4 mm) compared to HFpEF (9.6 ± 2.8 mm; p < 0.05) and controls (7.7 ± 2.3 mm; p < 0.05). Greater EAT thickness was associated with better LV and reservoir LA function in patients with HFrEF/HFmrEF but worse LV and reservoir LA function in patients with HFpEF (p for interaction <0.05). Thickened EAT (EAT thickness >10 mm) was associated with LA dysfunction (LAGLS at reservoir phase <23%) in HFpEF, but not in HFrEF/HFmrEF. Conclusion: Epicardial adipose tissue thickness is greater in patients with HFpEF than HFrEF/HFmrEF. Increased EAT thickness is associated with worse LA and LV function in HFpEF but the opposite in HFrEF/HFmrEF. [ABSTRACT FROM AUTHOR]

Skeletal muscle haemodynamics and circulating adenosine triphosphate (ATP) responses during hypoxia and exercise are blunted in older (OA) vs. young (YA) adults, which may be associated with impaired red blood cell (RBC) ATP release. Rho‐kinase inhibition improves deoxygenation‐induced ATP release from OA isolated RBCs. We tested the hypothesis that Rho‐kinase inhibition (via fasudil) in vivo would improve local haemodynamic and ATP responses during hypoxia and exercise in OA. Healthy YA (25 ± 3 years; n = 12) and OA (65 ± 5 years; n = 13) participated in a randomized, double‐blind, placebo‐controlled, crossover study on two days (≥5 days between visits). A forearm deep venous catheter was used to administer saline/fasudil and sample venous plasma ATP ([ATP]V). Forearm vascular conductance (FVC) and [ATP]V were measured at rest, during isocapnic hypoxia (80% SpO2${S_{{\rm{p}}{{\rm{O}}_{\rm{2}}}}}$), and during graded rhythmic handgrip exercise that was similar between groups (5, 15 and 25% maximum voluntary contraction (MVC)). Isolated RBC ATP release was measured during normoxia/hypoxia. With saline, ΔFVC was lower (P < 0.05) in OA vs. YA during hypoxia (∼60%) and during 15 and 25% MVC (∼25–30%), and these impairments were abolished with fasudil. Similarly, [ATP]V and ATP effluent responses from normoxia to hypoxia and rest to 25% MVC were lower in OA vs. YA and improved with fasudil (P < 0.05). Isolated RBC ATP release during hypoxia was impaired in OA vs. YA (∼75%; P < 0.05), which tended to improve with fasudil in OA (P = 0.082). These data suggest Rho‐kinase inhibition improves haemodynamic responses to hypoxia and moderate intensity exercise in OA, which may be due in part to improved circulating ATP. Key points: Skeletal muscle blood flow responses to hypoxia and exercise are impaired with age. Blunted increases in circulating ATP, a vasodilator, in older adults may contribute to age‐related impairments in haemodynamics.Red blood cells (RBCs) are a primary source of circulating ATP, and treating isolated RBCs with a Rho‐kinase inhibitor improves age‐related impairments in deoxygenation‐induced RBC ATP release.In this study, treating healthy older adults systemically with the Rho‐kinase inhibitor fasudil improved blood flow and circulating ATP responses during hypoxia and moderate intensity handgrip exercise compared to young adults, and also tended to improve isolated RBC ATP release.Improved blood flow regulation with fasudil was also associated with increased skeletal muscle oxygen delivery during hypoxia and exercise in older adults.This is the first study to demonstrate that Rho‐kinase inhibition can significantly improve age‐related impairments in haemodynamic and circulating ATP responses to physiological stimuli, which may have therapeutic implications. [ABSTRACT FROM AUTHOR]

In patients with heart failure, the beneficial effects of drug and device therapies counteract to some extent ongoing cardiac damage. According to the net balance between these two factors, cardiac geometry and function may improve (reverse remodelling, RR) and even completely normalize (remission), or vice versa progressively deteriorate (adverse remodelling, AR). RR or remission predict a better prognosis, while AR has been associated with worsening clinical status and outcomes. The remodelling process ultimately involves all cardiac chambers, but has been traditionally evaluated in terms of left ventricular volumes and ejection fraction. This is the second part of a review paper by the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology dedicated to ventricular remodelling. This document examines the proposed criteria to diagnose RR and AR, their prevalence and prognostic value, and the variables predicting remodelling in patients managed according to current guidelines. Much attention will be devoted to RR in patients with heart failure with reduced ejection fraction because most studies on cardiac remodelling focused on this setting. [ABSTRACT FROM AUTHOR]

Background: The risk of esophageal adenocarcinoma (EAC) is associated with gastro‐esophageal reflux disease (GERD) and obesity. Lipid metabolism‐targeted therapies decrease the risk of progressing from Barrett's esophagus (BE) to EAC, but the precise lipid metabolic changes and their roles in genotoxicity during EAC development are yet to be established. Methods: Esophageal biopsies from the normal epithelium (NE), BE, and EAC, were analyzed using concurrent lipidomics and proteomics (n = 30) followed by orthogonal validation on independent samples using RNAseq transcriptomics (n = 22) and immunohistochemistry (IHC, n = 80). The EAC cell line FLO‐1 was treated with FADS2 selective inhibitor SC26196, and/or bile acid cocktail, followed by immunofluorescence staining for γH2AX. Results: Metabolism‐focused Reactome analysis of the proteomics data revealed enrichment of fatty acid metabolism, ketone body metabolism, and biosynthesis of specialized pro‐resolving mediators in EAC pathogenesis. Lipidomics revealed progressive alterations (NE‐BE‐EAC) in glycerophospholipid synthesis with decreasing triglycerides and increasing phosphatidylcholine and phosphatidylethanolamine, and sphingolipid synthesis with decreasing dihydroceramide and increasing ceramides. Furthermore, a progressive increase in lipids with C20 fatty acids and polyunsaturated lipids with ≥4 double bonds were also observed. Integration with transcriptome data identified candidate enzymes for IHC validation: Δ4‐Desaturase, Sphingolipid 1 (DEGS1) which desaturates dihydroceramide to ceramide, and Δ5 and Δ6‐Desaturases (fatty acid desaturases, FADS1 and FADS2), responsible for polyunsaturation. All three enzymes showed significant increases from BE through dysplasia to EAC, but transcript levels of DEGS1 were decreased suggesting post‐translational regulation. Finally, the FADS2 selective inhibitor SC26196 significantly reduced polyunsaturated lipids with three and four double bonds and reduced bile acid‐induced DNA double‐strand breaks in FLO‐1 cells in vitro. Conclusions: Integrated multiomics revealed sphingolipid and phospholipid metabolism rewiring during EAC development. FADS2 inhibition and reduction of the high polyunsaturated lipids effectively protected EAC cells from bile acid‐induced DNA damage in vitro, potentially through reduced lipid peroxidation. [ABSTRACT FROM AUTHOR]

Objective: The use of twin-specific vs singleton growth charts in the assessment of twin pregnancy has been controversial. The aim of this study was to assess whether a diagnosis of small-for-gestational age (SGA) made using twin-specific estimated-fetal-weight (EFW) and birth-weight (BW) charts is associated more strongly with adverse neonatal outcomes in twin pregnancies, compared with when the diagnosis is made using singleton charts.Methods: This was a cohort study of twin pregnancies delivered at St George's Hospital, London, between January 2007 and May 2020. Twin pregnancies complicated by intrauterine death of one or both twins, fetal aneuploidy or major abnormality, twin-twin transfusion syndrome or twin anemia-polycythemia sequence and those delivered before 32 weeks' gestation, were excluded. SGA was defined as EFW or BW below the 10th centile, and was assessed using both twin-specific and singleton EFW and BW charts. The main study outcome was composite adverse neonatal outcome. Mixed-effects logistic regression analysis with random pregnancy-level intercepts was used to test the association between SGA classified using the different charts and adverse neonatal outcome.Results: A total of 1329 twin pregnancies were identified, of which 913 (1826 infants) were included in the analysis. Of these pregnancies, 723 (79.2%) were dichorionic and 190 (20.8%) were monochorionic. Using the singleton charts, 33.3% and 35.7% of pregnancies were classified as SGA based on EFW and BW, respectively. The corresponding values were 5.9% and 5.6% when using the twin-specific charts. Classification as SGA based on EFW using the twin charts was associated significantly with composite adverse neonatal outcome (odds ratio (OR), 4.78 (95% CI, 1.47-14.7); P = 0.007), as compared with classification as appropriate-for-gestational age (AGA). However, classification as SGA based on EFW using the singleton standard was not associated significantly with composite adverse neonatal outcome (OR, 1.36 (95% CI, 0.63-2.88); P = 0.424). Classification as SGA based on EFW using twin-specific standards provided a significantly better model fit than did using the singleton standard (likelihood ratio test, P < 0.001). When twin-specific charts were used, classification as SGA based on BW was associated significantly with a 9.3 times increased odds of composite adverse neonatal outcome (OR, 9.27 (95% CI, 2.86-30.0); P < 0.001). Neonates classified as SGA according to the singleton BW standard but not according to the twin-specific BW standards had a significantly lower rate of composite adverse neonatal outcome than did AGA twins (OR, 0.24 (95% CI, 0.07-0.66); P = 0.009).Conclusions: The singleton charts classified one-third of twins as SGA, both prenatally and postnatally. Infants classified as SGA according to the twin-specific charts, but not those classified as SGA according to the singleton charts, had a significantly increased risk of adverse neonatal outcome compared with infants classified as AGA. This study provides further evidence that twin-specific charts perform better than do singleton charts in the prediction of adverse neonatal outcome in twin pregnancies. The use of these charts may reduce misclassification of twins as SGA and improve identification of those that are truly growth restricted. © 2021 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Wisconsin's plant communities are responding to shifting disturbance regimes, habitat fragmentation, aerial nitrogen deposition, exotic species invasions, ungulate herbivory, and successional processes. To better understand how plant functional traits mediate species' responses to changing environmental conditions, we collected a large set of functional trait data for vascular plant species occupying Wisconsin forests and grasslands. We used standard protocols to make 76,213 measurements of 34 quantitative traits. These data provide rich information on genome size, physical leaf traits (length, width, circularity, thickness, dry matter content, specific leaf area, etc.), chemical leaf traits (carbon, nitrogen, phosphorus, potassium, calcium, magnesium, ash), life history traits (vegetative and flower heights, seed mass), and traits affecting plant palatability (leaf fiber, fat, and lignin). These trait values derive from replicate measurements on 12+ individuals of each species from multiple sites and 45+ individuals for a selected subset of species. Measurements typically reflect values for individuals although some chemical traits involved composite samples from several individuals at the same site. We also qualitatively characterized each species by plant family, woodiness, functional group, and Raunkiaer lifeform. These data allow us to characterize trait dimensionality, differentiation, and covariation among temperate plant species (e.g., leaf and stem economic syndromes). We can also characterize species' responses to environmental gradients and drivers of ecological change. With survey and resurvey data available from >400 sites in Wisconsin, we can analyze variation in community trait distributions and diversity over time and space. These data therefore allow us to assess how trait divergence vs. convergence affects community assembly and how traits may be related to half‐century shifts in the distribution and abundance of these species. The data set can be used for non‐commercial purposes. The data set is licensed as follows: CC‐By Attribution 4.0 International. We request users cite both the OSF data set and this Ecology data paper publication. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Endurance athletes demonstrate altered regional right ventricular (RV) wall mechanics, characterized by lower basal deformation, in comparison to non‐athletic control subjects at rest. We hypothesized that regional adaptations at the RV base reflect an enhanced functional reserve capacity in response to haemodynamic volume loading.What is the main finding and its importance?Free wall RV longitudinal strain is elevated in response to acute volume loading in both endurance athletes and control subjects. However, the RV basal segment longitudinal strain response to acute volume infusion is greater in endurance athletes. Our findings suggest that training‐induced cardiac remodelling might involve region‐specific adaptation in the RV functional response to volume manipulation. Eccentric remodelling of the right ventricle (RV) in response to increased blood volume and repetitive haemodynamic load during endurance exercise is well established. Structural remodelling is accompanied by decreased deformation at the base of the RV free wall, which might reflect an enhanced functional reserve capacity in response to haemodynamic perturbation. Therefore, in this study we examined the impact of acute blood volume expansion on RV wall mechanics in 16 young endurance‐trained men (aged 24 ± 3 years) and 13 non‐athletic male control subjects (aged 27 ± 5 years). Conventional echocardiographic parameters and the longitudinal strain and strain rate were quantified at the basal and apical levels of the RV free wall. Measurements were obtained at rest and after 7 ml/kg i.v. Gelofusine infusion, with and without a passive leg raise. After infusion, blood volume increased by 12 ± 4 and 14 ± 5% in endurance‐trained individuals versus control subjects, respectively (P = 0.264). Both endurance‐trained individuals (8 ± 10%) and control subjects (7 ± 9%) experienced an increase in free wall strain from baseline, which was also similar following leg raise (7 ± 10 and 6 ± 10%, respectively; P = 0.464). However, infusion evoked a greater increase in basal longitudinal strain in endurance‐trained versus control subjects (16 ± 14 vs. 6 ± 11%; P = 0.048), which persisted after leg raise (16 ± 18 vs. 3 ± 11%; P = 0.032). Apical longitudinal strain and RV free wall strain rates were not different between groups and remained unchanged after infusion across all segments. Endurance training results in a greater contribution of longitudinal myocardial deformation at the base of the RV in response to a haemodynamic volume challenge, which might reflect a greater region‐specific functional reserve capacity. [ABSTRACT FROM AUTHOR]

An increasing number of ecological studies have used chemical diversity as a functionally relevant, scalable measure of phytochemical mixtures, demanding more rigorous attention to how chemical diversity is estimated. Most studies have focused on the composition of phytochemical mixtures and have largely ignored structural concerns, which may have greater importance for ecological function. Here, we explore the development of structural complexity and compositional diversity resulting from different biotic and abiotic interactions in Piper kelleyi Tepe (Piperaceae). We also describe how variation in structural complexity and compositional diversity differs between two congeners, P. kelleyi and P. reticulatum. To better interpret these results, we have developed a framework for interpreting these dimensions of chemical diversity in phytochemical mixtures.We used the tropical shrub, P. kelleyi, as a model system to examine interactions between ecological factors and dimensions of phytochemical diversity. We also compared compositional diversity and metabolic complexity in P. kelleyi and P. reticulatum using liquid chromatography and 1H NMR, respectively, to examine trade‐offs between compositional diversity and structural complexity. A framework is provided to generate meaningful estimates of the structural complexity of phytochemical mixtures as measured by 1H NMR.Piper is an abundant plant genus that supports diverse insect communities throughout the tropics. Subtle changes in understorey forest light were associated with increases in herbivory that directly increased compositional diversity and indirectly decreased structural complexity in P. kelleyi. This was attributed to the production of oxidation products resulting from herbivory‐driven decomposition of structurally complex defence compounds. This type of complex result would remain undetected using standard chemical ecology approaches and accounts for the detailed molecular changes that are likely to affect species interactions.Synthesis. Our quantitative framework provides a method for considering trade‐offs between structural complexity and compositional diversity and the interpretation of analytical approaches for each. This methodology will provide new theoretical insights and a more sophisticated model for examining the ecology and evolution of chemically mediated interactions. [ABSTRACT FROM AUTHOR]

Summary: Crop diversity underpins the productivity, resilience and adaptive capacity of agriculture. Loss of this diversity, termed crop genetic erosion, is therefore concerning. While alarms regarding evident declines in crop diversity have been raised for over a century, the magnitude, trajectory, drivers and significance of these losses remain insufficiently understood. We outline the various definitions, measurements, scales and sources of information on crop genetic erosion. We then provide a synthesis of evidence regarding changes in the diversity of traditional crop landraces on farms, modern crop cultivars in agriculture, crop wild relatives in their natural habitats and crop genetic resources held in conservation repositories. This evidence indicates that marked losses, but also maintenance and increases in diversity, have occurred in all these contexts, the extent depending on species, taxonomic and geographic scale, and region, as well as analytical approach. We discuss steps needed to further advance knowledge around the agricultural and societal significance, as well as conservation implications, of crop genetic erosion. Finally, we propose actions to mitigate, stem and reverse further losses of crop diversity. [ABSTRACT FROM AUTHOR]

Recent evidence suggests pulmonary hypertension (PH), a disease of the pulmonary vasculature actually has multiorgan pathophysiology and perhaps etiology. Herein, we demonstrated that fecal matter transplantation from angiotensin‐converting enzyme 2 overexpressing mice counteracted the effects of chronic hypoxia to prevent pulmonary hypertension, neuroinflammation, and gut dysbiosis in wild type recipients. [ABSTRACT FROM AUTHOR]

Drainage reorganization generally occurs on geological time scales under unstable river network conditions. A few local‐scale studies indicate that recent climatic changes might accelerate the drainage reorganization process. However, large‐scale drainage reorganization during the modern era is rarely documented. This study examines ongoing drainage reorganization on the endorheic Tibetan Plateau (TP) as a primary result of drastic lake expansion. A total of 11 drainage system reorganization events comprising 24 different lake basins and covering a total area of 61,115 km2 occurred between 2000 and 2018. Assuming the continued growth rate of TP lakes, we project another 20 basins will be reorganized before 2030. These drainage basin reorganizations not only alter hydrological processes in the endorheic TP but may also cause the endorheic‐exorheic transition, leading to the upstream sprawl of the Yangtze River Basin and posing outburst flooding risks on China's key infrastructure such as the Qinghai‐Tibet Railway. Plain Language Summary: Recent climatic changes have intensified the global hydrologic cycle, and have likely accelerated drainage system evolution. We have provided a holistic picture of ongoing drainage reorganization driven by drastic lake expansions on the Tibetan Plateau (TP). Our results indicate that 24 different lake drainage systems have undergone reorganization between 2000 and 2018, and the number of basins is expected to increase to 44 by the year 2030. One notable drainage reorganization is between the endorheic Lake Yanhu and the exorheic Chumaer river, resulting in the upstream expansion of the Yangtze River Basin. These findings provide an increased understanding of ongoing drainage reorganization events driven by climatic changes. Further, this work advances our understanding of the connections between ongoing hydrologic changes and their effect on related geological disasters (e.g., outburst floods) within the TP. Key Points: Rapid lake growths drive large‐scale drainage reorganizations on the Tibetan Plateau24 lake drainage systems have undergone reorganization from 2000 to 2018 and this number is expected to increase to 44 by the year 2030The northern portion of the upstream Yangtze basin has expanded by around 8,400 km2 due to an endorheic‐exorheic transition [ABSTRACT FROM AUTHOR]

Background and Purpose: P2X4 is a ligand‐gated cation channel activated by extracellular ATP involved in neuropathic pain, inflammation and arterial tone. Experimental Approach Natural products were screened against human or mouse P2X4 activity using fura‐2 loaded 1321N1 cells for measurement of intracellular Ca2+ responses. Whole‐cell currents were measured by patch clamp. Human primary macrophage chemokine release was used to assess effect of taspine on inflammatory cell function. An enzymatic assay was performed to assess the effect of taspine on recombinant PI3‐kinase. Key Results: A natural product screen identified taspine as an inhibitor of human P2X4 activity. Taspine inhibits human and mouse P2X4‐mediated Ca2+ influx in 1321N1 cells expressing receptors but lacked activity at human P2X2, P2X3, P2X2/3 and P2X7 receptors. Taspine inhibited the maximal response at human and mouse P2X4 but effective on ATP potency. Taspine has a slow onset rate (~15 min for half‐maximal inhibition), irreversible over 30 min of washout. Taspine inhibits P2X4‐mediated Ca2+ signalling in mouse BV‐2 microglia cells and human primary macrophage. Taspine inhibited P2X4‐mediated CXCL5 secretion in human primary macrophage. Taspine reversed ivermectin‐induced potentiation of P2X4 currents in 1321N1 stably expressing cells. The PI3‐kinase inhibitor LY294002 mimicked the properties of taspine on P2X4‐mediated Ca2+ influx and whole‐cell currents. Taspine directly inhibited the enzymatic activity of recombinant PI3‐kinase in a competitive manner. Conclusion and Implications: Taspine is a novel natural product P2X4 receptor inhibitor, mediating its effect through PI3‐kinase inhibition rather than receptor antagonism. Taspine can inhibit the pro‐inflammatory signalling by P2X4 in human primary macrophage. [ABSTRACT FROM AUTHOR]

Aim: Forecasting the influence of climate change on coral biodiversity and reef functioning is important for informing policy decisions. Dominance shifts, tropicalization and local extinctions are common responses of climate change, but uncertainty surrounds the reliability of predicted coral community transformations. Here, we use species distribution models (SDMs) to assess changes in suitable coral habitat and associated patterns in biodiversity across Western Australia (WA) under present‐day and future climate scenarios (RCP 2.6 and RCP 8.5). Location: Coral reef systems and communities in WA. Methods: We developed SDMs with model prediction uncertainty analyses, using specimen‐based occurrence records of 188 hermatypic scleractinian coral species and seven variables to estimate present‐day and future changes to coral species distribution and biodiversity patterns in WA under climate change conditions. Results: We found that suitable habitat is predicted to increase across all regions in WA under RCP2.62050, RCP8.52050 and RCP2.62100 scenarios with all tropical and subtropical regions remaining coral biodiversity strongholds. Under the extreme RCP8.52100 scenario, however, a clear tropicalization trend could be observed with coral species expanding their range to mid‐high latitude regions, while a substantial drop in coral species richness was predicted at low latitude tropical coral reefs, such as the inshore Kimberley and offshore NW reefs. Despite the predicted expansion south, we identified a net decline in coral biodiversity across the WA coastline. Main conclusions: Results from the models predicted higher net coral biodiversity loss at low latitude tropical regions compared with net gains at mid‐high latitude regions under RCP8.52100. These results are likely to be representative of latitudinal trends across the Southern Hemisphere and highlight that increases in habitat suitability at higher latitudes may not lead to equivalent biodiversity benefits. Urgent action is needed to limit climate change to prevent spatial erosion of tropical coral communities, extinction events and loss of tropical ecosystem services. [ABSTRACT FROM AUTHOR]

Quantifying fish species diversity in rich tropical marine environments remains challenging. Environmental DNA (eDNA) metabarcoding is a promising tool to face this challenge through the filtering, amplification, and sequencing of DNA traces from water samples. However, because eDNA concentration is low in marine environments, the reliability of eDNA to detect species diversity can be limited. Using an eDNA metabarcoding approach to identify fish Molecular Taxonomic Units (MOTUs) with a single 12S marker, we aimed to assess how the number of sampling replicates and filtered water volume affect biodiversity estimates. We used a paired sampling design of 30 L per replicate on 68 reef transects from 8 sites in 3 tropical regions. We quantified local and regional sampling variability by comparing MOTU richness, compositional turnover, and compositional nestedness. We found strong turnover of MOTUs between replicated pairs of samples undertaken in the same location, time, and conditions. Paired samples contained non‐overlapping assemblages rather than subsets of one another. As a result, non‐saturated localized diversity accumulation curves suggest that even 6 replicates (180 L) in the same location can underestimate local diversity (for an area <1 km). However, sampling regional diversity using ~25 replicates in variable locations (often covering 10 s of km) often saturated biodiversity accumulation curves. Our results demonstrate variability of diversity estimates possibly arising from heterogeneous distribution of eDNA in seawater, highly skewed frequencies of eDNA traces per MOTU, in addition to variability in eDNA processing. This high compositional variability has consequences for using eDNA to monitor temporal and spatial biodiversity changes in local assemblages. Avoiding false‐negative detections in future biomonitoring efforts requires increasing replicates or sampled water volume to better inform management of marine biodiversity using eDNA. [ABSTRACT FROM AUTHOR]

New biomarkers are being evaluated for their ability to advance the management of patients with heart failure. Despite a large pool of interesting candidate biomarkers, besides natriuretic peptides virtually none have succeeded in being applied into the clinical setting. In this review, we examine the most promising emerging candidates for clinical assessment and management of patients with heart failure. We discuss high‐sensitivity cardiac troponins (Tn), procalcitonin, novel kidney markers, soluble suppression of tumorigenicity 2 (sST2), galectin‐3, growth differentiation factor‐15 (GDF‐15), cluster of differentiation 146 (CD146), neprilysin, adrenomedullin (ADM), and also discuss proteomics and genetic‐based risk scores. We focused on guidance and assistance with daily clinical care decision‐making. For each biomarker, analytical considerations are discussed, as well as performance regarding diagnosis and prognosis. Furthermore, we discuss potential implementation in clinical algorithms and in ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Aim: Environmental DNA (eDNA) metabarcoding has demonstrated its applicability as a highly sensitive biomonitoring tool across small spatial and temporal scales in marine ecosystems. However, it has rarely been tested across large spatial scales or biogeographical barriers. Here, we scale up marine eDNA metabarcoding, test its ability to detect a major marine biogeographic break and evaluate its use as a regional biomonitoring tool in Australia. Location: North‐western Australia (NWA). Methods: We applied metabarcoding assays targeting the mitochondrial 16S rRNA and CO1 genes to 284 surface seawater eDNA samples collected from 71 mid‐shelf, inshore, coastal and nearshore estuarine sites over 700 km of the NWA coastline. Results: Metabarcoding detected a wide range of bony fish (404 taxa), elasmobranchs (44) and aquatic reptiles (5). We detected bioregional and depth differentiation within inshore bony fish communities. These findings support the presence of a marine biogeographic break, which is purported to occur in the vicinity of Cape Leveque, demarcating the border between the Kimberley and Canning bioregions. Inshore bony fish and elasmobranch communities, as well as coastal bony fish assemblages, were additionally found to differ between the South and North Kimberley regions suggesting previously unrecognized subregional differentiation amongst these taxa. The overall compositional data have been used to update distribution information for a number of endangered, elusive and data‐deficient taxa, including sawfish (family: Pristidae), northern river shark (Glyphis garricki) and wedgefish (genus: Rhynchobatus). Main conclusions: eDNA metabarcoding demonstrated a high level of sensitivity that was able to discern fine‐scale patterns across the large‐scale, remote and oceanographically complex region of North‐western Australia. Importantly, this study highlights the potential of integrating broad‐scale eDNA metabarcoding alongside other baseline surveys and long‐term monitoring approaches, which are crucial for the sustainable management and conservation of marine biodiversity in this unique marine region. [ABSTRACT FROM AUTHOR]

Objectives: To construct chorionicity-specific birth-weight reference charts for dichorionic diamniotic (DCDA) and monochorionic diamniotic (MCDA) twin pregnancies, incorporating estimated-fetal-weight (EFW) data in order to adjust for the relationship between suboptimal growth and preterm delivery. An additional aim was to determine if the inclusion of complicated twin pregnancies impacts on the reference charts produced.Methods: The inclusion criteria for this retrospective cohort study were twin pregnancy of known DCDA or MCDA chorionicity, known pregnancy outcome, last ultrasound scan within 14 days before birth and delivery between 25 and 38 weeks' gestation (Analysis A). An analysis was also conducted excluding pregnancies with complications recorded (Analysis B). Previously published twin EFW reference ranges were used in the analysis. A joint statistical model for EFW and observed birth weight for each pregnancy was created in order to estimate population birth-weight reference ranges corresponding to the distribution expected if all pregnancies delivered at any given gestational age. It was not assumed that the median EFW was equal to birth weight for any given gestational age. The models were fitted using a Bayesian approach.Results: We retrieved data on 1664 twin pregnancies, of which 707 DCDA and 241 MCDA pregnancies met the inclusion criteria. In Analysis A, the estimated population median birth weight was similar to the median EFW at around 27 weeks' gestation but fell below the EFW values with increasing gestation, being 156 g lower in both DCDA and MCDA pregnancies at 35 weeks; this finding was confirmed by direct comparison of the last EFW and birth-weight values in each pregnancy. When the analysis was repeated after excluding complicated twin pregnancies (Analysis B), compared with Analysis A, there was very little difference in the median birth-weight results obtained across gestation. The largest absolute difference between Analyses A and B for DCDA twins was at 31, 32 and 33 weeks, with a 9-g lower median birth weight in Analysis A compared with Analysis B. The largest absolute difference for MCDA twins was greater than that for DCDA twins, with a 21-g lower median birth weight at 25 weeks in Analysis A compared with Analysis B.Conclusions: We have established population chorionicity-specific birth-weight reference charts for DCDA and MCDA twin pregnancies, corresponding to the range expected were all pregnancies to deliver at any given gestational age. In this population of twins, the median birth weight was consistently lower than that reported for singletons, and there was variation in the median birth weight at different gestational ages according to chorionicity. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. - Legal Statement: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. [ABSTRACT FROM AUTHOR]

Summary: Background: Variants in multiple genetic loci modify the risk of non‐alcoholic fatty liver disease (NAFLD) and cirrhosis but there are limited data on the quantitative impact of variant copies on liver fibrosis. Aim: To investigate the effect of PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13 genotype on liver fibrosis assessed by magnetic resonance elastography (MRE), a reproducible, accurate, continuous biomarker of liver fibrosis. Methods: This is a cross‐sectional analysis derived from a well‐characterised cohort at risk for NAFLD who underwent genotyping and MRE assessment. Liver stiffness (LS) was estimated using MRE and advanced fibrosis was defined as liver stiffness ≥3.63 kilopascals (kPa). Univariable and multivariable linear and logistic regression analysis, were used to assess the association between genotype and MRE. Results: Two hundred sixty‐four patients (63% women) with a mean age 53 (±17) years, and 31% Hispanic ethnicity with genotyping and MRE were included. The odds of advanced fibrosis were 3.1 (95% CI: 1.1‐8.9, P = 0.04) for CG and 6.5 (95% CI: 2.2‐18.9, P < 0.01) for GG compared to CC PNPLA3 genotype. Each PNPLA3 risk variant copy was associated with 0.40 kPa (95% CI: 0.19‐0.61, P < 0.01) increase in LS on MRE in analysis adjusted for age, sex and BMI and there was significant genotype‐age interaction (P < 0.01). Conversely, the protective TA allele in HSD17B13 was associated with a −0.41 kPa (95% CI: −0.76 to −0.05, P = 0.03) decrease in liver stiffness on MRE multivariable analysis. Conclusion: Knowledge of PNPLA3 and HSD17B13 genotype may assist in the non‐invasive risk stratification of NAFLD with closer monitoring recommended for those with high genetic risk. [ABSTRACT FROM AUTHOR]