bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mifepristone as a pharmacological intervention for stress-Induced alcohol craving: a translational crossover randomized trial
Authors: Haass-Koffler Carolina L. , Magill Molly , Cannella Nazzareno , Brown Joshua C. , Aoun Elie G. , Cioe Patricia A. , Sinha Rajita , Swift Robert M. , Ciccocioppo Roberto , Leggio Lorenzo 
Published: January 2023

AbstractPreclinical and clinical work suggests that mifepristone (glucocorticoid receptor antagonist), may be a viable treatment for alcohol use disorder (AUD). The aim of this work was to translate our preclinical mifepristone study using yohimbine (α2 receptor antagonist) stress-induced reinstatement of alcohol-seeking to a clinical setting. This was a Phase 1/2, outpatient, cross-over, randomized, double-blind, placebo-controlled trial with non-treatment-seeking individuals with AUD (N=32). We investigated the safety, alcohol craving and consumption after oral administration of mifepristone (600mg daily for a week) in a human laboratory study comprised of administration of yohimbine in a cue-reactivity procedure and alcohol self-administration. Outcomes were assessed using Generalized Estimating Equations and mediation and moderation analyses assessed mechanisms of action and precision medicine targets. We did not observe serious adverse events related to the study drugs or study procedure and mild to moderate non-serious adverse events were reported by both study conditions. Also, there was no statistically-significant difference between the mifepristone and placebo in the hemodynamic response, alcohol subjective effects and pharmacokinetics parameters. Mifepristone significantly reduced alcohol craving and increased cortisol levels. Mifepristone-induced cortisol increase was not a mediator of alcohol craving. Moderation analysis with family history density of AUD (FHDA) and mifepristone, suggested that reduced craving was present in individuals withlow, but nothighFHDA. Mifepristone, compared to placebo, did not reduce alcohol consumption in the laboratory or in a naturalistic setting. This study successfully translated a preclinical paradigm to a human laboratory study confirming safety, tolerability and efficacy of mifepristone in an alcohol paradigm. Mediation analysis showed that the effect of mifepristone on craving was not related to mifepristone-induced increases in cortisol and moderation of FHDA suggested the importance of evaluating AUD endophenotypes for pharmacotherapies.Clinical trial registrationClinicaltrials.gov;NCT02243709IND/FDA121984, mifepristone and yohimbine (Holder: Haass-Koffler)
Leveraging global genomic sequencing data to estimate local variant dynamics
Authors: Susswein Zachary , Johnson Kaitlyn E. , Kassa Robel , Parastaran Mina , Peng Vivian , Wolansky Leo , Scarpino Samuel V. , Bento Ana I. 
Published: January 2023

ABSTRACTAccurate, reliable, and timely estimates of pathogen variant risk are essential for informing public health responses. Unprecedented rates of genomic sequencing have generated new insights into variant dynamics. However, estimating the fitness advantage of a novel variant shortly after emergence, or its dynamics more generally in data-sparse settings, remains difficult. This challenge is exacerbated in countries where surveillance is limited or intermittent. To stabilize inference in these data-sparse settings, we develop a hierarchical modeling approach to estimate variant fitness advantage and prevalence by pooling data across geographic regions. We demonstrate our method by reconstructing SARS-CoV-2 BA.5 variant emergence, and assess performance using retrospective, out-of-sample validation. We show that stable and robust estimates can be obtained even when sequencing data are sparse. Finally, we discuss how this method can inform risk assessment of novel variants and provide situational awareness on circulating variants for a range of pathogens and use-cases.
The Physical Basis of Osmosis
Authors: Manning Gerald S. , Kay Alan R. 
Published: January 2023

ABSTRACTOsmosis is an important force in all living organisms, yet the molecular basis of osmosis is widely misunderstood as arising from differences in water concentration in solutions of differing osmolarities. In 1923 Debye proposed a physical model for a semipermeable membrane that was hardly noticed at the time and slipped out of view. We show that Debye’s analysis of van’t Hoff’s law for osmotic equilibrium provides a consistent and plausible explanation for osmotic flow. A difference in osmolyte concentrations in solutions separated by a semipermeable membrane generates different pressures at the two water-membrane interfaces. Water is therefore driven through the membrane for exactly the same reason that pure water flows in response to an imposed hydrostatic pressure difference. In this paper we present the Debye model in both equilibrium and flow conditions. We point out its applicability regardless of the nature of the membrane with examples ranging from predominantly convective flow of water through synthetic membranes to purely diffusive flow of independent water molecules through a lipid bilayer and the flow of strongly interacting water molecules in single file across narrow protein channels.
Estimating long-term vaccine effectiveness against SARS-CoV-2 variants: a model-based approach
Authors: Hogan Alexandra B , Doohan Patrick , Wu Sean L , Mesa Daniela Olivera , Toor Jaspreet , Watson Oliver J , Winskill Peter , Charles Giovanni , Barnsley Gregory , Riley Eleanor M , Khoury David S , Ferguson Neil M , Ghani Azra C 
Published: January 2023

AbstractWith the ongoing evolution of the SARS-CoV-2 virus, variant-adapted vaccines are likely to be required. Given the challenges of conducting clinical trials against a background of widespread infection-induced immunity, updated vaccines are likely to be adopted based on immunogenicity data. We extended a modelling framework linking immunity levels and protection and fitted the model to vaccine effectiveness data from England for three vaccines (Oxford/AstraZeneca AZD1222, Pfizer-BioNTech BNT162b2, Moderna mRNA-1273) and two variants (Delta and Omicron) to predict longer-term effectiveness against mild disease, hospitalisation and death. We use these model fits to predict the effectiveness of the Moderna bivalent vaccine (mRNA1273.214) against the Omicron variant using immunogenicity data. Our results suggest sustained protection against hospitalisation and death from the Omicron variant over the first six months following boosting with the monovalent vaccines but a gradual waning to moderate protection after 1 year (median predicted vaccine effectiveness at 1 year in 65+ age group: AZD1222 38.9%, 95% CrI 31.8%-46.8%; BNT162b2 53.3%, 95% CrI 49.1%-56.9%; mRNA-1273 60.0%, 95% CrI 56.0%-63.6%). Furthermore, we predict almost complete loss of protection against mild disease over this period (mean predicted effectiveness at 1 year 7.8% for AZD1222, 13.2% for BNT162b2 and 16.7% for mRNA-1273). Switching to a second booster with the bivalent mRNA1273.214 vaccine against Omicron BA.1/2 is predicted to prevent nearly twice as many hospitalisations and deaths over a 1-year period compared to administering a second booster with the monovalent mRNA1273 vaccine. Ongoing production and administration of variant-specific vaccines are therefore likely to play an important role in protecting against severe outcomes from the ongoing circulation of SARS-CoV-2.
Diagnostic testing in people with primary ciliary dyskinesia: an international participatory study
Authors: Schreck Leonie D , Pedersen Eva SL , Cizeau Isabelle , Müller Loretta , Kruljac Catherine , Lucas Jane S , Goutaki Myrofora ,   COVID-PCD patient advisory group, Kuehni Claudia E 
Published: January 2023

AbstractDiagnostic tests are important in primary ciliary dyskinesia (PCD), a rare disease, to confirm the diagnosis and characterize the disease. We compared diagnostic tests for PCD between countries worldwide, assessed whether people with PCD recall their tests, and identified factors associated with the use of tests. We used cross-sectional data from COVID-PCD—an international participatory cohort study collecting information directly from people with PCD. The baseline questionnaire inquired about tests used for PCD diagnosis. Using logistic regression, we investigated factors associated with measurement of nasal nitric oxide (nNO), biopsy for electron or video microscopy, and genetic testing. We included data from 747 participants (60% females) from 49 countries worldwide with median age 27 (interquartile range 12–44). Most (92%) reported diagnostic tests for PCD. Participants reported measurements of nNO (342; 49%), biopsy samples (561; 75%), and genetic tests (435; 58%). The reported use of individual tests, such as genetics, varied between countries from 38% in Switzerland to 68% in North America. Participant recall of test type also differed between countries with lowest recall in Switzerland. One-third (232; 36%) of participants reported all three tests (nNO, biopsy, and genetics). Recently diagnosed people reported more tests [nNO odds ratio (OR) 2.2, 95% Confidence Interval (CI) 1.5–3.2; biopsy OR 3.2, 95%CI 2.1–4.9; genetics OR 4.7, 95%CI 3.2–6.9] and those with situs abnormalities fewer tests (nNO OR 0.5, 95%CI 0.4–0.7; biopsy OR 0.5, 95%CI 0.4–0.8; genetics OR 0.7, 95%CI 0.5–0.94). Our results indicate PCD diagnostic testing differed widely around the world and many patients received incomplete diagnostic work-up based only on clinical features or single tests. People diagnosed long ago and those with situs abnormalities possibly benefit from supplementary testing to refine their diagnosis as a prerequisite for personalized medicine.
A CLOSER LOOK AT INDIRECT CAUSES OF DEATH AFTER HURRICANE MARIA USING A SEMIPARAMETRIC MODEL
Authors: Lugo Oscar , Rivera Roberto 
Published: January 2023

AbstractThe Covid-19 pandemic as well as other recent natural emergencies have put the spotlight on emergency planning. One important aspect is that natural disasters or emergencies often lead to indirect deaths and studying the behavior of indirect deaths during emergencies can guide emergency planning. While many studies have implied a large number of indirect deaths in Puerto Rico due to Hurricane Maria; the specific causes of these deaths have not being carefully studied. In this paper, we use a semiparametric model and mortality data to evaluate cause of death trends. Our model adjusts for cause of death effect potentially varying over time while also inferring on how long excess deaths occurred. From September 2017 to March 2018, after adjusting for intra-annual variability and population displacement, we find evidence of significant excess deaths due to Alzheimer’s/Parkinson, heart disease, sepsis, diabetes, renal failure, and pneumonia & influenza. In contrast, for the same time period we find no evidence of significant excess deaths due to cancer, hypertension, respiratory diseases, cerebrovascular disease, suicide, homicide, falling accidents and traffic accidents.
Consistency across multi-omics layers in a drug-perturbed gut microbial community
Authors: Wuyts Sander , Alves Renato , Zimmermann-Kogadeeva Maria , Nishijima Suguru , Blasche Sonja , Driessen Marja , Geyer Philipp E. , Hercog Rajna , Kartal Ece , Maier Lisa , Müller Johannes B. , Santamarina Sarela Garcia , Schmidt Thomas Sebastian B. , Sevin Daniel C. , Telzerow Anja , Treit Peter V. , Wenzel Tobias , Typas Athanasios , Patil Kiran R. , Mann Matthias , Kuhn Michael , Bork Peer 
Published: January 2023

AbstractMulti-omics analyses are increasingly employed in microbiome studies to obtain a holistic view of molecular changes occurring within microbial communities exposed to different conditions. However, it is not always clear to what extent each omics data type contributes to our understanding of the community dynamics and whether they are concordant with each other. Here we map the molecular response of a synthetic community of 32 human gut bacteria to three non-antibiotic drugs by using five omics layers, namely 16S rRNA gene profiling, metagenomics, metatranscriptomics, metaproteomics, and metabolomics. Using this controlled setting, we find that all omics methods with species resolution in their readouts are highly consistent in estimating relative species abundances across conditions. Furthermore, different omics methods complement each other in their ability to capture functional changes in response to the drug perturbations. For example, while nearly all omics data types captured that the antipsychotic drug chlorpromazine selectively inhibits Bacteroidota representatives in the community, the metatranscriptome and metaproteome suggested that the drug induces stress responses related to protein quality control and metabolomics revealed a decrease in polysaccharide uptake, likely caused by Bacteroidota depletion. Taken together, our study provides insights into how multi-omics datasets can be utilised to reveal complex molecular responses to external perturbations in microbial communities.
The prospect of universal coronavirus immunity: a characterization of reciprocal and non-reciprocal T cell responses against SARS-CoV2 and common human coronaviruses
Authors: Soni Mithil , Migliori Edoardo , Fu Jianing , Assal Amer , Chan Hei Ton , Pan Jian , Khatiwada Prabesh , Ciubotariu Rodica , May Michael S. , Pereira Marcus , De Giorgi Valeria , Sykes Megan , Mapara Markus Y , Muranski Pawel 
Published: January 2023

AbstractT cell immunity plays a central role in clinical outcomes of Coronavirus Infectious Disease 2019 (COVID-19). Therefore, T cell-focused vaccination or cellular immunotherapy might provide enhanced protection for immunocompromised patients. Pre-existing T cell memory recognizing SARS-CoV2 antigens antedating COVID-19 infection or vaccination, may have developed as an imprint of prior infections with endemic non-SARS human coronaviruses (hCoVs) OC43, HKU1, 229E, NL63, pathogens of “common cold”. In turn, SARS-CoV2-primed T cells may recognize emerging variants or other hCoV viruses and modulate the course of subsequent hCoV infections. Cross-immunity between hCoVs and SARS-CoV2 has not been well characterized. Here, we systematically investigated T cell responses against the immunodominant SARS-CoV2 spike, nucleocapsid and membrane proteins and corresponding antigens from α- and β-hCoVs among vaccinated, convalescent, and unexposed subjects. Broad T cell immunity against all tested SARS-CoV2 antigens emerged in COVID-19 survivors. In convalescent and in vaccinated individuals, SARS-CoV2 spike-specific T cells reliably recognized most SARS-CoV2 variants, however cross-reactivity against theomicronvariant was reduced by approximately 50%. Responses against spike, nucleocapsid and membrane antigens from endemic hCoVs were more extensive in COVID-19 survivors than in unexposed subjects and displayed cross-reactivity between α- and β-hCoVs. In some, non-SARS hCoV-specific T cells demonstrated a prominent non-reciprocal cross-reactivity with SARS-CoV2 antigens, whereas a distinct anti-SARS-CoV2 immunological repertoire emerged post-COVID-19, with relatively limited cross-recognition of non-SARS hCoVs. Based on this cross-reactivity pattern, we established a strategy forin-vitroexpansion of universal anti-hCoV T cells for adoptive immunotherapy. Overall, these results have implications for the future design of universal vaccines and cell-based immune therapies against SARS- and non-SARS-CoVs.
Calling pangenes from plant genome alignments confirms presence-absence variation
Authors: Contreras-Moreira Bruno , Saraf Shradha , Naamati Guy , Casas Ana M. , Amberkar Sandeep S. , Flicek Paul , Jones Andrew R. , Dyer Sarah 
Published: January 2023

ABSTRACTConsistent gene annotation in crops is becoming harder as genomes for new cultivars are frequently published. Gene sets from recently sequenced accessions have different gene identifiers to those on the reference accession, and might be of higher quality due to technical advances. For these reasons there is a need to define pangenes, which represent all known syntenic orthologues for a gene model and can be linked back to the original annotation sources. A pangene set effectively summarizes our current understanding of the coding potential of a crop and can be used to inform gene model annotation in new cultivars. Here we present an approach (get_pangenes) to identify and analyze pangenes that is not biased towards the reference annotation. The method involves computing Whole Genome Alignments (WGA), which are used to estimate gene model overlaps. After a benchmark onArabidopsis, rice, wheat and barley datasets, we find that minimap2 performs better than the GSAlign WGA algorithm. Our results show that pangenes recapitulate known phylogeny-based orthologies while adding extra core gene models in rice. More importantly, get_pangenes can also produce clusters of genome segments (gDNA) that overlap with gene models annotated in other cultivars. By lifting-over CDS sequences, gDNA clusters can help refine gene models across individuals and confirm or reject observed gene Presence-Absence Variation. A collection of flowering-related genes from the barley pangenome are discussed in detail. Documentation and source code are available athttps://github.com/Ensembl/plant-scripts.
The genetic architecture of the human skeletal form
Authors: Kun Eucharist , Javan Emily M. , Smith Olivia , Gulamali Faris , de la Fuente Javier , Flynn Brianna I. , Vajrala Kushal , Trutner Zoe , Jayakumar Prakash , Tucker-Drob Elliot M. , Sohail Mashaal , Singh Tarjinder , Narasimhan Vagheesh M. 
Published: January 2023

AbstractThe human skeletal form underlies our ability to walk on two legs, but unlike standing height, the genetic basis of limb lengths and skeletal proportions is less well understood. Here we applied a deep learning model to 31,221 whole body dual-energy X-ray absorptiometry (DXA) images from the UK Biobank (UKB) to extract 23 different image-derived phenotypes (IDPs) that include all long bone lengths as well as hip and shoulder width, which we analyzed while controlling for height. All skeletal proportions are highly heritable (∼40-50%), and genome-wide association studies (GWAS) of these traits identified 179 independent loci, of which 102 loci were not associated with height. These loci are enriched in genes regulating skeletal development as well as associated with rare human skeletal diseases and abnormal mouse skeletal phenotypes. Genetic correlation and genomic structural equation modeling indicated that limb proportions exhibited strong genetic sharing but were genetically independent of width and torso proportions. Phenotypic and polygenic risk score analyses identified specific associations between osteoarthritis (OA) of the hip and knee, the leading causes of adult disability in the United States, and skeletal proportions of the corresponding regions. We also found genomic evidence of evolutionary change in arm-to-leg and hip-width proportions in humans consistent with striking anatomical changes in these skeletal proportions in the hominin fossil record. In contrast to cardiovascular, auto-immune, metabolic, and other categories of traits, loci associated with these skeletal proportions are significantly enriched in human accelerated regions (HARs), and regulatory elements of genes differentially expressed through development between humans and the great apes. Taken together, our work validates the use of deep learning models on DXA images to identify novel and specific genetic variants affecting the human skeletal form and ties a major evolutionary facet of human anatomical change to pathogenesis.
Experiments in micro-patterned model membranes support the narrow escape theory
Authors: Meiser Elisabeth , Mohammadi Reza , Vogel Nicolas , Holcman David , Fenz Susanne F. 
Published: January 2023

AbstractThe narrow escape theory (NET) predicts the escape time distribution of Brownian particles confined to a domain with reflecting borders except for one small window. Applications include molecular activation events in cell biology and biophysics. Specifically, the mean first passage timecan be analytically calculated from the size of the domain, the escape window, and the diffusion coefficient of the particles. In this study, we systematically tested the NET in a disc by variation of the escape opening. Our model system consisted of micro-patterned lipid bilayers. For the measurement of, we imaged diffusing fluorescently-labeled lipids using single-molecule fluorescence microscopy. We overcame the lifetime limitation of fluorescent probes by re-scaling the measured time with the fraction of escaped particles. Experiments were complemented by matching stochastic numerical simulations. To conclude, we confirmed the NET predictionin vitroandin silicofor the disc geometry in the limit of small escape openings.Significance StatementIn the biological context of a cell, a multitude of reactions are facilitated by diffusion. It is astonishing how Brownian motion as a cost-efficient but random process is mediating especially fast reactions. The formalism of the narrow escape theory is a tool to determine the average timescale of such processes to be completed (mean first passage time, MFPT) from the reaction space and diffusion coefficient. We present the systematic proof of this formalism experimentally in a bio-mimetic model system and by random walk simulations. Further, we demonstrate a straightforward solution to determine the MFPT from incomplete experimental traces. This will be beneficial for measurements of the MFPT, reliant on fluorescent probes, that have prior been inaccessible.
Stepwise molecular specification of excitatory synapse diversity on a target neuron
Authors: Paul Maëla A. , Sigoillot Séverine M. , Marti Léa , Delagrange Marine , Mailly Philippe , Selimi Fekrije 
Published: January 2023

SummaryBrain function relies on the generation of a large variety of morphologically and functionally diverse, but specific, neuronal synapses. Here, we show that, initially, synapse formation on a common target neuron, the cerebellar Purkinje cells, involves a presynaptic secreted protein common for all types of excitatory inputs. The molecular program then evolves only in one of the inputs with the additional expression of a combination of presynaptic secreted proteins that specify the mature pattern of connectivity on the target. These results show that some inputs actively and gradually specify their synaptic molecular identity while others rely on the “original code”. Thus, the molecular specification of excitatory synapses, crucial for proper circuit function, is acquired in a stepwise manner during mouse postnatal development and obeys input-specific rules.
Uncursing winner’s curse: on-line monitoring of directed evolution convergence
Authors: Nemoto Takahiro , Ocari Tommaso , Planul Arthur , Tekinsoy Muge , Zin Emilia A. , Dalkara Deniz , Ferrari Ulisse 
Published: January 2023

AbstractDirected evolution (DE) is a versatile protein-engineering strategy, successfully applied to a range of proteins, including enzymes, antibodies, and viral vectors. However, DE can be time-consuming and costly, as it typically requires many rounds of selection to identify desired mutants. Next-generation sequencing allows monitoring of millions of variants during DE and can be leveraged to reduce the number of selection rounds. Unfortunately the noisy nature of the sequencing data impedes the estimation of the performance of individual variants. Here, we propose ACIDES that combines statistical inference and in-silico simulations to improve performance estimation in DE by providing accurate statistical scores. We tested ACIDES first on a novel random-peptide-insertion experiment and then on several public datasets from DE of viral vectors and phage-display. ACIDES allows experimentalists to reliably estimate variant performanceon the flyand can aid protein engineering pipelines in a range of applications, including gene therapy.