Article Gate
Not a member yet
471 research outputs found
Sort by
Alix is required for activity-dependent bulk endocytosis at brain synapses
Full text linkIn chemical synapses undergoing high frequency stimulation, vesicle components can be retrieved from the plasma membrane via a clathrin-independent process called activity-dependent bulk endocytosis (ADBE). Alix (ALG-2-interacting protein X/PDCD6IP) is an adaptor protein binding to ESCRT and endophilin-A proteins which is required for clathrin-independent endocytosis in fibroblasts. Alix is expressed in neurons and concentrates at synapses during epileptic seizures. Here, we used cultured neurons to show that Alix is recruited to presynapses where it interacts with and concentrates endophilin-A during conditions triggering ADBE. Using Alix knockout (ko) neurons, we showed that this recruitment, which requires interaction with the calcium-binding protein ALG-2, is necessary for ADBE. We also found that presynaptic compartments of Alix ko hippocampi display subtle morphological defects compatible with flawed synaptic activity and plasticity detected electrophysiologically. Furthermore, mice lacking Alix in the forebrain undergo less seizures during kainate-induced status epilepticus and reduced propagation of the epileptiform activity. These results thus show that impairment of ADBE due to the lack of neuronal Alix leads to abnormal synaptic recovery during physiological or pathological repeated stimulations
A new test suggests hundreds of amino acid polymorphisms in humans are subject to balancing selection
Full text linkThe role that balancing selection plays in the maintenance of genetic diversity remains unresolved. Here, we introduce a new test, based on the McDonald–Kreitman test, in which the number of polymorphisms that are shared between populations is contrasted to those that are private at selected and neutral sites. We show that this simple test is robust to a variety of demographic changes, and that it can also give a direct estimate of the number of shared polymorphisms that are directly maintained by balancing selection. We apply our method to population genomic data from humans and provide some evidence that hundreds of nonsynonymous polymorphisms are subject to balancing selectio
Safety and immunogenicity of heterologous boost immunization with an adenovirus type-5-vectored and protein-subunit-based COVID-19 vaccine (Convidecia/ZF2001): A randomized, observer-blinded, placebo-controlled trial
Full text linkHeterologous boost vaccination has been proposed as an option to elicit stronger and broader, or longer-lasting immunity. We assessed the safety and immunogenicity of heterologous immunization with a recombinant adenovirus type-5-vectored Coronavirus Disease 2019 (COVID-19) vaccine (Convidecia, hereafter referred to as CV) and a protein-subunit-based COVID-19 vaccine (ZF2001, hereafter referred to as ZF).
Methods and findings
We conducted a randomized, observer-blinded, placebo-controlled trial, in which healthy adults aged 18 years or older, who have received 1 dose of Convidecia, with no history of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, were recruited in Jiangsu, China. Sixty participants were randomly assigned (2:1) to receive either 1 dose of ZF2001 or placebo control (trivalent inactivated influenza vaccine (TIV)) administered at 28 days after priming, and received the third injection with ZF2001 at 5 months, referred to as CV/ZF/ZF (D0-D28-M5) and CV/ZF (D0-M5) regimen, respectively. Sixty participants were randomly assigned (2:1) to receive either 1 dose of ZF2001 or TIV administered at 56 days after priming, and received the third injection with ZF2001 at 6 months, referred to as CV/ZF/ZF (D0-D56-M6) and CV/ZF (D0-M6) regimen, respectively. Participants and investigators were masked to the vaccine received but not to the boosting interval. Primary endpoints were the geometric mean titer (GMT) of neutralizing antibodies against wild-type SARS-CoV-2 and 7-day solicited adverse reactions. The primary analysis was done in the intention-to-treat population. Between April 7, 2021 and May 6, 2021, 120 eligible participants were randomly assigned to receive ZF2001/ZF2001 (n = 40) or TIV/ZF2001 (n = 20) 28 days and 5 months post priming, and receive ZF2001/ZF2001 (n = 40) or TIV/ZF2001 (n = 20) 56 days and 6 months post priming. Of them, 7 participants did not receive the third injection with ZF2001. A total of 26 participants (21.7%) reported solicited adverse reactions within 7 days post boost vaccinations, and all the reported adverse reactions were mild, with 13 (32.5%) in CV/ZF/ZF (D0-D28-M5) regimen, 7 (35.0%) in CV/ZF (D0- M5) regimen, 4 (10.0%) in CV/ZF/ZF (D0-D56-M6) regimen, and 2 (10.0%) in CV/ZF (D0-M6) regimen, respectively. At 14 days post first boost, GMTs of neutralizing antibodies in recipients receiving ZF2001 at 28 days and 56 days post priming were 18.7 (95% CI 13.7 to 25.5) and 25.9 (17.0 to 39.3), respectively, with geometric mean ratios of 2.0 (1.2 to 3.5) and 3.4 (1.8 to 6.4) compared to TIV. GMTs at 14 days after second boost of neutralizing antibodies increased to 107.2 (73.7 to 155.8) in CV/ZF/ZF (D0-D28-M5) regimen and 141.2 (83.4 to 238.8) in CV/ZF/ZF (D0-D56-M6) regimen. Two-dose schedules of CV/ZF (D0-M5) and CV/ZF (D0-M6) induced antibody levels comparable with that elicited by 3-dose schedules, with GMTs of 90.5 (45.6, 179.8) and 94.1 (44.0, 200.9), respectively. Study limitations include the absence of vaccine effectiveness in a real-world setting and current lack of immune persistence data
Why does viral RNA sometimes persist after recovery from acute infections?
Full text linkDNA viruses often persist in the body of their host, becoming latent and recurring many months or years later. By contrast, most RNA viruses cause acute infections that are cleared from the host as they lack the mechanisms to persist. However, it is becoming clear that viral RNA can persist after clinical recovery and elimination of detectable infectious virus. This persistence can either be asymptomatic or associated with late progressive disease or nonspecific lingering symptoms, such as may be the case following infection with Ebola or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Why does viral RNA sometimes persist after recovery from an acute infection? Where does the RNA come from? And what are the consequences
Recommendations for improving statistical inference in population genomics
Full text linkThe field of population genomics has grown rapidly in response to the recent advent of affordable, large-scale sequencing technologies. As opposed to the situation during the majority of the 20th century, in which the development of theoretical and statistical population genetic insights outpaced the generation of data to which they could be applied, genomic data are now being produced at a far greater rate than they can be meaningfully analyzed and interpreted. With this wealth of data has come a tendency to focus on fitting specific (and often rather idiosyncratic) models to data, at the expense of a careful exploration of the range of possible underlying evolutionary processes. For example, the approach of directly investigating models of adaptive evolution in each newly sequenced population or species often neglects the fact that a thorough characterization of ubiquitous nonadaptive processes is a prerequisite for accurate inference. We here describe the perils of these tendencies, present our consensus views on current best practices in population genomic data analysis, and highlight areas of statistical inference and theory that are in need of further attention. Thereby, we argue for the importance of defining a biologically relevant baseline model tuned to the details of each new analysis, of skepticism and scrutiny in interpreting model fitting results, and of carefully defining addressable hypotheses and underlying uncertainties
Extreme freshwater events, scientific realities, curriculum inclusions, and perpetuation of cultural beliefs
Full text linkThe purpose of this research was to explore and open dialogue about possible connections between the scientific realities of extreme freshwater events (EFWE), a lack of EFWE-related curricular content in schools, and future teachers’ awareness and perceptions of EFWE. In phase one, an analysis of existing weather data demonstrated ongoing moderate to severe EFWE in the two regions under investigation, Queensland, Australia and Saskatchewan, Canada, at the time of data collection. In phase two, a content analysis of school curricula in the two regions shows a dearth of mandatory content related to EFWE, though Queensland, Australia had slightly more mandated content than did Saskatchewan, Canada. In phase 3, a survey of pre-service teachers in the two regions showed a demonstrable lack of recognition of undergoing moderate to severe EFWE at time of data collection, along with a general satisfaction with the current level of curricular coverage of the topic. While respondents’ overall concern was low, there were consistent regional differences. Queenslanders were more likely to recognize their lived experience with EFWE and perceived it to be a more important inclusion in school curricula than their Saskatchewanian counterparts. Taken together, results suggested that learned cultural truths were reflected in and perpetuated by school curricula. Results highlighted cultural denial of EFWE severity and a need to change false truths by increasing visibility of EFWE in mandated school curricula. The authors propose that results warrant further research and discussion as it relates to public policy and prioritizing EFWE in formal school curricula
A novel class of antimicrobial drugs selectively targets a Mycobacterium tuberculosis PE-PGRS protein
Full text linkThe continued spread of drug-resistant tuberculosis is one of the most pressing and complex challenges facing tuberculosis management worldwide. Therefore, developing a new class of drugs is necessary and urgently needed to cope with the increasing threat of drug-resistant tuberculosis. This study aims to discover a potential new class of tuberculosis drug candidates different from existing tuberculosis drugs. By screening a library of compounds, methyl (S)-1-((3-alkoxy-6,7-dimethoxyphenanthren-9-yl)methyl)-5-oxopyrrolidine-2-carboxylate (PP) derivatives with antitubercular activity were discovered. MIC ranges for PP1S, PP2S, and PP3S against clinically isolated drug-resistant Mycobacterium tuberculosis strains were 0.78 to 3.13, 0.19 to 1.56, and 0.78 to 6.25 μg/ml, respectively. PPs demonstrated antitubercular activities in macrophage and tuberculosis mouse models, showing no detectable toxicity in all assays tested. PPs specifically inhibited M. tuberculosis without significantly changing the intestinal microbiome in mice. Mutants selected in vitro suggest that the drug targets the PE-PGRS57, which has been found only in the genomes of the M. tuberculosis complex, highlighting the specificity and safety potency of this compound. As PPs show an excellent safety profile and highly selective toxicity specific to M. tuberculosis, PPs are considered a promising new candidate for the treatment of drug-resistant tuberculosis while maintaining microbiome homeostasis
Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index
Full text linkNovel drug targets for sustained reduction in body mass index (BMI) are needed to curb the epidemic of obesity, which affects 650 million individuals worldwide and is a causal driver of cardiovascular and metabolic disease and mortality. Previous studies reported that the Arg95Ter nonsense variant of GPR151, an orphan G protein-coupled receptor, is associated with reduced BMI and reduced risk of Type 2 Diabetes (T2D). Here, we further investigate GPR151 with the Pakistan Genome Resource (PGR), which is one of the largest exome biobanks of human homozygous loss-of-function carriers (knockouts) in the world. Among PGR participants, we identify eleven GPR151 putative loss-of-function (plof) variants, three of which are present at homozygosity (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7), with a cumulative allele frequency of 2.2%. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits and find that GPR151 deficiency in complete human knockouts is not associated with clinically significant differences in these traits. Relative to Gpr151+/+ mice, Gpr151-/- animals exhibit no difference in body weight on normal chow and higher body weight on a high-fat diet. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach to treatment of obesity.
Author summary
Human genetics studies can provide compelling targets for therapeutic intervention. While some therapeutic targets, such as PCSK9, are based on extensive genetic validation, many others are based on weaker associations with variants of unknown consequence that require further validation. Recent publications reported associations between loss of GPR151 function and low body mass index (BMI), raising the possibility of inhibiting GPR151 for the treatment of obesity and metabolic syndromes. To evaluate the relationship between GPR151 and BMI, we (1) identified and experimentally confirmed loss-of-function variants present in the Pakistan Genome Resource (PGR) biobank, one of the world’s largest biobanks of human gene “knockouts”, (2) analyzed these loss-of-function variants individually and in burden tests for association with BMI and other metabolic traits or diseases, and (3) verified the evolutionary conservation of our findings in mice lacking Gpr151. We observe that GPR151 loss does not affect BMI to a clinically relevant extent and conclude that inhibiting GPR151 may not be effective at treating obesity
Consistent Site-Specific Foraging Behaviours of Yellow-eyed Penguins/Hoiho Breeding on Stewart Island, New Zealand
Full text linkThe endangered yellow-eyed penguin/hoiho (Megadyptes antipodes) predominantly forages benthically within its mainland range and shows high foraging site fidelity. Identifying consistencies in foraging locations can allow effective conservation, especially when managing bycatch risk. This study investigated the at-sea distribution of penguins breeding on Stewart Island to explore site-specific foraging strategies and inform fisheries management. During the 2020/21 season, 19 adult breeding yellow-eyed penguins from Port Pegasus, Paterson Inlet, and Codfish Island were fitted with GPS-TDR dive loggers to track their movements and diving behaviours. A total of 25,696 dives were recorded across 91 foraging trips. Birds from Port Pegasus reached significantly greater depths, spent longer at the seafloor, and performed longer dives. They also had the smallest foraging distribution, with most activity concentrated inshore. Compared to Port Pegasus, foraging radii and trip lengths were twice as large for Paterson Inlet and four times larger at Codfish Island. Despite differences in available foraging habitat, considerable individual and intra-site consistency for preferred foraging locations was observed. Localised behaviour and inter-site differences in dive metrics suggest significant plasticity in foraging ecology across their mainland range; however, individual behaviour and preferred foraging locations were extremely predictable. Thus, risk of mortality from fisheries can be quantified and managed accordingly
Antagonization of Ghrelin Suppresses Muscle Protein Deposition by Altering Gut Microbiota and Serum Amino Acid Composition in a Pig Model
Full text linkGhrelin is an appetite-stimulating hormone that can increase food intake and has been reported to prevent muscle loss; however, the mechanism is not yet fully understood. In this study, [D-Lys3]-GHRP-6 (GHRP) was used to investigate the effects of the antagonization of ghrelin on muscle protein deposition, eating patterns and gut microbiota in a pig model. We found that the growth performance and muscle fiber cross-sectional area of pigs treated with GHRP were significantly reduced compared with the control (CON) group. Moreover, the levels of serum isoleucine, methionine, arginine and tyrosine in the GHRP group were lower than that of the CON group. The abundance of acetate-producing bacteria (Oscillospiraceae UCG-005, Parabacteroides and Oscillospiraceae NK4A214 group) and acetate concentration in the colons of pigs treated with GHRP were significantly reduced. In addition, the injection of GHRP down-regulated the mRNA expression of MCT-1 and mTOR, and it up-regulated the mRNA expression of HDAC1, FOXO1 and Beclin-1. In summary, the antagonization of ghrelin reduced the concentration of important signal molecules (Arg, Met and Ile) that activate the mTOR pathway, concurrently reduce the concentration of HDAC inhibitors (acetate), promote autophagy and finally reduce protein deposition in muscles