bluuebunny/crossref_metadata_2025 huggingface dataset:
Deciphering the Soybean Rust Arsenal: Effectorome Studies and Host-Pathogen Interaction (HPI) network inPhakopsora pachyrhiziandGlycine maxPathosystem
Authors: Oliveira E.S. , Pereira W.A.
Published: June 2024

Asian soybean rust (ASR), cause by the fungal pathogenPhakopsora pachyrhizi, stands out as the paramount menace to soybean cultivation, resulting in staggering yield decreases that can surpass 90%. Despite extensive endeavors, the development of cultivars endowed with comprehensive or enduring resistance against the myriad pathotypes remains elusive, thereby underscoring the imperative for pioneering improvement tactics. Fungal effectors, orchestrating the infiltration and colonization of hosts, constitute pivotal determinants in the infection cascade, thus emerging as prime targets for unraveling pathogenicity mechanisms. In this investigation, we endeavored to integrate effectoromics analysis with host-pathogen protein-protein interaction networks (HPPI) to delineate the modus operandi ofP. pachyrhizieffectors in subverting plant host immunity. By meticulously delineating the repertoire of predicted effectors and prognosticating protein-protein interactions between effectors and soybean target proteins, we discerned pivotal candidate targets. Notably, a repertoire of 324 host proteins was anticipated to engage in interactions with 21 effectors, predominantly hailing from the Lysophospholipase (LysoPLs) cohort. Particularly conspicuous was the identification of a robust effector candidate (PhapaK8108_7408047) implicated in the targeting of 171 soybean proteins. Its functional involvement in RNA splicing, chromatin organization, histone deacetylation, protein stabilization, and protein folding signifies its pivotal role in the infectious process. Furthermore, our endeavor encompassed the categorization of effectors into carbohydrate-active families, illuminating the prominence of Carbohydrate esterases family 12, primarily catalyzing cellulose and xylan degradation. By amalgamating these multifaceted methodologies, our study provides invaluable insights leading to the formulation of more effective ASR molecular strategies, demonstrating its relevance and innovation in the fields of plant pathology and molecular biology.
Epineuston vortex recapture enhances thrust in tiny water skaters
Authors: Rohilla Pankaj , O’Neil Johnathan N. , Bose Chandan , Ortega-Jimenez Victor M. , Choi Daehyun , Bhamla Saad
Published: June 2024

Vortex recapture underpins the exceptional mobility of nature’s finest fliers and swimmers. Utilized by agile fruit flies and efficient jellyfish, this phenomenon is well-documented in bulk fluids. Despite extensive studies on the neuston—a vital fluidic interface where diverse life forms interact between air and water—neuston vortical hydrodynamics remain unexplored. We investigate epineuston (on water) vortical hydrodynamics inMicrovelia americana, one of the smallest and fastest water striders, skating at 50 BL/s (15 cm/s). Their middle legs shed counter-rotating vortices, re-energized by hind legs, demonstrating epineuston vortex recapture. High-speed imaging, particle imaging velocimetry, physical models, and CFD simulations show re-energization increases thrust by creating positive pressure at the hind tarsi, acting as a virtual wall. This vortex capture is facilitated by the tripod gait, leg morphology, and precise spatio-temporal placement of the hind tarsi during the power stroke. Our study extends vortex recapture principles from bulk fluids to the neuston, offering insights into efficient epineuston locomotion, where surface tension and capillary waves challenge movement. Understanding epineuston vortex hydrodynamics can guide the development of energy-efficient microrobots to explore the planet’s neuston niches, critical frontlines of climate change and pollution.
Bidirectional valence coding in amygdala intercalated clusters: A neural substrate for the opponent-process theory of motivation
Authors: Hagihara Kenta M. , Lüthi Andreas
Published: June 2024

Processing emotionally meaningful stimuli and eliciting appropriate valence-specific behavior in response is a critical brain function for survival. Thus, how positive and negative valence are represented in neural circuits and how corresponding neural substrates interact to cooperatively select appropriate behavioral output are fundamental questions. In previous work, we identified that two amygdala intercalated clusters show opposite response selectivity to fear- and anxiety-inducing stimuli – negative valence (Hagihara et al. 2021). Here, we further show that the two clusters also exhibit distinctly different representations of stimuli with positive valence, demonstrating a broader role of the amygdala intercalated system beyond fear and anxiety. Together with the mutually inhibitory connectivity between the two clusters, our findings suggest that they serve as an ideal neural substrate for the integrated processing of valence for the selection of behavioral output.
Covert actions of epidural stimulation on spinal locomotor circuits
Authors: Garcia-Ramirez D. Leonardo , McGrath Jenna R. , Ha Ngoc T. , Wheel Jaimena H. , Atoche Sebastian J. , Yao Lihua , Stachowski Nicholas J. , Giszter Simon F. , Dougherty Kimberly J.
Published: June 2024

Spinal circuitry produces the rhythm and patterning of locomotion. However, both descending and sensory inputs are required to initiate and adapt locomotion to the environment. Spinal cord injury (SCI) disrupts descending controls of the spinal cord, producing paralysis. Epidural stimulation (ES) is a promising clinical therapy for motor control recovery and is capable of reactivating the lumbar spinal locomotor networks, yet little is known about the effects of ES on locomotor neurons. Previously, we found that both sensory afferent pathways and serotonin exert mixed excitatory and inhibitory actions on lumbar interneurons involved in the generation of the locomotor rhythm, identified by the transcription factor Shox2. However, after chronic complete SCI, sensory afferent inputs to Shox2 interneurons become almost exclusively excitatory and Shox2 interneurons are supersensitive to serotonin. Here, we investigated the effects of ES on these SCI-induced changes. Inhibitory input from sensory pathways to Shox2 interneurons was maintained and serotonin supersensitivity was not observed in SCI mice that received daily sub-motor threshold ES. Interestingly, the effects of ES were maintained for at least three weeks after the ES was discontinued. In contrast, the effects of ES were not observed in Shox2 interneurons from mice that received ES after the establishment of the SCI-induced changes. Our results demonstrate mechanistic actions of ES at the level of identified spinal locomotor circuit neurons and the effectiveness of early treatment with ES on preservation of spinal locomotor circuitry after SCI, suggesting possible therapeutic benefits prior to the onset of motor rehabilitation.
Immunophenotype signatures in acute leukemias unveiled by integrative systems immunology
Authors: Bahia Ian Antunes Ferreira , Lima Rafael Duarte , de Medeiros Oliveira Gustavo Henrique , Neta Antonia Pereira Rosa , Filgueiras Igor Salerno , Marques Lena Schimke , Marques Alexandre Henrique , Dennyson Leandro M Fonseca , Barcelos Pedro Marçal , Nóbile Adriel Leal , Adri Anny Silva , Usuda Júlia Nakanishi , Ochs Hans D. , Dias Haroldo Dutra , Nakaya Helder I , de Souza Barroso Rodrigo , Luchessi André Ducati , Cabral-Marques Otávio , Junior Geraldo Barroso Cavalcanti
Published: June 2024

Acute leukemias (ALs) are complex hematological disorders, and accurate diagnosis is crucial for guiding treatment decisions and predicting patient outcomes. While changes in cell marker levels are well documented, the impact of these changes on marker relationships through an integrative systems approach remains uncharacterized. To address this gap, we conducted a 12-year study investigating 41 markers, including ontogenic markers and those used to diagnose both common and rare leukemia types, using immunophenotyping flow cytometry (IFC) data from 1,069 leukocyte samples obtained from peripheral blood (PB) or bone marrow (BM) aspirates of patients with suspected ALs. Machine learning techniques, such as principal component analysis (PCA) and random forest (RF) classification, demonstrated the stratification power of the cellular markers. Hierarchical clustering analysis of leukocyte ontogenetic markers revealed disease-specific clusters, irrespective of sex or sample type (PB or BM). Additionally, we found that patients with acute myeloid leukemia (AML) showed mild disruption in cell marker correlations, whereas the most significant dysregulation was observed in patients with T-cell acute lymphoblastic leukemia (T-ALL). Importantly, we identified ontogenic correlation changes indicating clusters of immature versus mature leukocyte markers, as well as cell lineage-specific markers influencing cellular relationships. These findings underscore the value of integrating systems strategies into conventional IFC analyses to enhance synthetic diagnosis and deepen our understanding of ALs pathophysiology.
Permanent lymphocyte subset elimination upon a single dose of AAV-delivered depletion antibody dissects immune control of chronic viral infection
Authors: Kastner Anna Lena , Marx Anna-Friederike , Dimitrova Mirela , Abreu-Mota Tiago , Ertuna Yusuf I. , Bonilla Weldy V. , Stauffer Karsten , Wagner Ingrid , Kreutzfeldt Mario , Merkler Doron , Pinschewer Daniel D.
Published: June 2024

To interrogate the role of specific immune cells in infection, cancer and autoimmunity, immunologists commonly use monoclonal depletion antibodies (depletion-mAbs) or genetically engineered mouse models (GEMMs). To generate a tool that combines specific advantages and avoids select drawbacks of the two methods we engineer adeno-associated viral vectors expressing depletion-mAbs (depletion-AAVs). Single-dose depletion-AAV administration permanently eliminates lymphocyte subsets in mice while avoiding accessory deficiencies of GEMMs such as marginal zone defects in B cell-deficient animals. Depletion-AAVs can be used irrespective of the animals’ genetic background, and multiple depletion-AAVs can readily be combined. Exploiting depletion-AAV technology, we show that B cells are required for unimpaired CD4 and CD8 T cell responses to chronic viral infection. Importantly, CD8 T cells fail to suppress viremia when B cells are depleted, and they only help resolving chronic infection if antibodies suppress viral loads. Our study positions depletion-AAVs as a versatile tool for immunological research.
Frequent genetic exchanges revealed by a pan-mitogenome graph of a fungal plant pathogen
Authors: van Westerhoven Anouk C. , Dijkstra Jelmer , Palop Jose L. Aznar , Wissink Kyran , Bell Jasper , Kema Gert H. J. , Seidl Michael F.
Published: June 2024

Mitochondria are present in almost all eukaryotic lineages. The mitochondrial genomes (mitogenomes) evolve separately from nuclear genomes, and they can therefore provide relevant insights into the evolution of their host species.Fusarium oxysporumis a major fungal plant pathogen that is assumed to reproduce clonally. However, horizontal chromosome transfer between strains can occur through heterokaryon formation, and recently signs of sexual recombination have been observed. Similarly, signs of recombination inF. oxysporummitogenomes challenged the prevailing assumption of clonal reproduction in this species. Here, we construct, to our knowledge, the first fungal pan-mitogenome graph of nearly 500F. oxysporummitogenome assemblies to uncover the variation and evolution. In general, the gene order of fungal mitogenomes is not well conserved, yet the mitogenome ofF. oxysporumand related species are highly co-linear. We observed two strikingly contrasting regions in theFusarium oxysporumpan-mitogenome, comprising a highly conserved core mitogenome and a long variable region (6-16 kb in size), of which we identified three distinct types. The pan-mitogenome graph reveals that only five intron insertions occurred in the core mitogenome and that the long variable regions drive the difference between mitogenomes. Moreover, we observed that their evolution is neither concurrent with the core mitogenome nor with the nuclear genome. Our large-scale analysis of long variable regions uncovers frequent recombination between mitogenomes, even between strains that belong to different taxonomic clades. This challenges the common assumption of incompatibility between genetically diverseF. oxysporumstrains and provides new insights into the evolution of this fungal species.

Importance statement

Insights into plant pathogen evolution is essential for the understanding and management of disease.Fusarium oxysporumis a major fungal pathogen that can infect many economically important crops. Pathogenicity can be transferred between strains by the horizontal transfer of pathogenicity chromosomes. The fungus has been thought to evolve clonally, yet recent evidence suggests active sexual recombination between related isolates, which could at least partially explain the horizontal transfer of pathogenicity chromosomes. By constructing a pan-genome graph of nearly 500 mitochondrial genomes, we describe the genetic variation of mitochondria in unprecedented detail and demonstrate frequent mitochondrial recombination. Importantly, recombination can occur between genetically diverse isolates from distinct taxonomic clades and thus can shed light on genetic exchange between fungal strains.
Morphological changes in the mandible associated with the presence of exostoses: a study in two archaeological populations from southern France
Authors: Casazza Estelle , Ballester Benoit , Philip-Alliez Camille , Ardagna Yann , Raskin Anne
Published: June 2024

This study aimed to investigate morphological changes in the mandible of subjects in archaeological collections associated with the presence of bony exostoses at the mandibular angle, which are described in the literature as related to specific behaviours of the manducatory apparatus like parafunctional activities. The skeletal sample investigated comprised adult individuals from two archaeological series. Sixteen measurements of the mandible were selected to evaluate anatomic variation in the two populations. Mandibles from both series were pooled for statistical analysis into two groups according to the number of exostoses at the mandibular angles: group 1 (number of exostoses ≤1) and group 2 (number of exostoses ≥ 2). Measurements could be made on eighty mandibles. A statistically significant difference was demonstrated between group 1 and group 2 for the following parameters: distance between mandibular angles, bicondylar width, ramus height, left condyle length, right and left coronoid process height. For each of these parameters, values were higher in group 2 than in group 1. This study presents an original methodology for studying anatomical variations of the mandible in the context of parafunctional activity, highlighting certain mandibular modifications. The impact of parafunctional behaviours such as bruxism on the mandible therefore has many anatomical expressions. The considerable variability of results found in the literature shows that more studies are needed to reach a consensus on the impact of parafunctional activities on the mandible.
Effectiveness and efficiency of immunisation strategies to prevent RSV among infants and older adults in Germany: a modelling study
Authors: Krauer Fabienne , Guenther Felix , Treskova-Schwarzbach Marina , Schoenfeld Viktoria , Koltai Mihaly , Jit Mark , Hodgson David , Schneider Udo , Wichmann Ole , Harder Thomas , Sandmann Frank G. , Flasche Stefan
Published: June 2024

Background

Recently, several novel RSV immunisation products that protect infants and older adults against RSV disease have been licensed in Europe. We estimated the effectiveness and efficiency of introducing these RSV immunisation strategies in Germany.

Methods

We used a Bayesian framework to fit an age-structured dynamic transmission model of RSV to sentinel surveillance and RSV-specific hospitalisation data in Germany from 2015-2019. The calibrated model was used to evaluate different RSV intervention strategies over five years: long-acting, single-dose monoclonal antibodies (mAbs) in high-risk infants aged 1-5 months; long-acting mAbs in all infants aged 1-5 months; seasonal vaccination of pregnant women and one-time seasonal vaccination of older adults (75+/65+/55+ years). We performed sensitivity analysis on vaccine uptake, seasonal vs. year-round maternal vaccination, and the effect of under-ascertainment for older adults.

Results

The model was able to match the various RSV datasets. Replacing the current short-acting mAB for high-risk infants with long-acting mAbs prevented 1.1% of RSV-specific hospitalisations in infants per year at the same uptake. Expanding the long-acting mAB programme to all infants prevented 39.3% of infant hospitalisations per year. Maternal vaccination required a larger number to be immunised to prevent one additional hospitalisation than a long-acting mAB for the same uptake. Vaccination of adults older than 75 years at an uptake of 40% in addition to Nirsevimab in all infants prevented an additional 4.5% of all RSV-hospitalisations over five years, with substantial uncertainty in the correction for under-ascertainment of the RSV burden.

Conclusions

Immunisation has the potential to reduce the RSV disease burden in Germany.
One year of gluten free diet impacts gut function and microbiome in celiac disease
Authors: Costigan Carolyn M. , Warren Frederick J. , Duncan Anthony P. , Hoad Caroline L. , Lewis Nina , Hill Trevor , Crooks Colin J. , Morgan Paul S. , Ciacci Carolina , Iovino Paola , Sanders David S. , Hildebrand Falk , Gowland Penny A. , Spiller Robin C. , Marciani Luca
Published: June 2024

BACKGROUND & AIMS

Currently, the main treatment option for coeliac disease (CD) is a gluten free diet (GFD). This observational cohort study investigated the impact of CD and 1 year of GFD on gut function and microbiome.

METHODS

36 newly diagnosed patients and 36 healthy volunteers (HV) were studied at baseline and at 12 months follow up. Small bowel water content (SBWC), whole gut transit time (WGTT) and colon volumes were measured by MRI. Stool samples DNA was subjected to shotgun metagenomic sequencing. Species level abundances and gene functions, including carbohydrate active enzymes (CAZymes) were determined.

RESULTS

SBWC was significantly higher in people with CD 157±15 mL versus HVs 100±12 mL (p=0.003). WGTT was delayed in people with CD 68±8 hours versus HVs 41±5 hours (p=0.002). The differences reduced after 12 months of GFD but not significantly. Wellbeing in the CD group significantly improved after GFD but did not recover to control values. CD faecal microbiota showed high abundance of proteolytic gene functions, associated withEscherichia coli, EnterobacterandPeptostreptococcus. GFD significantly reducedBifidobacteriaand increasedBlautia wexerelae. Microbiome composition correlated positively with WGTT, colonic volume andAkkermansia municphiliabut negatively withB.wexerelae. Following GFD the reduction in WGTT and colonic volume significantly associated with increased abundance ofB.wexerelae. There were also significant alterations in CAZyme profiles, specifically starch and arabinoxylan degrading families.

CONCLUSIONS

CD impacted gut function and microbiota. GFD ameliorated but did not reverse these effects, significantly reducingBifidobacteriaassociated with reduced intake of resistant starch and arabinoxylan from wheat.
Beyond brain size: disentangling the effect of sex and brain size on brain morphometry and cognitive functioning
Authors: Brzezinski-Rittner Aliza , Moqadam Roqaie , Iturria-Medina Yasser , Chakravarty Mallar , Dadar Mahsa , Zeighami Yashar
Published: June 2024

It is imperative to study sex differences in brain morphology and function. However, there are major observable and unobservable confounding factors that can contribute to the estimated differences. Males have larger head sizes than females. Head size differences not only act as a confounding factor in studying sex differences in the brain, but also impact its anatomy and functioning. In this work, we seek to disentangle the effect of head size from sex in studying sex differentiated aging trajectories, its relation to canonical functional networks and cytoarchitectural classes, brain allometry, cognition. Using the UK Biobank (UKBB) neuroimaging data (N = 35,732 participants, 19,281 females, 44-82 years of age), we created a subsample (N = 11,294) where females (N = 5,657) and males were matched by their total intracranial volume (TIV) and age, a subsample that maintains the UKBB sample distribution, one matched only by age, and one that exaggerated the TIV difference between sexes. We then modeled the aging trajectories at both regional and vertex-wise levels in the four subsamples, and compared the estimations of the models. Our results show that when females and males have the same head size, the overall sex estimations tend towards zero, suggesting that most of the variability results from head size differences. Our approach also revealed bidirectional sex differences in brain neuroanatomy previously masked by the effect of head size. Further, the scaling relationship between regional and total brain volume remains fairly consistent across the lifespan and is not sex differentiated overall. We evaluated how the results of cognitive tests with perceived sex differences are influenced and explained by head size and found that although the correlation between TIV and cognitive scores is low, the matching process changes the direction of the effect sizes of differences between sexes in “verbal and numerical reasoning” and “working memory” cognitive domains. Taken together, employing a matching approach that is widely used in causal modeling studies, we provide new evidence for disentanglement of sex differences in the brain from head size as a biological confound.
Large-scale genomic analysis of SARS-CoV-2 Omicron BA.5 emergence in the United States
Authors: Pham Kien , Chaguza Chrispin , Lopes Rafael , Cohen Ted , Taylor-Salmon Emma , Wilkinson Melanie , Katebi Volha , D. Grubaugh Nathan , Hill Verity
Published: June 2024

The COVID-19 pandemic is marked by the continuing emergence of novel SARS-CoV-2 variants. Questions remain about the mechanisms with which these lineages establish themselves in new geographical areas. In this study, we performed a discrete phylogeographic analysis on ∼19,000 SARS-CoV-2 sequences of Omicron BA.5 lineages between February and June 2022 to better understand how it emerged in different regions of the United States (U.S.). We found that the earliest introductions came from Africa, the putative origin of the variant, but the majority were from Europe, correlating with the high volume of air travelers. Additionally, the analysis revealed extensive domestic transmission between different regions of the U.S. driven by population size and cross-country transmission. Results suggest that most of the within-U.S. spread was between three regions that include California, New York, and Florida. Our results form a framework for understanding novel SARS-CoV-2 variant emergence in the U.S.
ACE2 decoy Fc-fusions and bi-specific killer engager (BiKEs) require Fc engagement forin vivoefficacy against SARS-CoV-2
Authors: Dick Jenna K. , Hicks Dustin , Krishna Venkatramana D , Sangala Jules A. , Zandstra Benjamin T. , Baehr Carly , Verbeek J Sjef , Cragg Mark S. , Cheeran Maxim C-J , Pravetoni Marco , Hart Geoffrey T
Published: June 2024

SARS-CoV-2 virus has continued to evolve over time necessitating the adaptation of vaccines to maintain efficacy. Monoclonal antibodies (mAbs) against SARS-CoV-2 were a key line of defense for unvaccinated or immunocompromised individuals. However, these mAbs are now ineffective against current SARS-CoV-2 variants. Here, we tested three aspects of αSARS-CoV-2 therapeutics. First, we tested whether Fc engagement is necessary forin vivoclearance of SARS-CoV-2. Secondly, we tested bi-specific killer engagers (BiKEs) that simultaneously engage SARS-CoV-2 and a specific Fc receptor. Benefits of these engagers include the ease of manufacturing, stability, more cell-specific targeting, and high affinity binding to Fc receptors. Using both mAbs and BiKEs, we found that both neutralization and Fc receptor engagement were necessary for effective SARS-CoV-2 clearance. Thirdly, due to ACE2 being necessary for viral entry, ACE2 will maintain binding to SARS-CoV-2 despite viral evolution. Therefore, we used an ACE2 decoy Fc-fusion or BiKE, instead of an anti-SARS-CoV-2 antibody sequence, as a potential therapeutic that would withstand viral evolution. We found that the ACE2 decoy approach also required Fc receptor engagement and, unlike traditional neutralizing antibodies against specific variants, enabled the clearance of two distinct SARS-CoV-2 variants. These data show the importance of Fc engagement for mAbs, the utility of BiKEs as therapies for infectious disease, and thein vivoeffectiveness of the ACE2 decoy approach. With further studies, we predict combining neutralization, the cellular response, and this ACE2 decoy approach will benefit individuals with ineffective antibody levels.

Abbreviations

ACE2, scFv, mAb, BiKE, COVID-19, Fc, CD16, CD32b, CD64, d.p.i

Key points

With equal dosing, both neutralization and Fc engagement are necessary for the optimal efficacy ofin vivoantibodies and bi-specific killer engagers (BiKEs) against SARS-CoV-2.

BiKEs can clear SARS-CoV-2 virus and protect against severe infection in the hACE2-K18 mouse model.

ACE2 decoys as part of Fc-fusions or BiKEs providein vivoclearance of two disparate SARS-CoV-2 variants.
EngineeringSaccharomyces cerevisiaefor the production of punicic acid-rich yeast biomass
Authors: Wang Juli , Chen Guanqun
Published: June 2024

Punicic acid (PuA), an unusual conjugated linolenic acid found in pomegranate, offers diverse health benefits and potential applications in the food industry. The limited production of PuA from its natural plant sources has led to a growing interest in producing it through microbial fermentation. In this study, the “generally recognized as safe” yeastSaccharomyces cerevisiaewas engineered to produce PuA. Candidate genes related to PuA synthesis were directly shuffled within the yeast genome. Subsequent screening and optimization resulted in a strain that synthesized 26.7% of its total fatty acids as PuA. Further analyses revealed that the strain’s storage lipids contained over 22% PuA. By incorporating the health-promoting lipid component into the nutritional profile ofS. cerevisiae, the engineered strain could potentially serve as a sustainable source of yeast biomass with enhanced nutritional value.
The Inverse Association between Testosterone Replacement Therapy and Cardiovascular Disease Risk: A Systematic 25-year Review and Meta-Analysis Analysis of Prospective Cohort Studies from 1999 to 2024
Authors: Borges Julian Yin Vieira
Published: June 2024

Background

Testosterone deficiency in men has historically been associated with an increased risk of cardiovascular disease (CVD), including myocardial infarction, heart failure, and mortality. The potential benefits of testosterone replacement therapy (TRT) on cardiovascular outcomes remain controversial. This systematic review and meta-analysis aimed to investigate if there could be potential benefits of TRT on cardiovascular disease risk and, if so, uncover the underlying mechanisms.

Methods

A comprehensive literature search for Level A evidence in multiple databases (PubMed, Embase, Cochrane Library) was conducted, including randomized controlled trials (RCTs), systematic reviews, meta-analyses, cohort studies, review articles and experimental studies published between 1999 and 2024 that investigated the association between TRT and cardiovascular outcomes in men. The primary outcome was the risk of major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular mortality. Secondary outcomes included changes in ejection fraction, lipid profiles, side effects, and other cardiovascular risk factors.

Results

From 3,727 records identified using the selected criteria, a total of 51 studies were selected for the meta-analysis, comprising 4 RCTs, 9 cohort studies, 6 experimental studies, 23 review articles, 4 systematic reviews, and 5 meta-analyses, with a combined sample size of approximately 3,134,054 men. The findings from the meta-analysis suggests an 18% reduction in the risk of cardiovascular events among men receiving TRT compared to those receiving a placebo.

TRT was found to be associated with significant improvements in ejection fraction, lipid profiles (reduction in total cholesterol and low-density lipoprotein cholesterol), and other cardiovascular risk factors, including insulin resistance and inflammatory markers. Potential mechanisms underlying the cardioprotective effects of TRT include improvements in endothelial function, vasodilation, and myocardial remodeling.

Subgroup analyses revealed that the beneficial effects of TRT were more pronounced in men with established cardiovascular disease or risk factors, such as diabetes or metabolic syndrome.

Conclusion

This systematic review and meta-analysis of high-quality evidence suggest that testosterone deficiency is associated with an increased risk of cardiovascular disease. Conversely, TRT is associated with a reduced risk of cardiovascular events, particularly in men with pre-existing cardiovascular disease or risk factors. TRT was linked to a reduced risk of MACE, improved ejection fraction, and favorable changes in lipid profiles and other cardiovascular risk factors. Despite the relatively large sample size, further long-term studies are needed to confirm these findings and establish optimal dosing and monitoring strategies for TRT in cardiovascular disease prevention.
MicroRNA signature predicts post-operative atrial fibrillation after coronary artery bypass grafting
Authors: Yerukala Sathipati Srinivasulu , Carter Tonia , Soodi Deepa , Somto Nwaedozie , Shukla Sanjay K , Petronovich John , Ingrid Glurich , Braxton John , Sharma Param
Published: June 2024

Background

Early detection of atrial fibrillation (AFib) is crucial for altering its natural progression and complication profile. Traditional demographic and lifestyle factors often fail as predictors of AFib, particularly in studies with small samples. This study investigated pre-operative, circulating microRNAs (miRNAs) as potential biomarkers for post-operative AFib (POAF) in patients undergoing coronary artery bypass grafting (CABG).

Methods

We used an array polymerase chain reaction method to detect pre-operative, circulating miRNAs in seven patients who subsequently developed POAF after CABG (cases) and eight patients who did not develop POAF after CABG (controls). The top 10 miRNAs from 84 candidates were selected and assessed for their performance in predicting POAF using machine learning models, including Random Forest, K-Nearest Neighbors (KNN), XGBoost, and Support Vector Machine (SVM).

Results

The Random Forest and XGBoost models showed superior predictive performance, with test sensitivities of 0.76 and 0.83, respectively. Differential expression analysis revealed four upregulated miRNAs—hsa-miR-96-5p, hsa-miR-184, hsa-miR-17-3p, and hsa-miR-200-3p—that overlapped with the AFib-miRNA signature. The AFib-miRNA signature was significantly associated with various cardiovascular diseases, including acute myocardial infarction, hypertrophic cardiomyopathy, and heart failure. Biological pathway analysis indicated these miRNAs target key signaling pathways involved in cardiovascular pathology, such as the MAPK, PI3K-Akt, and TGF-beta signaling pathways.

Conclusion

The identified miRNAs demonstrate significant potential as predictive biomarkers for AFib post-CABG, implicating critical cardiovascular pathways and highlighting their role in AFib development and progression. These findings suggest that miRNA signatures could enhance predictive accuracy for AFib, offering a novel, noninvasive approach to early detection and personalized management of this condition.
Evolutionary origins of archaeal and eukaryotic RNA-guided RNA modification in bacterial IS110 transposons
Authors: Vaysset Hugo , Meers Chance , Cury Jean , Bernheim Aude , Sternberg Samuel H.
Published: June 2024

Transposase genes are ubiquitous in all domains of life and provide a rich reservoir for the evolution of novel protein functions. Here we report deep evolutionary links between bacterial IS110 transposases, which catalyze RNA-guided DNA recombination using bridge RNAs, and archaeal/eukaryotic Nop5-family proteins, which promote RNA-guided RNA 2’-O-methylation using C/D-box snoRNAs. Based on conservation in the protein primary sequence, domain architecture, and three-dimensional structure, as well as common architectural features of the non-coding RNA components, we propose that programmable RNA modification emerged via exaptation of components derived from IS110-like transposons. Alongside recent studies highlighting the origins of CRISPR-Cas9 and Cas12 in IS605-family transposons, these findings underscore how recurrent domestication events of transposable elements gave rise to complex RNA-guided biological mechanisms.
Molecular principles of redox-coupled sodium pumping of the ancient Rnf machinery
Authors: Kumar Anuj , Roth Jennifer , Kim Hyunho , Saura Patricia , Bohn Stefan , Reif-Trauttmansdorff Tristan , Schubert Anja , Kaila Ville R. I. , Schuller Jan M. , Müller Volker
Published: June 2024

The Rnf complex is the primary respiratory enzyme of several anaerobic prokaryotes that transfers electrons from ferredoxin to NAD+and pumps sodium ions (Na+) across a membrane, powering ATP synthesis. Rnf is widespread in primordial organisms and the evolutionary predecessor of the Na+-pumping NADH-quinone oxidoreductase (Nqr)1. By running in reverse, Rnf reduces ferredoxin with NADH as reductant at the expense of the transmembrane electrochemical ion gradient and provides low potential electrons for nitrogenases as well as CO2reductases. Yet, the molecular principles that couple the long-range electron transfer to the Na+translocation across the membrane remain elusive. Here we resolve key functional states along the electron transfer pathway using redox-controlled cryo-electron microscopy (cryo-EM) that, in combination with biochemical functional assays and atomistic molecular simulations, provide key insight into the redox-driven Na+pumping mechanism. We show that the reduction of the unique membrane-embedded [2Fe2S] cluster in the vestibule between the RnfA/E subunits electrostatically attracts the sodium ions, and in turn, triggers aninward/outwardtransition with alternating membrane access driving the Na+pump and the reduction of NAD+. Our study unveils an ancient mechanism for redox-driven ion pumping, and provides key understanding of the fundamental principles governing energy conversion in biological systems.
Immune correlates of early clearance ofMycobacterium tuberculosisamong tuberculosis household contacts in Indonesia
Authors: Setiabudiawan Todia P. , Apriani Lika , Verrall Ayesha J. , Utami Fitria , Schneider Marion , Indrati Agnes R. , Halim Pauline P. , Kaplonek Paulina , Malca Hadar , Lee Jessica Shih-Lu , Moorlag Simone J.C.F.M. , de Bree L. Charlotte J. , Mourits Vera P. , Joosten Leo A.B. , Netea Mihai G. , Alisjahbana Bachti , McNamara Ryan P. , Alter Galit , van Laarhoven Arjan , Ussher James E. , Sharples Katrina , Koeken Valerie A. C. M. , Hill Philip C. , van Crevel Reinout
Published: June 2024

Some individuals, even when heavily exposed to an infectious tuberculosis patient, do not develop a specific T-cell response as measured by interferon-gamma release assay (IGRA). This could be explained by an IFN-γ-independent adaptive immune response, or an effective innate host response clearingMycobacterium tuberculosis (Mtb)without adaptive immunity. In heavily exposed Indonesian tuberculosis household contacts (n=1347), a persistently IGRA negative status was associated with presence of a BCG scar, and - especially among BCG-vaccinated individuals - with altered innate immune cells dynamics, higher heterologous (Escherichia coli-induced) proinflammatory cytokine production, and higher inflammatory proteins in the IGRA mitogen tube. Neither circulating concentrations ofMtb-specific antibodies nor functional antibody activity associated with IGRA status at baseline or follow-up. In a cohort of adults in a low tuberculosis incidence setting, BCG vaccination induced heterologous innate cytokine production, but only marginally affectedMtb-specific antibody profiles. Our findings suggest that a more efficient host innate immune response, rather than a humoral response, mediates early clearance ofMtb. The protective effect of BCG vaccination againstMtbinfection may be linked to innate immune priming, also termed ‘trained immunity’.
PathwayPilot: A User-Friendly Tool for Visualizing and Navigating Metabolic Pathways
Authors: Vande Moortele Tibo , Verschaffelt Pieter , Huang Qingyao , T. Doncheva Nadezhda , Holstein Tanja , Jachmann Caroline , Dawyndt Peter , Martens Lennart , Mesuere Bart , Van Den Bossche Tim
Published: June 2024

Background

Metaproteomics, the study of collective proteomes in environmental communities, plays a crucial role in understanding microbial functionalities affecting ecosystems and human health. Pathway analysis offers structured insights into the biochemical processes within these communities. However, no existing tool effectively combines pathway analysis with peptide- or protein-level data.

Results

This manuscript introduces PathwayPilot, a user-friendly web application for exploring and visualizing metabolic pathways. PathwayPilot can compare functional annotations across different samples or organisms within a sample. A case study on the impact of caloric restriction on gut microbiota demonstrated the tool’s efficacy in deciphering complex metaproteomic data. The re-analysis revealed significant shifts in enzyme expressions related to short-chain fatty acid biosynthesis, aligning with existing research findings and showcasing PathwayPilot’s capability for accurate functional annotation and comparison across different microbial communities.

Conclusions

PathwayPilot represents a significant advancement in metaproteomic data analysis, offering a user-friendly interface for exploring and visualizing metabolic pathways. This study not only validates the tool’s applicability in real-world scenarios but also highlights its potential for broader research implications in microbial ecology and health sciences.
The silicon transporters (SITs) gene was found inSynechococcussp. XM24
Authors: Han Yabo , Sun Jun
Published: June 2024

Silicate serves as a crucial nutrient for diatoms, which are capable of absorbing dissolved silicon from their surroundings through silicon transporters (SITs), thus playing a significant role in the global ocean’s silicon cycle. Recent studies have indicated that marine single-celledSynechococcusalso has the ability to accumulate silicon. Given that the evolution ofSynechococcuspredates that of diatoms, it is postulated thatSynechococcusmay utilize transporters such as SITs found in diatoms, to absorb dissolved silicon in the ocean. This research delves into the silicon accumulation inSynechococcussp. XM24, particularly focusing on two key aspects. Firstly, the study investigates the potential presence of SITs inSynechococcussp. XM24 under the condition of Depleted-Repleted silicate. Subsequently, two gene sequences suspected to encodeSITs, were identified, and their protein sequences and functions were successfully predicted, shedding light on their involvement in membrane transport processes.
Pre- and postnatal maternal depressive symptoms associate with local connectivity of the left amygdala in 5-year-olds
Authors: Vartiainen Elena , Copeland Anni , Pulli Elmo P. , Kumpulainen Venla , Silver Eero , Rajasilta Olli , Jolly Ashmeet , Luotonen Silja , Audah Hilyatushalihah K. , Hashempour Niloofar , Bano Wajiha , Suuronen Ilkka , Saukko Ekaterina , Häkkinen Suvi , Karlsson Hasse , Karlsson Linnea , Tuulari Jetro J.
Published: June 2024

Background

Maternal depressive symptoms can influence brain development in offspring, prenatally through intrauterine programming, and postnatally through caregiving related mother–child interaction.

Methods

The participants were 5-year-old mother-child dyads from the FinnBrain Birth Cohort Study (N = 68; 28 boys, 40 girls). Maternal depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale (EPDS) at gestational week 24, 3 months, 6 months, and 12 months postnatal. Children’s brain imaging data were acquired with task-free functional magnetic resonance imaging (fMRI) at the age of 5 years in 7 min scans while watching theInscapesmovie. The derived brain metrics included whole brain regional homogeneity (ReHo) and seed-based connectivity maps of the bilateral amygdalae.

Results

We found that maternal depressive symptoms were positively associated with ReHo values of the left amygdala. The association was highly localised and strongest with the maternal depressive symptoms at three months postnatal. Seed-based connectivity analysis did not reveal associations between distal connectivity of the left amygdala region and maternal depressive symptoms.

Conclusions

These results suggest that maternal depressive symptoms soon after birth may influence offspring’s neurodevelopment in the local functional coherence in the left amygdala. They underline the potential relevance of postnatal maternal distress exposure on neurodevelopment that has received much less attention than prenatal exposures. These results offer a possible thus far understudied pathway of intergenerational effects of perinatal depression that should be further explored in future studies.
Isolation and characterization ofSporomusa carbonissp. nov., a carboxydotrophic hydrogenogen in the genus ofSporomusaisolated from a charcoal burning pile
Authors: Böer Tim , Rosenbaum Florian P. , Eysell Lena , Müller Volker , Daniel Rolf , Poehlein Anja
Published: June 2024

A Gram-negative bacterial strain, designated ACPtT, was isolated from the covering top soil of an active charcoal burning pile. Cells of ACPtTwere strictly anaerobic, rod-shaped and grew optimally at 40°C and pH 7. The substrates ribose, glucose, sucrose, raffinose, melezitose, pyruvate, vanillate, syringate, methanol and CO were utilized for growth. Phylogenomic analysis of the 4.1 Mb genome showed that strain ACPt represented a novel species of the genusSporomusa. The most closely related species to ACPtTwasSporomusa malonicawith an average amino acid identity of 80.1%. The genome of ACPtTencoded cytochromes, ubiquinones, the Wood-Ljungdahl gene cluster and an Rnf complex, which were identified as common features allSporomusatype strains. However, strain ACPt did not ferment H2+ CO2via acetogenesis as otherSporomusaspecies, but employed the metabolism of a carboxydotrophic hydrogenogen converting CO to H2+ CO2. Based on the genomic, morphological and physiological features presented in this study, strain ACPtTis proposed as a novel species in the genusSporomusawith the nameSporomusa carbonissp. nov. (DSM 116159Tand CCOS 2105T).
RecombiCraft Library construction: A novel method for DNA Library cloning and expansion using non-enzymatic single-step DNA recombination and liquid culture
Authors: Kawai-Harada Yuki , Mardikoraem Mehrsa , Lauro Katherine , Nimmagadda Vasudha , Tong Quynh , Bello Kayla , Woldring Daniel , Harada Masako
Published: June 2024

In this study, we introduceRecombiCraft, an innovative, rapid, and cost-efficient method for constructing DNA libraries inE. coli. This method uses seamless ligation cloning extract (SLiCE) coupled with liquid culture amplification to effectively minimize sequence biases. The technique capitalizes on the natural homologous recombination capabilities ofE. colicell lysates, eliminating the need for multiple purified enzymes and reducing costs. We first synthesized the library backbone and inserts via PCR, employing high-fidelity polymerase to minimize sequence bias. The SLiCE technique was then used to assemble the DNA fragments introduced intoE. colithrough electroporation. To ensure the integrity of the library, we optimized culture times based on next-generation sequencing analysis which confirmed the minimal sequence bias. The RecombiCraft method demonstrates that this approach is economical and maintains the library’s uniformity. It is a promising tool for genetic research and biotechnological applications with a significantly shorter library generation period.
Unveiling Cas8 Dynamics and Regulation within a transposon-encoded Cascade-TniQ Complex
Authors: Patel Amun C. , Sinha Souvik , Arantes Pablo R. , Palermo Giulia
Published: June 2024

TheVibrio choleraeCascade-TniQ complex unveiled a new paradigm in biology, demonstrating that CRISPR-associated proteins can direct DNA transposition. Despite the tremendous potential of “knocking in” genes at desired sites, the mechanisms underlying DNA binding and transposition remain elusive. In this system, a conformational change of the Cas8 protein is essential for DNA binding, yet how it occurs is unclear. Here, structural modeling and free energy simulations reconstruct the Cas8 helical bundle and reveal an open-to-close conformational transition at key steps of the complex’s function. We show that when Cascade-TniQ binds RNA, the Cas8 bundle changes conformation mediated by the interaction with the Cas7.1 protein. This interaction alleviates unfavorable contacts and synchronizes Cas8’s shift with neighboring subunits, lowering the barrier for the transition to the open state, a critical requirement for DNA binding. As DNA fully pairs with RNA, the open state becomes increasingly accessible, favoring interactions with DNA and aiding the formation of an R-loop. These outcomes provide the first dynamic representation of a critical conformational change in one of the largest CRISPR systems and illustrate its role at critical steps of the Cascade-TniQ biophysical function, advancing our understanding of nucleic acid binding and transposition mechanisms.
Flagellar Motility is Mutagenic
Authors: Bhattacharyya Souvik , Lopez Shelby , Singh Abhyudai , Harshey Rasika M.
Published: June 2024

Flagella are highly complex rotary molecular machines that enable bacteria to not only migrate to optimal environments but to also promote range expansion, competitiveness, virulence, and antibiotic survival. Flagellar motility is an energy-demanding process, where the sum of its production (biosynthesis) and operation (rotation) costs has been estimated to total ∼10% of the entire energy budget of anE. colicell. The acquisition of such a costly adaptation process is expected to secure short-term benefits by increasing competitiveness and survival, as well as long-term evolutionary fitness gains. While the role of flagellar motility in bacterial survival has been widely reported, its direct influence on the rate of evolution remains unclear. We show here that both production and operation costs contribute to elevated mutation frequencies. Our findings suggest that flagellar movement may be an important player in tuning the rate of bacterial evolution.