Using monotonicity methods, the Lagrange multiplier rule and some variational arguments, we consider a type of localization results pertaining to the existence of critical points to action functionals on a closed ball. A variant of the Schechter critical point theorem on a ball in Hilbert and Banach spaces is obtained. Applications to nonlinear Dirichlet problem and to partial difference equations are given in the final part of this paper.
Background: Postpartum haemorrhage (PPH) rates are increasing in developed countries. A reliable prognostic tool for PPH has potential to aid prevention efforts. Objective: To systematically identify and appraise prognostic modelling studies for prediction of PPH. Search strategy: MEDLINE, Embase, CINAHL and the Cochrane Library were searched using a combination of terms and synonyms including ‘prediction tool’, ‘risk score’ and ‘postpartum haemorrhage’. Selection criteria: Any observational or experimental study developing a prognostic model for women’s risk of PPH. English language publications. Data collection and analysis: Predesigned data extraction form to record: data source; participant criteria; outcome; candidate predictors; actual predictors; sample size; missing data; model development; model performance; model evaluation; interpretation. Main Results: Of 1723 citations screened, 10 studies were eligible for inclusion. An additional paper was published and identified following completion of the search. Studies addressed populations of women who experienced; placenta praevia; vaginal births; caesarean birth; and the general obstetric population. Primary study authors deemed four models to be confirmatory. There was a high risk of bias across all studies due to a combination of retrospective selection of women, low sample size, no internal validation, suboptimal external validation and no reporting of missing data. Conclusion: Of eleven prognostic models for PPH risk, one developed for women undergoing caesarean section is deemed suitable for external validation. Future research requires robust internal and external validation of existing tools and development of a model that can be used to predict PPH in the general obstetric population. Protocol registration number: PROSPERO 95587
Anthropogenic perturbations such as harvesting often select against a large body size, and are predicted to induce rapid evolution towards smaller body sizes and earlier maturation. However, the evolvability of body size and size-correlated traits remains seldom evaluated in wild populations. Here, we use a laboratory experiment over 6 generations to measure the ability of wild-caught medaka fish (Oryzias latipes) to evolve in response to bidirectional size-dependent selection mimicking opposite harvest regimes. Specifically, we imposed selection against a small body size (Large line), against a large body size (Small line) or random selection (Control line), and measured correlated responses across multiple phenotypic, life-history and endocrine traits. As expected, the Large line evolved faster somatic growth and delayed maturation, but also evolved smaller body sizes at hatch, with no change in average levels of pituitary gene expressions of luteinizing, follicle-stimulating or growth (GH) hormones. In contrast, the Small medaka line was unable to evolve smaller body sizes or earlier maturation, but showed marginally-significant signs of increased reproductive investment, including larger egg sizes and elevated pituitary GH production. Natural selection on medaka body size was too weak to significantly hinder the effect of artificial selection, indicating that the asymmetric body-size response to size-dependent selection reflected an asymmetry in body-size evolvability. Our results show that trait evolvability may be contingent upon the direction of selection, and that a detailed knowledge of trait evolutionary potential is needed to forecast population response to anthropogenic change.
Gene annotation is a critical bottleneck in genomic research, especially for the comprehensive study of very large gene families in the genomes of non-model organisms. Despite the recent progress in automatic methods, state-of-the-art tools used for this task often produce inaccurate annotations, such as fused, chimeric, partial or even completely absent gene models for many family copies, errors that require considerable extra efforts to be corrected. Here we present BITACORA, a bioinformatics solution that integrates popular sequence similarity-based search tools and Perl scripts to facilitate both the curation of these inaccurate annotations and the identification of previously undetected gene family copies directly in genomic DNA sequences. We tested the performance of BITACORA in annotating the members of two chemosensory gene families with different repertoire size in seven available genome sequences, and compared its performance with that of Augustus-PPX, a tool also designed to improve automatic annotations using a sequence similarity-based approach. Despite the relatively high fragmentation of some of these drafts, BITACORA was able to improve the annotation of many members of these families and detected thousands of new chemoreceptors encoded in genome sequences. The program creates general feature format (GFF) files, with both curated and newly identified gene models, and FASTA files with the predicted proteins. These outputs can be easily integrated in genomic annotation editors, greatly facilitating subsequent manual annotation and downstream evolutionary analyses.
1. Plant leaf stomata are the gatekeepers of the atmosphere-plant interface and are essential building blocks of land surface models as they control transpiration and photosynthesis. Although more stomatal trait data is needed to significantly reduce the error in these model predictions, recording these traits is time-consuming and no standardized protocol is currently available. Some attempts were made to automate stomatal detection from photomicrographs, however, these approaches have the disadvantage of using classic image processing or targeting a narrow taxonomic entity which makes these technologies less robust and generalizable to other plant species. We propose an easy-to-use and adaptable workflow from leaf to label. A methodology for automatic stomata detection was developed using deep neural networks according to the state-of-the-art and its applicability demonstrated across the phylogeny of the angiosperms. 2. We used a patch-based approach for training/tuning three different deep learning architectures. For training, we used 431 micrographs taken from leaf prints made according the nail polish method from herbarium specimens of 19 species. The best performing architecture was tested on 595 images of 16 additional species spread across the angiosperm phylogeny. 3. The nail polish method was successfully applied in 78% of the species sampled here. The VGG19 architecture slightly outperformed the basic shallow and deep architectures, with a confidence threshold equal to 0.7 resulting in an optimal trade-off between precision and recall. Applying this threshold the VGG19 architecture obtained an average F-score of 0.87, 0.89 and 0.67 on the training, validation and unseen test set, respectively. The average accuracy was very high (94%) for computed stomatal counts on unseen images of species used for training. 4. The leaf-to-label pipeline is an easy-to-use workflow for researchers of different areas of expertise interested in detecting stomata more efficiently. The described methodology was based on multiple species and well-established methods so that it can serve as a reference for future work.
Glutathione (GSH) plays a central role in the redox balance maintenance in mammalian cells. The study of industrial CHO cell lines have demonstrated a close link between GSH metabolism and clone productivity. However, a deep investigation is still required to understand this correlation and highlights new potential targets for cell engineering. In this study, we have modulated the GSH intracellular content of an industrial cell line under bioprocess conditions in order to further elucidate the role of the GSH synthesis pathway. Two strategies were used : the variation of cystine supply and the direct inhibition of the GSH synthesis using buthionine sulfoximine (BSO). Cysteine supply modulation have revealed a correlation between intracellular GSH and product titer over time. Analysis of metabolites uptake/secretion rates and proteome comparison between BSO-treated cells and non-treated cells has highlighted a slow down of the TCA cycle leading to a secretion of lactate and alanine in the extracellular environment. Moreover, an adaptation of the glutathione related proteome has been observed with a up-regulation of the regulatory subunit of glutamate cysteine ligase and a down-regulation of a specific glutathione transferase subgroup, the Mu family. Surprisingly, the main impact of BSO treatment was observed on a global down-regulation of the cholesterol synthesis pathways. As cholesterol is required for protein secretion, it can be the missing part of the jigsaw to finally elucidate the link between GSH synthesis and productivity.
Manufacturers have been promoting multi-material designs. So, the dissimilar material welding methods are being developed. We focused on heat welding technologies for friction stir spot welding of aluminum alloy and carbon fiber-reinforced plastic. This study investigated the effect of changes to jig constraint of joined members on the fatigue properties of joints. Also the fatigue life estimation was carried out by considering the singular stress at the welding joint interface. As a result, the fatigue strength of joint in a less constrained state is higher than that in a more constrained state. The singular stress intensity at the slit tip was uniformly predicted by the differences in welding parameters of joints.
This letter is a response to the commentary by Jonson & Do (Johnson and Do 2020) on our paper, entitled “A Vietnamese human genetic variation database” (Vinh et al. 2019). The commentators concerned about two issues: Firstly, the relation of Southeast Asian (SEA) and East Asian (EA) groups to African and European groups; Secondly, the history of migration and settlement in Southeast Asia. Our responses will clarify both concerns from the commentators.
Recurrent sea urchin mass mortality has recently affected eastern Atlantic populations of the barren-forming sea urchin Diadema africanum. This new episode of die-off affords the opportunity to determine common meteorological and oceanographic conditions that may promote disease outbreaks. The population dynamics of this sea urchin species are well known—urchin barrens have persisted for many decades along most of the coastlines off the archipelagos of Madeira, Selvages and the Canary Islands, where they limit macroalgae biomass growth. However, this new and explosive mortality event decimated the sea urchin population by 93% on Tenerife and La Palma Islands. Two severe episodes of southwestern rough sea that lead to winter storms, in February 2010 (Xynthia) and February 2018 (Emma), preceded both mass mortality events. The autumn and winter months of those years were anomalous and characterized by swells with an average wave height above 2 m that hit the south and southwest sides of the islands. The amoeba Paramoeba brachiphila was the only pathogen isolated this time from the moribund and dead sea urchins, suggesting that the amoeba was the primary cause of the mortality. This new sea urchin die-off event supports the “killer-storm” hypothesis that has been already described for western Atlantic coasts. These anomalous southwest storms during winters generate pronounced underwater sediment movement and large-scale vertical mixing, detected in local tide gauge, which may promote paramoebiasis. This study presents valuable insights about climate-mediated changes in disease frequency and its impacts on the future of coastal marine ecosystems in the Atlantic.
Parallel evolution can occur through novel mutations, standing genetic variation, or adaptive introgression. Uncovering parallelism and introgressed populations can complicate management of threatened species, particularly as admixed populations are not generally considered under conservation legislations. We examined high coverage whole-genome sequences of 30 caribou (Rangifer tarandus) from across North America and Greenland, representing divergent intra-specific lineages, to investigate parallelism and levels of introgression contributing to the formation of ecotypes. Caribou are split into four subspecies and 11 extant conservation units, known as Designatable Units (DUs), in Canada. Using genomes from all four subspecies and six DUs, we undertake demographic reconstruction and confirm two previously inferred instances of parallel evolution in the woodland subspecies and uncover an additional instance of parallelism of the eastern migratory ecotype. Detailed investigations reveal introgression in the woodland subspecies, with introgressed regions found spread throughout the genomes encompassing both neutral and functional sites. Our comprehensive investigations using whole genomes highlight the difficulties in unequivocally demonstrating parallelism through adaptive introgression in non-model species with complex demographic histories, with standing variation and introgression both potentially involved. Additionally, the impact of parallelism and introgression on the designation of conservation units has not been widely considered, and the caribou designations will need amending in light of our results. Uncovering and decoupling parallelism and differential patterns of introgression will become prevalent with the availability of comprehensive genomic data from non-model species, and we highlight the need to incorporate this into conservation unit designations.
The aim of this study was to investigate the pathogenesis of combination ipilimumab and nivolumab-associated colitis (IN-COL) by measuring gut-derived and peripheral blood mononuclear cell (GMNC; PBMC) profiles. We studied GMNC and PBMC from patients with IN-COL, IN-treated with no adverse-events (IN-NAE), ulcerative colitis (UC) and healthy volunteers by flow cytometry. In the gastrointestinal-derived cells we found high levels of activated CD8+ T cells and mucosal-associated invariant T (MAIT) cells in IN-COL, changes that were not evident in IN-NAE or UC. UC but not IN-C was associated with a high proportion of regulatory T cells (Treg). We sought to determine if local tissue responses could be measured in peripheral blood. Peripherally, checkpoint-inhibition instigated a rise in activated memory CD4+ and CD8+ T cells, regardless of colitis. Low circulating MAIT cells at baseline was associated with IN-COL patients, compared with IN-NAE in one of two cohorts. UC but not IN-COL was associated with high levels of circulating plasmablasts. In summary, the alterations in T cell subsets measured in IN-COL-affected tissue, characterised by high levels of activated CD8+ T cells and MAIT cells and a low proportion of Treg, reflected a pathology distinct from UC. These tissue changes differed from the periphery, where T cell activation was a widespread on-treatment effect, and circulating MAIT cell count was low but not reliably predictive of colitis (Figure1).
Since news of COVID-19 outbreak hit the mainstream media, I have received several calls from acquaintances about if and how they should be worried. I suspect many readers of the Journal of Evaluation in Clinical Practice have experienced the same. What makes communicating the risk difficult can be illustrated through a recent assignment I gave to my undergraduate class focused on how we use science in public policy. I asked the students to identify claims in the media regarding the virus and then search the literature to assess the level of support for such claims. Suffice it to say, they found several claims unsupported, and several others to be inconclusive. Not very good grounding for providing definitive (or even satisfying) advice.
Cough is an adverse effect that may hinder the delivery of drugs into the lungs. Chemical or mechanical stimulants activate the transient receptor potential in some airway afferent nerves (C or A fibres) to trigger cough. Types of inhaler device and drug, dose, excipients, formulation characteristics including pH, tonicity, aerosol output and particle size may trigger cough by stimulating the cough receptors. Release of inflammatory mediators may increase the sensitivity of the cough receptors to stimulants. The cough-provoking effect of aerosols is enhanced by bronchoconstriction in diseased airways and reduces drug deposition in the target pulmonary regions. In this article, we review the factors by which inhalation products may cause cough.
Fungi are a key component of tropical biodiversity. Due to their inconspicuous and largely subterranean nature, they are however usually neglected in biodiversity inventories. The goal of this study was to identify the key determinants of fungal richness, community composition, and turnover in tropical rainforests. We tested specifically for the effect of soil properties, habitat, and locality in Amazonia. For these analyses, we used high-throughput sequencing data of short and long reads of fungal DNA present in soil and organic litter samples, combining existing and novel genomic data. Habitat type (phytophysiognomies) emerges as the strongest factor in explaining fungal community composition. Naturally open areas – campinas – are the richest habitat overall. Soil properties have different effects depending on the soil layer (litter or mineral soil) and the choice of genetic marker. We suggest that campinas could be a neglected hotspot of fungal diversity. An underlying cause for their rich diversity may be the overall low soil fertility, which increases the reliance on biotic interactions essential for nutrient absorption in these environments, notably ectomycorrhizal fungi–plant associations. Our results highlight the advantages of using both short and long DNA reads produced through high-throughput sequencing to characterize fungal diversity. While short-reads can suffice for diversity and community comparison, long-reads add taxonomic precision and have the potential to reveal population diversity.
In order to maximize the productivity of engineered metabolic pathway, in silico model is an established means to provide features of enzyme reaction dynamics. In our previous study, E.coli engineered with acrylate pathway yielded low propionic acid titre. To understand the bottleneck behind this low productivity, a kinetic model was developed that incorporates the enzymatic reactions of the acrylate pathway. The resulting model was capable of simulating the fluxes reported under in vitro studies with good agreement, suggesting repression of propionyl-CoA transferase by carboxylate metabolites as the main limiting factor for propionate production. Furthermore, the predicted ﬂux control coeﬃcients of the pathway enzymes under steady state conditions revealed that the control of ﬂux is shared between propionyl-CoA transferase and lactoyl-CoA dehydratase. Increase in lactate concentration showed gradual decrease in ﬂux control coeﬃcients of propionyl-CoA transferase that in turn confirmed the control exerted by the carboxylate substrate. To interpret these in silico predictions under in vivo system, an organized study was conducted with a Lactic Acid Bacteria (LAB) strain engineered with acrylate pathway. Analysis reported a decreased product formation rate on attainment of inhibitory titre by suspected metabolites and supported the model.