bluuebunny/crossref_metadata_2025_split huggingface dataset:
Centrin-deficient Leishmania mexicana confers protection against Old World visceral leishmaniasis
Authors: Karmakar Subir , Volpedo Greta , Zhang Wen-Wei , Lypaczewski Patrick , Ismail Nevien , Oliveira Fabiano , Oristian James , Meneses Claudio , Gannavaram Sreenivas , Kamhawi Shaden , Hamano Shinjiro , Valenzuela Jesus G. , Matlashewski Greg , Satoskar Abhay R , Dey Ranadhir , Nakhasi Hira L. 
Published: June 2022

ABSTRACTLeishmaniasis is one of the top neglected tropical diseases with significant morbidity and mortality in low and middle-income countries (LMIC). However, this disease is also spreading in the developed world. Currently, there is a lack of effective strategies to control this disease. Vaccination can be an effective measure to control leishmaniasis and has the potential to achieve disease elimination. Recently, we have generated centrin gene-deleted new world L. mexicana (LmexCen-/-) parasites using CRISPR/Cas9 and showed that they protect mice against a homologous L. mexicana infection that causes cutaneous disease. In this study, we tested whether LmexCen-/- parasites can also protect against visceral leishmaniasis caused by L. donovani in a hamster model. We show that immunization with LmexCen-/- parasites is safe and does not cause lesions. Furthermore, such immunization conferred protection against visceral leishmaniasis caused by a needle-initiated L. donovani challenge, as indicated by a significant reduction in the parasite burdens in the spleen and liver and lack of mortality. Similar control of parasite burden was also observed against a sand fly mediated L. donovani challenge. Importantly, immunization with LmexCen-/- down-regulated the Th2 response as indicated by a significant reduction in the anti-inflammatory cytokines such as IL-10 and IL-4 and increased pro-inflammatory cytokine IFN-γ resulting in higher IFN-γ/IL-10 and IFN-γ/IL4 ratios compared to non-immunized animals. This contrasts with our studies with L. major centrin deletion mutants that showed a dominant Th1 response compared to L. major wild-type infection suggesting the divergent mechanisms of protection in the two mutant parasites. LmexCen-/- immunization resulted in long-lasting protection against L. donovani infection. Further, since the efficacy of LmCen-/- has not been determined against Leishmania strains prevalent in the Americas, LmexCen-/- may be a viable alternative. Taken together, our study demonstrates that immunization with LmexCen-/- parasites is safe and efficacious against old world visceral leishmaniasis.
Prioritizing transcription factor perturbations from single-cell transcriptomics
Authors: Singh Rohit , Li Joshua Shing Shun , Tattikota Sudhir Gopal , Liu Yifang , Xu Jun , Hu Yanhui , Perrimon Norbert , Berger Bonnie 
Published: June 2022

SummaryThe explosive growth of regulatory hypotheses from single-cell datasets demands accurate prioritization of hypotheses forin vivovalidation. However, current computational methods emphasize overall accuracy in regulatory network reconstruction rather than prioritizing a limited set of causal transcription factors (TFs) that can be feasibly tested. We developed Haystack, a hybrid computational-biological algorithm that combines active learning and the concept of optimal transport theory to nominate and validate high-confidence causal hypotheses. Our novel approach efficiently identifies and prioritizes transient but causally-active TFs in cell lineages. We applied Haystack to single-cell observations, guiding efficient and cost-effectivein vivovalidations that reveal causal mechanisms of cell differentiation inDrosophilagut and blood lineages. Notably, all the TFs shortlisted for the final, imaging-based assays were validated as drivers of differentiation. Haystack’s hypothesis-prioritization approach will be crucial for validating concrete discoveries from the increasingly vast collection of low-confidence hypotheses from single-cell transcriptomics.
No Ramp Needed: Spandrels, Statistics, and a Slippery Slope
Authors: Sejour Richard , Leatherwood Janet , Yurovsky Alisa , Futcher Bruce 
Published: June 2022

SummaryPreviously, Tuller et al. found that the first 30 to 50 codons of the genes of yeast and other eukaryotes are slightly enriched for rare codons, so are presumably translated somewhat slowly. They argued, based on informatics, that this initial slow translation “ramp” was adaptive; and increased efficiency of translation by queuing ribosomes to prevent collisions. Today, the translational speeds of different codons are known, and indeed rare codons are translated slowly. We re-examined the slow translation ramp. We confirm the finding that 5’ regions are enriched for rare codons. However, we also find that the 5’ ends of yeast genes are poorly conserved in evolution, suggesting that they are unstable and turn over relatively rapidly. When a new 5’ end formsde novo, it is likely to include codons that would otherwise be rare. Because evolution has had a relatively short time to select against these codons, 5’ ends are typically slightly enriched for rare, slow codons. Opposite to the expectation of Tuller et al., we show by direct experiment that genes with slowly translated codons at the 5’ end are expressed relatively poorly, and substituting faster codons improves expression. Further informatic studies suggest that for natural genes, slow 5’ ends are correlated with poor gene expression, opposite to the expectation of Tuller et al. Thus we conclude that slow 5’ translation is a “spandrel”; it is a non-adaptive consequence of something else, in this case the turnover of 5’ ends in evolution, and it does not improve translation.HighlightThe 5’ ends of yeast genes are unstable over evolutionary time, enriching for rare codons, slowing translation; slow initial translation does not enhance expression.
Increasing Muscle Hypertrophy with a Natural Product Designed to Inhibit SIRT1
Authors: Pathak Suraj , Wallace Marita , Athalye Sonia , Schenk Simon , Langer Henning T. , Baar Keith 
Published: June 2022

AbstractMuscle mass and strength are predictors of longevity. We have previously identified a series of molecular brakes that slow muscle growth in response to stress. One potential stress that we hypothesized would limit muscle growth is caloric stress through the activation of SIRT1. We therefore identified natural product inhibitors of SIRT1 and tested their effects on load-induced increases in muscle fiber cross-sectional area (fCSA) using an incomplete factorial design. Supplying varying amounts of three natural products for the full two-week period of overload resulted in increases in fCSA that varied from −2 to 113%. Using these data, we produced a model that predicted the optimal combination and concentration of each natural product and validated this model in a separate cohort of animals. Following two weeks of overload, fCSA in the optimal group increased 62%, whereas in the placebo fCSA increased only 3%. The greater increase in fCSA was not the result of an increase in ribosomal mass. In fact, the optimal group showed significantly less of the 5⍰ external transcribed spacer, a marker of 47S ribosomal RNA synthesis, and a trend for decreased total RNA. In spite of the lower ribosome mass, the increase in protein synthesis was similar, suggesting that the natural product cocktail may be increasing ribosomal efficiency rather than capacity. These data suggest that inhibition of SIRT1, together with exercise, may be useful in increasing muscle fCSA.
The disconnect2 mutation disrupts the tjp1b gene that is required for electrical synapse formation
Authors: Michel Jennifer Carlisle , Lasseigne Abagael M. , Marsh Audrey J. , Miller Adam C. 
Published: June 2022

AbstractTo investigate electrical synapse formation in vivo we used forward genetics to disrupt genes affecting Mauthner cell electrical synapses in larval zebrafish. We identify the disconnect2 (dis2) mutation for its failure to localize neural gap junction channels at electrical synapses. We mapped this mutation to chromosome 25 and identified a splice-altering mutation in the tjp1b gene. We demonstrated that the dis2 mutation disrupts tjp1b function using complementation analysis with CRISPR generated mutants. We conclude that the dis2 mutation disrupts the tjp1b gene that is required for electrical synapse formation.DescriptionNeural networks are circuits of neurons wired together during development that provide an animal with specialized behavioral outputs. Dedicated adhesions called neuronal synapses create sites of communication between neurons and can be categorized as either electrical or chemical. This work identifies a new mutation in tjp1b that is shown to be required for electrical synapse formation.
Electrical synapse formation is differentially regulated by distinct isoforms of a postsynaptic scaffold
Authors: Michel Jennifer Carlisle , Grivette Margaret M. B. , Harshfield Amber T. , Huynh Lisa , Komons Ava P. , Loomis Bradley , McKinnis Kaitlan , Miller Brennen T. , Nguyen Ethan Q. , Huang Tiffany W. , Lauf Sophia , Michel Elias S. , Michel Mia E. , Marsh Audrey J. , Kaye Lila E. , Lasseigne Abagael M. , Lukowicz-Bedford Rachel M. , Farnsworth Dylan R. , Martin E. Anne , Miller Adam C. 
Published: June 2022

AbstractElectrical synapses are neuronal gap junction (GJ) channels associated with a macromolecular complex called the electrical synapse density (ESD), which regulates development and dynamically modifies electrical transmission. However, the proteomic makeup and molecular mechanisms utilized by the ESD that direct electrical synapse formation are not well understood. Using the Mauthner cell of zebrafish as a model, we previously found that the intracellular scaffolding protein ZO1b is a member of the ESD, localizing postsynaptically, where it is required for GJ channel localization, electrical communication, neural network function, and behavior. Here, we show that the complexity of the ESD is further diversified by the genomic structure of the ZO1b gene locus. The ZO1b gene is alternatively initiated at three transcriptional start sites resulting in isoforms with unique N-termini that we call ZO1b-Alpha, -Beta, and - Gamma. We demonstrate that ZO1b-Beta and ZO1b-Gamma are broadly expressed throughout the nervous system and localize to electrical synapses. By contrast, ZO1b-Alpha is expressed mainly non-neuronally and is not found at synapses. We generate mutants in all individual isoforms, as well as double mutant combinationsin cison individual chromosomes, and find that ZO1b-Beta is necessary and sufficient for robust GJ channel localization. ZO1b-Gamma, despite its localization to the synapse, plays an auxiliary role in channel localization. This study expands the notion of molecular complexity at the ESD, revealing that an individual genomic locus can contribute distinct isoforms to the macromolecular complex at electrical synapses. Further, independent scaffold isoforms have differential contributions to developmental assembly of the interneuronal GJ channels. We propose that ESD molecular complexity arises both from the diversity of unique genes and from distinct isoforms encoded by single genes. Overall, ESD proteomic diversity is expected to have critical impacts on the development, structure, function, and plasticity of electrical transmission.
A Note on the Effects of Digital Primary Health Care on Utilization: Concepts, Evidence, and Descriptive Analysis of Non-Experimental Register Data from Sweden
Authors: Ekman Björn , Thulesius Hans , Wilkens Jens , Arvidsson Eva 
Published: June 2022

AbstractDigital technologies for health care may lower costs while enhancing access to services. However, concerns have been raised that digital care may lead to over-use of services and not be as effective as in-person visits. Previous studies have found varying effects across different contexts, study designs, and outcome measures. This study contributes to the emerging evidence on the effects of digital care on primary care utilization by developing a conceptual model for primary care use and then comparing the effects of digital primary care with in-person visits and telephone contacts. Register data from Sweden over a two-year period (2017-2018) in a sample of patients diagnosed with an infection are used to describe the effects. Findings show that the majority of patients require a single consultation across either model of care. A relatively small share of patients makes multiple consultations per episode of care both across and within models of care. Compared with in-person visits and telephone contacts, digital care is associated with fewer consultations per episode of care and involve lower rates of laboratory tests and antibiotic prescriptions. Digital care is provided by a physician to a larger extent compared with the other models of care in the current sample. Further analysis will be conducted to establish any causal effects of digital primary contacts on identified outcomes.
Retrospective analysis of SARS-CoV-2 omicron invasion over delta in French regions in 2021-22: a status-based multi-variant model
Authors: Haschka Thomas , Vergu Elisabeta , Roche Benjamin , Poletto Chiara , Opatowski Lulla 
Published: June 2022

AbstractBackgroundSARS-CoV-2 is a rapidly spreading disease affecting human life and the economy on a global scale. The disease has caused so far more then 5.5 million deaths. The omicron outbreak that emerged in Botswana in the south of Africa spread around the globe at further increased rates, and caused unprecedented SARS-CoV-2 infection incidences in several countries. At the start of December 2021 the first omicron cases were reported in France.MethodsIn this paper we investigate the contagiousness of this novel variant relatively to the delta variant that was also in circulation in France at that time. Using a dynamic multi-variant model accounting for cross-immunity through a status-based approach, we analyze screening data reported by Santé Publique France over 13 metropolitan French regions between 1st of December 2021 and the 30th of January 2022. During the investigated period, the delta variant was replaced by omicron in all metropolitan regions in approximately three weeks. The analysis conducted retrospectively allows us to consider the whole replacement time window and compare regions with different times of omicron introduction and baseline levels of variants’ transmission potential. As large uncertainties regarding cross-immunity among variants persist, uncertainty analyses were carried out to assess its impact on our estimations.ResultsAssuming that 80% of the population was immunized against delta, a cross delta/omicron cross-immunity of 25% and omicron generation time was 3.5 days, the relative strength of omicron to delta, expressed as the ratio of their respective reproduction rates,, was found to range between 1.51 and 1.86 across regions. Uncertainty analysis on epidemiological parameters led ranging over 1.57-2.13 when averaged over the metropolitan French regions, weighting by population size.ConclusionsUpon introduction, omicron spread rapidly through the French territory and showed a high fitness relative to delta. We documented considerable geographical heterogeneities on the spreading dynamics. The historical reconstruction of variant emergence dynamics provide valuable ground knowledge to face future variant emergence events.
Assessment of Regional Body Composition, Physical Function and Sarcopenia among Peruvian women aging with HIV
Authors: Cabrera Diego M. , Cornejo Mijahil P. , Pinedo Yvett , Garcia Patricia J. , Hsieh Evelyn 
Published: June 2022

ABSTRACTBackgroundManagement of chronic conditions and optimization of overall health has become a primary global health concern in the care of people living with HIV, particularly in lower-and-middle income countries where infrastructure for chronic disease management may be fragmented. Alterations in body composition (BC) can reflect important changes in musculoskeletal health, particularly among populations at risk for developing fat and muscle redistribution syndromes, such as HIV-infected women. We aimed to explore this issue among Peruvian women aging with HIV.MethodsCross-sectional study among HIV-infected and uninfected Peruvian women aged ≥40. Dual X-ray absorptiometry was used to measure trunk and limb lean mass (LM) and fat mass (FM). Physical performance was assessed with the Short Physical Performance Battery (SPPB) and physical strength with a dynamometer. Sarcopenia was assessed based upon EWGSOP criteria. We used linear regression to model associations between BC, sarcopenia and physical scores.Results104 HIV-infected and 212 uninfected women were enrolled with a mean age of 55.1±8.8 years. Among the HIV-infected group, years since diagnosis was 11.8±6 and all were on antiretroviral treatment. Mean SPPB score was 9.9 vs 10.8 (p<0.001) between both groups. Sarcopenia spectrum was found in 25.9% of HIV-infected and 23.1% of uninfected women. In multivariate regression analysis, trunk FM and older age were negatively correlated with physical performance among HIV-infected women. An increased percentage of severe sarcopenia was found among the HIV-infected, although our study was not specifically powered for this comparison.ConclusionsHIV-infected women had significantly lower SPPB scores compared to women without HIV, and trunk FM and upper limb LM were independent predictors for the tests described. Prospective studies are needed in Latin America & the Caribbean to identify individuals at high risk for declines in physical function, and inform prevention guidelines.
Estimating the effect size of a hidden causal factor between SNPs and a continuous trait: a mediation model approach
Authors: Ding Zhuoran , Ritchie Marylyn D. , Voight Benjamin F. , Hwang Wei-Ting 
Published: June 2022

AbstractBackgroundObservational studies and Mendelian randomization experiments have been used to identify many causal factors for complex traits in humans. Given a set of causal factors, it is important to understand the extent to which these causal factors explain some, all, or none of the genetic heritability, as measured by single-nucleotide polymorphisms (SNPs) that are associated with the trait. Using the mediation model framework with SNPs as the exposure, a trait of interest as the outcome, and the known causal factors as the mediators, we hypothesize that any unexplained association between the SNPs and the outcome trait is mediated by an additional unobserved, hidden causal factor.ResultsWe propose a method to infer the effect size of this hidden mediating causal factor on the outcome trait by utilizing the estimated associations between a continuous outcome trait, the known causal factors, and the SNPs. The proposed method consists of three steps and, in the end, implements Markov chain Monte Carlo to obtain a posterior distribution for the hidden mediator’s effect size. We evaluate our proposed method via extensive simulations and show that when the model assumptions hold, our method estimates the effect size of the hidden mediator well and controls type I error rate if the hidden mediator does not exist.. In addition, we apply the method to the UK Biobank data and find that a potential hidden mediator for waist-hip ratio exists in the European population, and the hidden mediator has a large effect size relatively to the effect size of the known mediator BMI.ConclusionsWe develop a framework to infer the effect of potential, hidden mediators influencing complex traits. This framework can begin to place boundaries on unexplained risk factors contributing to complex traits.
Rapid non-destructive method to phenotype stomatal traits
Authors: Pathoumthong Phetdalaphone , Zhang Zhen , Roy Stuart J. , El Habti Abdeljalil 
Published: June 2022

AbstractBackgroundStomata are tiny pores on the leaf surface that are central to gas exchange. Stomatal number, size and aperture are key determinants of plant transpiration and photosynthesis, and variation in these traits can affect plant growth and productivity. Current methods to screen for stomatal phenotypes are tedious and not high throughput. This impedes research on stomatal biology and hinders efforts to develop resilient crops with optimised stomatal patterning. We have developed a rapid non-destructive method to phenotype stomatal traits in four species: wheat, rice, tomato and Arabidopsis.ResultsThe method consists of two steps. The first is the non-destructive capture of images of the leaf surface from plants in their growing environment using a handheld microscope; a process which only takes a few seconds compared to minutes for other methods. The second is to analyse stomatal features using a machine learning model that automatically detects, counts and measures stomatal number, size and aperture. The accuracy of the machine learning model in detecting stomata ranged from 76% to 99%, depending on the species, with a high correlation between measures of number, size and aperture between measurements using the machine learning models and by measuring them manually. The rapid method was applied to quickly identify contrasting stomatal phenotypes.ConclusionsWe developed a method that combines rapid non-destructive imaging of leaf surfaces with automated image analysis. The method provides accurate data on stomatal features while significantly reducing time for data acquisition and analysis. It can be readily used to phenotype stomata in large populations in the field and in controlled environments.
Host age-dependent evolution of a plant RNA virus
Authors: Melero Izan , González Rubén , Elena Santiago F. 
Published: June 2022

SummaryViruses are obligate pathogens that entirely rely on their host resources to complete their infectious cycle. The availability of such resources depends upon external and internal factors, being host age one of the most relevant ones. The interplay between host age and virus evolution has not been thoroughly studied in plants. Here, we have used the Arabidopsis thaliana - turnip mosaic virus (TuMV) pathosystem to study plant-virus interactions and virus evolution at three different host ages: vegetative (juvenile), bolting (transition) and reproductive (mature) stages. After infecting plants with a naïve and a well-adapted TuMV isolates, we observed that the older the host the faster and more severe the infections were. The same trend was observed for several other viruses. Thereafter, we experimentally evolved lineages of the naïve and the well-adapted TuMV isolates in plants from each of the three developmental stages. All evolved viruses enhanced their infection phenotypes, being this increase more intense on viruses evolved in younger hosts. The genomic changes of the evolved viral lineages revealed mutation patterns that strongly depended on the founder viral isolate as well as on the age of the host wherein the lineages evolved.