bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of parity and early pregnancy on peripheral blood leukocytes in dairy cattle
Authors: da Silva M. I. , Oli N. , Gambonini F. , Ott T.
Published: May 2024

Subfertility remains a major problem in the dairy industry. Only 35-40% of high-yielding dairy cows and 55-65% of nonlactating heifers become pregnant after their first service. The immune system plays a critical role in the establishment of pregnancy. However, it can also create challenges for embryo survival and contribute to reduced fertility. We conducted 2 separate experiments to characterize changes in subsets of peripheral blood leukocytes (PBL) and their phenotype over the estrous cycle and early pregnancy in heifers and cows. We used flow cytometry and RT-qPCR to assess protein and mRNA expression of molecules important for immune function. We observed that monocytes and T cells were most affected by pregnancy status in heifers, whereas, CD8+lymphocytes and natural killer (NK) cells were most affected during early pregnancy in cows. Changes in immune parameters measured appeared to be greater in heifers than cows including changes in expression of numerous immune function molecules. To test the hypothesis, we conducted a third experiment to simultaneously analyze the immunological responses to pregnancy between cows and heifers. We observed that cows had greater expression of proinflammatory cytokines and molecules associated with leukocyte migration and phagocytosis compared to heifers. Moreover, animals that failed to become pregnant showed altered expression of anti-inflammatory molecules. Overall, these findings support the hypothesis that early pregnancy signaling alters the proportions and functions of peripheral blood immune cells and differences between cows and heifers may yield insight into the reduced fertility of mature lactating dairy cows.

Interpretative summary

In dairy farming, 35-40% of high-yielding cows and 55-65% of nonlactating heifers conceive after their initial service. The immune system plays a crucial role in protecting cows from diseases and facilitating pregnancy establishment. This study investigates immune adaptation in bovine pregnancy by analyzing changes in immune cell populations and the expression of immunoregulatory molecules in the blood of heifers and lactating cows during early pregnancy. The findings support the hypothesis that early pregnancy signaling alters the proportions and functions of peripheral blood immune cells, offering insights into reduced fertility in mature lactating dairy cows.
STOP1 dominates Arabidopsis tolerance to ammonium over NRT1.1/NPF6.3/CHL1
Authors: Hachiya Takushi , Sakai Mako , Nakagawa Tsuyoshi , Sakakibara Hitoshi
Published: May 2024

The Arabidopsis nitrate transceptor NITRATE TRANSPORTER 1.1 (NRT1.1/NPF6.3/CHL1) plays significant roles even in the absence of nitrate. The loss-of-function of NRT1.1 alleviates growth suppression and chlorosis under toxic levels of ammonium as the sole nitrogen source. Recently, we reported that acidic stress-inducible genes are downregulated byNRT1.1deficiency under ammonium toxicity conditions, implying that NRT1.1 may exacerbate ammonium-dependent acidic stress. The transcription factor SENSITIVE TO PROTON RHIZOTOXICITY 1 (STOP1) enhances Arabidopsis tolerance to ammonium and acidic stresses. Furthermore, STOP1 directly activatesNRT1.1transcription. These previous findings prompted us to analyze the association between NRT1.1 and STOP1 on ammonium tolerance. Here, we show that ammonium-inducible STOP1 plays a dominant role over NRT1.1 in ammonium tolerance and expression of direct target genes of STOP1. We present a novel scheme in which NRT1.1 and STOP1 jointly regulate common target(s) associated with ammonium tolerance.
Deep learning based predictive modeling to screen natural compounds against TNF-alpha for the potential management of Rheumatoid Arthritis: Virtual screening to comprehensive in silico investigation
Authors: Nabi Tasnia , Riyed Tanver Hasan , Ornob Akid
Published: May 2024

Rheumatoid arthritis (RA) affects an estimated 0.1% to 2.0% of the world’s population, leading to a substantial impact on global health. The adverse effects and toxicity associated with conventional RA treatment pathways underscore the critical need to seek potential new therapeutic candidates, particularly those of natural sources that can treat the condition with minimal side effects. To address this challenge, this study employed a deep-learning (DL) based approach to conduct a virtual assessment of natural compounds against the Tumor Necrosis Factor-alpha (TNF-α) protein. TNF-α stands out as the primary pro-inflammatory cytokine, crucial in the development of RA. Our predictive model demonstrated appreciable performance, achieving MSE of 0.6, MAPE of 10%, and MAE of 0.5. The model was then deployed to screen a comprehensive set of 2563 natural compounds obtained from the Selleckchem database. Utilizing their predicted bioactivity (pIC50), the top 128 compounds were identified. Among them, 68 compounds were taken for further analysis based on drug-likeness analysis. Subsequently, selected compounds underwent additional evaluation using molecular docking (< − 8.7 kcal/mol) and ADMET resulting in four compounds posing nominal toxicity, which were finally subjected to MD simulation for 200 ns. Later on, the stability of complexes was assessed via analysis encompassing RMSD, RMSF, Rg, H-Bonds, SASA, and Essential Dynamics. Ultimately, based on the total binding free energy estimated using the MM/GBSA method, Imperialine, Veratramine, and Gelsemine are proven to be potential natural inhibitors of TNF-α.
Inferring intrinsic population growth rates andper capitainteractions from ecological time-series
Authors: Nguyen Phuong L. , Pomati Francesco , Rohr Rudolf P.
Published: May 2024

Knowledge about theper capitainteractions between organisms and their intrinsic growth rates, and how these vary over environmental gradients, allows understanding and predicting species coexistence and community dynamics. Estimating these crucial ecological parameters requires tedious experimental work, with isolation of organisms from their natural context. Here, we provide a novel approach for inferring these key parameters from time-series data by using weighted multivariate regression on theper capitagrowth rates of populations. Beyond the validation of our approach on synthetic data, we reveal from experimental data an expected allocative trade-off between grazing resistance and rapid growth in algae. Application of observational data suggests facilitation between cyanobacteria and chrysophyte, indicating a possible explanation for cyanobacteria bloom. Our approach offers a way forward for inferringper capitainteractions and intrinsic growth rates directly from natural communities, providing realism, mechanistic understanding of eco-evolutionary dynamics, and key parameters to develop predictive models.
Soybean phenotypic plasticity in response to dark chilling stress
Authors: Elmerich Chloé , Faucon Michel-Pierre , Boulch Guénolé , Jeanson Patrice , Lange Bastien
Published: May 2024

The expansion of soybean cultivation to high-latitude regions is hindered by the adverse effects of dark chilling stress. This study investigates the phenotypic plasticity of soybean in response to dark chilling stress, aiming to identify traits that contribute to adaptation in northern climates. Five soybean cultivars from early maturity groups (000 and 00) were grown in growth chambers set either at 25/18°C or 25/10°C (day/night), and a range of performance and functional traits were measured. The relative distance plasticity index highlighted variations in plasticity across traits and genotypes. Photosynthetic activity recovery traits, shoot growth rate, and tap root elongation rate showed high plasticity and significant differences between cultivars, making them suitable for assessing dark chilling tolerance. Moreover, distinct responses to dark chilling stress were exhibited by different soybean cultivars. For instance, cv. SOPRANA displayed a greater phenotypic plasticity in aboveground performance traits, such as shoot growth, while cv. SULTANA exhibited a greater plasticity in physiological traits like photosynthetic activity recovery. These differing strategies may lead to similar biomass production through distinct mechanisms, highlighting the complexity of soybean’s adaptive responses to dark chilling stress. These findings provide valuable insights for breeders seeking to develop soybean cultivars adapted to high latitudes, meeting the increasing demand for locally produced protein-based food. However, further research in real field conditions is essential to validate the potential benefits of these plastic traits and their role in improving soybean resilience to dark chilling stress. The identified plastic traits offer a promising avenue for screening a broader range of cultivars and enhancing soybean’s suitability for cultivation in northern regions.
The mechanistic rules for species coexistence
Authors: Zhang Zhijie , Becks Lutz
Published: May 2024

Global biodiversity loss requires effective ecological community management, reliant on accurate predictions of species coexistence and community assembly1-4. Traditional methods, predicting coexistence from the effect of one species on another5-8(i.e., phenomenologically), are sensitive to environmental context9-13. This is because they ignore the fundamental processes that can be applied across environments. While mechanistic approaches offer promise14-17, empirical tests remain rare18,19. Here, we integrated a mechanistic consumer-resource model with the growth of 12 phytoplankton species in monoculture over a range of phosphorous, nitrate or ammonium concentrations. We found that the mechanistic approach accurately predicts the composition of 960 communities across species richness and resource conditions. As confirmed by simulations, species competing for substitutable resources (ammonium vs. nitrate) exhibit greater diversity than those competing for essential resources (phosphorus vs. nitrate), especially when initial species richness is high. This is because when competing for essential resources, each species is likely to consume less of the resource that more limit its growth, violating the mechanistic rule of coexistence (each species must consume more of the resource that more limit it16). Our study highlights the power of the mechanistic approach in understanding and predicting species loss across environments and, ultimately, mitigating its pace.
Hematological Parameters as Predictors of COVID-19 Infection: A Cohort Study Using Brazilian Hospital Data
Authors: Utley James
Published: May 2024

Objectives

To determine if hematology test results can indicate COVID-19 infection.

Methods

A cohort study used 2020 Brazilian hospital data for 6,573 patients to run inferential analyses of fourteen red and white blood cell hematology test results, adjusted for age and sex, by patient COVID-19 status.

Results

Ten hematological biomarkers were statistically significant predictors of COVID-19 PCR test results; the strongest were Total White Blood Cells: OR=0.90 (0.88-0.93), Basophils: OR=0.97 (0.97-0.98), Total Red Blood Cells: OR=0.88 (0.78-0.99), Hemoglobin: OR=0.93 (0.89-0.97), Hematocrit: OR=0.97 (0.96-0.99). Patient sex was also a strong predictor of COVID-19 PCR test results: OR=1.43 (1.26-1.62).

Conclusions

COVID-19 produces measurable impacts on red and white blood cells that are significant predictors of PCR results. A routine blood draw may offer probabilistic insight as a diagnostic predictor of infection. The virus is associated with impacts in red blood cells’ vital oxygen transport attributes.

Public Health Implications

A faster diagnostic tool for COVID-19 will assist providers to triage and isolate those with the virus, reducing hospital transmission. Results are being used to develop a predictive model with high sensitivity and specificity.
Cardiovascular disease Multimorbidity is Associated with Decreased Health-Related Quality of Life in Haiti: Findings from a Population-based Cohort
Authors: Sabwa Shalom , Rouzier Vanessa , Sufra Rodney , St. Sauveur Reichling , Mourra Nour , Rasul Rehana , Inddy Joseph , Yan Lily D. , Sterling Madeline , Pinheiro Laura , Deschamps Marie , Pape Jean William , McNairy Margaret L.
Published: May 2024

Background

Multimorbidity is increasingly prevalent in lower-and middle-income countries (LMICs). Health-related quality of life (HRQOL) has been inversely associated with multimorbidity but is understudied in LMICs. We report cardiovascular disease (CVD) multimorbidity in Haiti and its association with HRQOL.

Methods

We used data from the Haiti CVD Cohort, a population-based longitudinal cohort of adults. CVD multimorbidity was 2+ CVD risk factors/diseases at enrollment. HRQOL was measured using the Short Form-12, yielding physical (PCS)/mental (MCS) component summary scores between 0-100, with higher scores indicating better HRQOL. We used linear regressions to assess the association between CVD multimorbidity and HRQOL and between individual CVD comorbidities and HRQOL. Additionally, we examined how gender and education modified the main effect.

Results

Among 2,996 participants, the median age was 40 (IQR: 27-55), 58.0% were female, and 70.3% earned <1 USD/day. CVD multimorbidity prevalence was 24.1%; compared to those without CVD multimorbidity, those with CVD multimorbidity were older (median 56.0 [IQR: 47.0, 53.0]) and female (70.5%). Adjusted models revealed CVD multimorbidity was inversely related to PCS (−2.7 [95% CI: −3.8, −1.6]) and MCS (−1.0 [95% CI: −1.8, −0.2]). Heart failure and hypertension showed the strongest CVD morbidities associated with poor HRQOL. In the interaction analysis, among men, CVD multimorbidity was associated with a 4.3-point lower PCS score, and among those with less education, CVD multimorbidity was associated with a 4.6-point lower PCS score than no CVD multimorbidity.

Conclusions

Our data are among the first to describe HRQOL data with high CVD multimorbidity in a young population in urban Haiti, and CVD multimorbidity was associated with decreased HRQOL.

(https://www.clinicaltrials.gov/ct2/show/NCT03892265, #NCT03892265)

Research Perspective

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This research raises the question of whether people with CVD multimorbidity in LMICs need specific interventions that are tailored to their high levels of comorbidity and if women and those with low socioeconomic status are at extra risk for experiencing the adverse effects of multimorbidity.

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Future research should investigate cut-off points for describing a population average relevant to an LMIC.
Fluid flow overcomes antimicrobial resistance by boosting delivery
Authors: Shuppara Alexander M. , Padron Gilberto C. , Sharma Anuradha , Modi Zil , Koch Matthias D. , Sanfilippo Joseph E.
Published: May 2024

Antimicrobial resistance is an emerging global threat to humanity. As resistance outpaces development, new perspectives are required. For decades, scientists have prioritized chemical optimization, while largely ignoring the physical process of delivery. Here, we used biophysical simulations and microfluidic experiments to explore how fluid flow delivers antimicrobials into communities of the highly resistant pathogenPseudomonas aeruginosa. We discover that increasing flow overcomes bacterial resistance towards three chemically distinct antimicrobials: hydrogen peroxide, gentamicin, and carbenicillin. Without flow, resistantP. aeruginosacells generate local zones of depletion by neutralizing all three antimicrobials through degradation or chemical modification. As flow increases, delivery overwhelms neutralization, allowing antimicrobials to regain effectiveness against resistant bacteria. Additionally, we discover that cells on the edge of a community shield internal cells, and cell-cell shielding is abolished in higher flow regimes. Collectively, our quantitative experiments reveal the unexpected result that physical flow and chemical dosage are equally important to antimicrobial effectiveness. Thus, our results should inspire the incorporation of flow into the discovery, development, and implementation of antimicrobials, and could represent a new strategy to combat antimicrobial resistance.
Genomic exploration of the complex journey ofPlasmodium vivaxin Latin America
Authors: Lefebvre M. J. M. , Degrugillier F. , Arnathau C. , Fontecha G. A. , Noya O. , Houzé S. , Severini C. , Pradines B. , Berry A. , Trape J-F. , Sáenz F. E. , Prugnolle F. , Fontaine M. C. , Rougeron V.
Published: May 2024

Plasmodium vivax, the predominant malaria parasite in Latin America, has a rich and complex colonization history in the region, with debated hypotheses about its origin. Our study employed cutting-edge population genomic techniques, to collect whole genome sequencing data from 620P. vivaxisolates, including 107 newly sequenced samples, thus representing nearly all potential source populations worldwide. Analyses of the genetic structure, diversity, ancestry, and also, coalescent-based inferences and scenario testing using Approximate Bayesian Computation, have revealed a more complex evolutionary history than previously envisioned. Indeed, according to our analysis, the current AmericanP. vivaxpopulations predominantly stemmed from a now-extinct European lineage, with the potential contribution also from unsampled populations, most likely of West African origin, during post-colonial human migration waves in the late 19th-century. This study provides a fresh perspective onP. vivaxintricate evolutionary journey and brings insights into the possible contribution of West AfricanP. vivaxpopulations to the colonization history of Latin America.
Phylogenomics of novel clones ofAeromonas veroniirecovered from a freshwater lake reveals unique biosynthetic gene clusters
Authors: Lawal Opeyemi U. , Bryan Noah , Parreira Valeria R. , Anderson Rebecca , Chen Yanhong , Precious Melinda , Goodridge Lawrence
Published: May 2024

Aquatic ecosystems are important reservoirs for clinically relevant pathogens and antimicrobial resistance genes, thus present a significant risk to global health. Here, we assessed the phylogenomics ofAeromonas veronii(A. veronii) recovered from Lake Wilcox in Ontario using a combination of morphological, biochemical, and whole-genome sequencing (WGS) techniques.

Eleven distinct bacterial colonies were isolated and identified asA. veronii(n=9), and two otherAeromonasspecies (A. caviaeandA. allosaccharophila), with significant discrepancies noted between biochemical and WGS identification methods. Of note, 67% (n=6/9) ofA. veroniiisolates were human pathogens (Pathogenicity score ≥ 0.50). The genomic analysis revealed high genetic diversity among theA. veroniiisolates, including the discovery of 41 novel alleles and seven new sequence types (ST) suggesting the lake as a reservoir for multiple human pathogenic clones of this bacterium. The comparison of the newly isolated and sequencedA. veroniiwith 214A. veroniigenomes revealed significant genetic diversity and suggests potential broad geographical dissemination of strains. Chromosomal genes (OXA-912andcphA[cphA3, cphA4, cphA7]) genes encoding resistance to β-lactamases were detected in all isolates. Human and non-human pathogenic strains ofA. veroniidiffered in their virulence gene content, with type III secretion systems being associated with human pathogenic isolates. Mobilome analysis revealed the absence of plasmids inA. veroniiisolates and the presence of 13 intact the great majority of which were P22-like (Peduoviridae) phages, and nine different insertion sequence families. Novel biosynthetic gene clusters were identified and characterized, indicating the potential for unique secondary metabolite production inA. veroniiwith different pathogenic potential. Overall, this study underscores the importance of continuous surveillance of aquatic ecosystems for the presence of pathogens, contributing to our understanding of their evolution, potential for human pathogenicity, and the ecological roles of their genetic elements.
Characterization of Tgl2, a putative lipase in yeast mitochondria
Authors: Tiku Vitasta , Tatsuta Takashi , Jung Martin , Rapaport Doron , Dimmer Kai Stefan
Published: May 2024

Mitochondria derive the majority of their lipids from other organelles through contact sites. These lipids, primarily phosphoglycerolipids, are the main components of mitochondrial membranes. In the cell, neutral lipids like triacylglycerides (TAGs) are stored in lipid droplets, playing an important role in maintaining cellular health. Enzymes like lipases mobilize these TAGs according to cellular needs. Neutral lipids have not yet been reported to play an important role in mitochondria so the presence of a putative TAG lipase – Tgl2, in yeast mitochondria is surprising. Moreover,TGL2andMCP2, a high-copy suppressor for ERMES deficient cells, display genetic interactions suggesting a potential link to lipid metabolism. In this study, we characterize in detail Tgl2. We show that Tgl2 forms dimers through intermolecular disulfide bridges and a cysteine-dependent high molecular weight complex. Furthermore, we could identify the lipase motif and catalytic triad of Tgl2 throughin silicocomparison with other lipases and mutated the catalytically active residues accordingly. Both mutants failed to rescue the growth phenotype ofmcp2Δ/tgl2Δ double deletion strain suggesting that the residues are indeed essential for the protein’s function. Additionally, we discovered that the catalytically active aspartate residue is important for protein stability. Steady state level analyses with non-functional variants of Tgl2 led to the identification of Yme1 as the protease responsible for its quality control. Finally, we provide evidence that the overall increase in TAGs in cells lacking Mcp2 and Tgl2 originates from the mitochondria. Collectively, our study provides new insights into a key player in mitochondrial lipid homeostasis.
Engineering anfgfr4knockout zebrafish to study its role in development and disease
Authors: Harrison Emma N. , Jay Amanda N. , Kent Matthew R. , Sukienik Talia P. , LaVigne Collette A. , Kendall Genevieve C.
Published: May 2024

Fibroblast growth factor receptor 4 (FGFR4) has a role in many biological processes, including lipid metabolism, tissue repair, and vertebrate development. In recent years, FGFR4 overexpression and activating mutations have been associated with numerous adult and pediatric cancers. As such,FGFR4presents an opportunity for therapeutic targeting which is being pursued in clinical trials. To understand the role of FGFR4 signaling in disease and development, we generated and characterized three alleles offgfr4knockout zebrafish strains using CRISPR/Cas9. To generatefgfr4knockout crispants, we injected single-cell wildtype zebrafish embryos withfgfr4targeting guide RNA and Cas9 proteins, identified adult founders, and outcrossed to wildtype zebrafish to create an F1 generation. The generated mutations introduce a stop codon within the second Ig-like domain of Fgfr4, resulting in a truncated 215, 223, or 228 amino acid Fgfr4 protein compared to 922 amino acids in the full-length protein. All mutant strains exhibited significantly decreasedfgfr4mRNA expression during development, providing evidence for successful knockout offgfr4in mutant zebrafish. We found that, consistent with otherFgfr4knockout animal models, thefgfr4mutant fish developed normally; however, homozygousfgfr4mutant zebrafish were significantly smaller than wildtype fish at three months post fertilization. Thesefgfr4knockout zebrafish lines are a valuable tool to study the role of FGFR4 in vertebrate development and its viability as a potential therapeutic target in pediatric and adult cancers, as well as other diseases.
Intracranial neurophysiological correlates of rumination
Authors: Chen Xiao , Fan Zhen , Chen Dong , Wang Liang , Chen Liang , Yan Chao-Gan
Published: May 2024

Rumination is a transdiagnostic psychological process that plays a prominent role in many common psychiatric disorders, albeit its neurophysiological basis remains elusive. Existing neuroimaging studies have highlighted the precuneus and hippocampus as two essential brain regions in rumination’s neural underpinnings. Here, we examined the intracranial electroencephalogram (iEEG) recordings from 21 patients with epilepsy during a naturalistic, continuous, active rumination state and measured the slow frequency (1-8 Hz) and high gamma (70-150 Hz) band oscillation powers. We observed enhanced slow frequency power in the precuneus and reduced high gamma power in the hippocampus during the rumination condition compared to the control condition. The hippocampal high gamma power reduction was associated with the self-reported reflection tendency. Our findings provided the first empirical evidence of the neurophysiological underpinnings of rumination and implicated a precuneus-hippocampus coupling across neural oscillation bands during an active rumination state.
Cell Competition Eliminates Aneuploid Human Pluripotent Stem Cells
Authors: Ya Amanda , Deng Chenhui , Godek Kristina M.
Published: May 2024

Human pluripotent stem cells (hPSCs) maintain diploid populations for generations despite a persistently high rate of mitotic errors that cause aneuploidy, or chromosome imbalances. Consequently, to maintain genome stability, aneuploidy must inhibit hPSC proliferation, but the mechanisms are unknown. Here, we surprisingly find that homogeneous aneuploid populations of hPSCs proliferate unlike aneuploid non-transformed somatic cells. Instead, in mosaic populations, cell non-autonomous competition between neighboring diploid and aneuploid hPSCs eliminates less fit aneuploid cells. Aneuploid hPSCs with lower Myc or higher p53 levels relative to diploid neighbors are outcompeted but conversely gain a selective advantage when Myc and p53 relative abundance switches. Thus, although hPSCs frequently missegregate chromosomes and inherently tolerate aneuploidy, Myc- and p53-driven cell competition preserves their genome integrity. These findings have important implications for the use of hPSCs in regenerative medicine and for how diploid human embryos are established despite the prevalence of aneuploidy during early development.
The Rubicon-WIPI axis regulates exosome biogenesis during aging
Authors: Yanagawa Kyosuke , Kuma Akiko , Hamasaki Maho , Kita Shunbun , Yamamuro Tadashi , Nishino Kohei , Nakamura Shuhei , Omori Hiroko , Kaminishi Tatsuya , Oikawa Satoshi , Kato Yoshio , Edahiro Ryuya , Kawagoe Ryosuke , Taniguchi Takako , Tanaka Yoko , Shima Takayuki , Tabata Keisuke , Iwatani Miki , Bekku Nao , Hanayama Rikinari , Okada Yukinori , Akimoto Takayuki , Kosako Hidetaka , Takahashi Akiko , Shimomura Iichiro , Sakata Yasushi , Yoshimori Tamotsu
Published: May 2024

Cells release intraluminal vesicles (ILVs) in multivesicular bodies as exosomes to communicate with other cells. Although recent studies suggest an intimate link between exosome biogenesis and autophagy, the detailed mechanism is not fully understood. Here we employed comprehensive RNAi screening for autophagy-related factors and discovered that Rubicon, a negative regulator of autophagy, is essential for exosome release. Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Interactome analysis of WIPI2d identified the ESCRT components that are required for ILV formation. Notably, we found that Rubicon is required for an age-dependent increase of exosome release in mice. In addition, small RNA sequencing of serum exosomes revealed that Rubicon determines the fate of exosomal microRNAs associated with cellular senescence and longevity pathways. Taken together, our current results suggest that the Rubicon-WIPI axis functions as a key regulator of exosome biogenesis and is responsible for the age-dependent changes in exosome quantity and quality.
Cell type- and layer-specific plasticity of olfactory bulb interneurons following olfactory sensory neuron ablation
Authors: Kunkhyen Tenzin , Brechbill Taryn R. , Berg Sarah P.R. , Pothuri Pranitha , Rangel Alex N , Gupta Ashna , Cheetham Claire E.J.
Published: May 2024

Lifelong neurogenesis endows the mouse olfactory system with a capacity for regeneration that is unique in the mammalian nervous system. Throughout life, olfactory sensory neurons (OSNs) are generated from olfactory epithelium (OE) stem cells in the nose, while the subventricular zone generates neuroblasts that migrate to the olfactory bulb (OB) and differentiate into multiple populations of inhibitory interneurons. Methimazole (MMZ) selectively ablates OSNs, but OE neurogenesis enables OSN repopulation and gradual recovery of OSN input to the OB within six weeks. However, it is not known how OB interneurons are affected by this loss and subsequent regeneration of OSN input following MMZ treatment. We found that dopaminergic neuron density was significantly reduced 7-14 days post-MMZ but recovered substantially at 35 days. The density of parvalbumin-expressing interneurons was unaffected by MMZ; however, their soma size was significantly reduced at 7-14 days post-MMZ, recovering by 35 days. Surprisingly, we found a transient increase in the density of calretinin-expressing neurons in the glomerular and external plexiform layers, but not the granule cell layer, 7 days post-MMZ. This could not be accounted for by increased neurogenesis but may result from increased calretinin expression. At subsequent time points, calretinin neurons in all three layers showed reduced density at 14 days but recovered to baseline by 35 days. Together, our data demonstrate cell type- and layer-specific changes in OB interneuron density and morphology after MMZ treatment, providing new insight into the range of plasticity mechanisms employed by OB circuits during loss and regeneration of sensory input.
Improving reproductive success in captive marmosets through active female choice
Authors: Drazan Taylor M , Bradley Sean P , Jones Aikeen , Allen-Worthington Krystal , Chudasama Yogita
Published: May 2024

The recent upsurge in the use of common marmosets (Callithrix jacchus) as a desirable model for high priority biomedical research has challenged local and global suppliers struggling to provide sufficient numbers of marmosets for large scale projects. Scientific research laboratories are increasingly establishing institutional breeding colonies, in part to combat the resulting shortage and high cost of commercially available animals, and in part to have maximum control over research lines involving reproduction and development. For such laboratories, efficient marmoset breeding can be challenging and time consuming. Random male/female pairings are often unsuccessful, with intervals of several months before attempting alternate pairings. Here we address this challenge through a behavioral task that promotes self-directed female selection of potential mates to increase the efficiency of breeding in captive marmosets. We created a partner preference test (‘love maze’) in which nulliparous females (n=12) had the opportunity to select between two eligible males (n=23) at a time, in a forced choice test. In this test, both males usually displayed sexual solicitations. However, the female would clearly indicate her preference for one. Most commonly, the female actively ignored the non-preferred male and directed overt prosocial behaviors (e.g. proceptive tongue-flicking, approach and grooming) to the preferred male. Moreover, once a male was selected in this context, the female would continue to prefer him over other males in three consecutive testing sessions. Compared with random pairings, this directed female choice showed a 2.5-fold improvement in breeding within 90 days compared to random pairings. This cost-effective and straightforward pairing practice can be used to enhance breeding efficiency in both small and large marmoset colonies.
Mechanical Properties of White Matter Tracts in Aging Assessed via Anisotropic MR Elastography
Authors: Caban-Rivera Diego A. , Williams Lance T. , McGarry Matthew D. J. , Smith Daniel R. , Van Houten Elijah E. W. , Paulsen Keith D. , Bayly Philip V. , Johnson Curtis L.
Published: May 2024

Magnetic resonance elastography (MRE) is a promising neuroimaging technique to probe tissue microstructure, which has revealed widespread softening with loss of structural integrity in the aging brain. Traditional MRE approaches assume mechanical isotropy. However, white matter is known to be anisotropic from aligned, myelinated axonal bundles, which can lead to uncertainty in mechanical property estimates in these areas when using isotropic MRE. Recent advances in anisotropic MRE now allow for estimation of shear and tensile anisotropy, along with substrate shear modulus, in white matter tracts. The objective of this study was to investigate age-related differences in anisotropic mechanical properties in human brain white matter tracts for the first time. Anisotropic mechanical properties in all tracts were found to be significantly lower in older adults compared to young adults, with average property differences ranging between 0.028-0.107 for shear anisotropy and between 0.139-0.347 for tensile anisotropy. Stiffness perpendicular to the axonal fiber direction was also significantly lower in older age, but only in certain tracts. When compared with fractional anisotropy measures from diffusion tensor imaging, we found that anisotropic MRE measures provided additional, complementary information in describing differences between the white matter integrity of young and older populations. Anisotropic MRE provides a new tool for studying white matter structural integrity in aging and neurodegeneration.
Basic reproduction number for pandemicEscherichia coliclones varies markedly and can be comparable to pandemic influenza viruses
Authors: Ojala Fanni , Pesonen Henri , Gladstone Rebecca A. , Mäklin Tommi , Tonkin-Hill Gerry , Marttinen Pekka , Corander Jukka
Published: May 2024

Extra-intestinal pathogenicEscherichia coli(ExPEC) ubiquitously colonize the human gut and represent clinically the most significant bacterial species causing urinary tract infections and bacteremia in addition to contributing to meningitis in neonates. During the last two decades, newE. colimulti-drug resistant clones such as ST131, particularly its clades C2 and C1, have spread globally, as has their generally less resistant sister clade ST131-A. Phylodynamic coalescent modeling has indicated exponential growth in the populations corresponding to these clades during the early 2000s. However, it remains unknown how their transmission dynamics compare to viral epidemics and pandemics in terms of key epidemiological quantities such as the basic reproduction number (R0). Estimation ofR0for opportunistic pathogenic bacteria poses a difficult challenge compared to viruses causing acute infections, since data onE. coliinfections accumulate with a much longer delay, even in the most advanced public health reporting systems. Here, we developed a compartmental model for asymptomatic gut colonization and onward transmission coupled with a stochastic epidemiological observation model for bacteremia and fitted the model to annual Norwegian nationalE. colidisease surveillance and bacterial population genomics data. Approximate Bayesian Computation leveraged by the ELFI software package was used to inferR0for the pandemic ST131 clades. The resultingR0estimates for ST131-A and ST131-C2 were 1.47 (1.31-1.60) and 1.13 (1.08-1.20), respectively, indicating that the ST131-A transmission potential is comparable to pandemic influenza viruses, such as H1N1. The significantly lower transmissibility of ST131-C2 suggests that its global dissemination has been aided by antibiotic selection pressure and that it may be more effectively transmitted through health care facilities instead of primarily community driven transmission. In summary our results provide a fundamental advance in understanding the transmissibility of these opportunistic pathogens and that it can vary markedly even between very closely relatedE. coli.
Myosin VI controls localization of Golgi satellites at active presynaptic boutons
Authors: Hertrich Nathalie , Doil Nathanael , Konietzny Anja , Mikhaylova Marina
Published: May 2024

Neurons, as long-living non-dividing cells with complex morphology, depend on highly elaborate secretory trafficking system which ensures the constant delivery, removal and recycling of proteins and membranes. Previously, we have shown that simplified Golgi-related structures called Golgi satellites (GS), distinct from the somatic Golgi complex, are present in dendrites of primary hippocampal neurons and are involved in glycosylation and local forward trafficking of membrane proteins. However, whether GS are also targeted to axons of principal neurons have not been explored. Here, we investigate the subcellular distribution of GS in adult hippocampal neurons and discover that mobile and stationary GS are present along the entire axonal length, extending to the distal tips of the growth cone. Live imaging experiments revealed that neuronal firing modulates the switch between long range transport mediated by kinesin and dynein and stalling. We found that GS frequently pause or stop at pre-synaptic sites in activity-dependent manner. This behavior depends on the actin cytoskeleton and the actin-based motor protein myosin VI. Overall, our study demonstrates that neuronal activity can dynamically regulate the positioning of GS in the axon, shedding light on the intricate mechanisms underlying organelle trafficking in neurons.

Significance statement

Our study unveils the presence and dynamic behavior of Golgi satellites (GS), specialized organelles implicated in glycosylation and membrane protein trafficking, within axons of adult neurons. We found that mobile and stationary GS are present throughout the axonal length, including distal growth cone regions. GS are transported bidirectionally and their preferential pausing at presynaptic sites is regulated by neuronal firing. GS positioning at presynaptic boutons relies on the actin cytoskeleton and the myosin VI motor protein. This work elucidates how neuronal activity modulates GS distribution, shedding light on fundamental mechanisms of organelle trafficking in neurons.
Syncing Minds for Learning: Student-Teacher Interaction Forecasts Academic Improvements Over Semesters
Authors: Xu Xiaomeng , Zhang Dan , Zhang Yu
Published: May 2024

Background

Student performance continuously fluctuates throughout the learning process, with teachers playing a pivotal role in shaping these changes. While previous research has established the influence of student-teacher interactions on learning outcomes, how such interactions drive variations in performance across different students remains an open question. In practice, teachers are often unclear about which students interact well with them, which may hinder the improvement of teaching strategies.

Aims

Leveraging advancements in hyperscanning technology, this study utilizes longitudinal EEG data collected in real classrooms to explore the impact of student-teacher inter-brain coupling on academic improvements.

Methods

The study employs a novel dynamic model and two static models to explore the relationship between teacher-student inter-brain coupling and students’ academic performance and progress, while controlling for the effects of teacher self-selection.

Results

The findings reveal that enhanced coupling predominately at the high-beta frequency band serves as a positive predictor of academic improvements in both Chinese and math subjects.

Conclusions

This study highlights the critical role of inter-brain coupling in learning, providing robust evidence of ecological validity and confirming its practical potential.
The Anomalous Effect of COVID-19 Pandemic Restrictions on the Duration of Untreated Psychosis (DUP)
Authors: Nicholls-Mindlin Jessica , Hazan Hadar , Zhou Bin , Li Fangyong , Ferrara Maria , Levine Nina , Riley Sarah , Karmani Sneha , Mathis Walter S , Keshavan Matcheri S , Srihari Vinod
Published: May 2024

We investigated the impact of COVID-19 restrictions on the duration of untreated psychosis (DUP). First-episode psychosis admissions (n=101) to STEP Clinic in Connecticut showed DUP reduction (p=.0015) in the pandemic, with the median reducing from 208 days during the pre-pandemic to 56 days in the early pandemic period and subsequently increasing to 154 days (p=.0281). Time from psychosis onset to anti-psychotic prescription decreased significantly in the pandemic (p=.0183), with the median falling from 117 to 35 days. This cohort study demonstrates an association between greater pandemic restrictions and marked DUP reduction and provides insights for future early detection efforts.
A new method using rapid Nanopore metagenomic cell-free DNA sequencing to diagnose bloodstream infections: a prospective observational study
Authors: Nielsen Morten Eneberg , Søgaard Kirstine Kobberøe , Karst Søren Michael , Krarup Anne Lund , Nielsen Hans Linde , Albertsen Mads
Published: May 2024

Background

Bloodstream infections (BSIs) remain a major cause of mortality, in part due to many patients developing sepsis or septic shock. To survive sepsis, it is paramount that effective antimicrobial therapy is initiated rapidly to avoid excess mortality, but the current gold-standard to identify the pathogen in BSIs, blood culturing, has great limitations with a long turnaround time and a poor sensitivity. This delay to correct empiric broad-spectrum antimicrobial treatments leads to excess mortality and antimicrobial resistance development.

Methods

In this study we developed a metagenomic next-generation sequencing (mNGS) assay utilizing the Oxford Nanopore Technologies platform to sequence microbial cell-free DNA from blood plasma. The method was evaluated in a prospective observational clinical study (n=40) in an emergency ward setting, where a study sample was taken from the same venipuncture as a blood culture sample from patients with a suspected BSI.

Findings

Nanopore mNGS confirmed all findings in patients with a positive blood culture (n=11), and identified pathogens relevant to the acute infection in an additional 11 patients with a negative blood culture. In an analysis of potential impact on the antibiotic treatment, we found that 59% (n=13) of mNGS positive answers could have impacted the treatment, with five cases of a change from ineffective to effective therapy.

Interpretation

This study demonstrates that culture-independent Nanopore mNGS directly on blood plasma could be a feasible alternative to blood culturing for infection diagnostics for patients admitted with a severe infection or sepsis. The method identified a relevant pathogen in patients with a broad range of etiologies including urinary tract infections and lower respiratory tract infections. With a turnaround time of 6 hours the method could provide unprecedented speed and sensitivity in BSI diagnostics.
Long-term effects of a coalmine fire on hospital and ambulance use: an interrupted time series study
Authors: Lane Tyler J. , Smith Catherine L. , Gao Caroline X. , Ikin Jillian F. , Xu Rongbin , Carroll Matthew T.C. , Nehme Emily , Abramson Michael J. , Guo Yuming
Published: May 2024

Background

In 2014, the Hazelwood coalmine fire in regional Victoria, Australia shrouded nearby communities in smoke for six weeks. Prior investigations identified substantial adverse effects, including increases in the use of health services. In this study, we examined the effects on hospital and ambulance use in the eight years following the fire.

Methods

Using Victorian hospital (Jan 2009-Jun 2022) and ambulance (Jan 2013-Dec 2021) data, we conducted an interrupted time series of changes to the rate of hospital admissions, emergency presentations, and ambulance attendances. A categorical exposure model compared two locations, most-exposed Morwell and less-exposed Latrobe Valley, to the rest of regional Victoria. A continuous exposure model used spatial estimates of fire-related PM2.5. Analyses were stratified by sex, age group (<65/65+ years), and condition (cardiovascular, respiratory, mental health, injury).

Results

There were small but significant increases in overall hospital admissions and emergency presentations across all analyses, but little evidence of change in overall ambulance attendances. Effects varied considerably by condition, with the biggest relative increases observed among hospital admissions for mental health conditions and injuries. While cardiovascular-related hospital admissions and emergency presentations increased post-fire, ambulance attendances decreased.

Conclusions

Our findings suggest the Hazelwood coalmine fire likely increased hospital usage. However, it is unclear whether this was due to the direct effects of smoke exposure on health, or the disruptive socioeconomic and behavioural impacts of an environmental disaster that affected how communities engaged with various health services.
DNA Methylation-Derived Immune Cell Proportions and Cancer Risk, Including Lung Cancer, in Black Participants
Authors: Semancik Christopher S. , Zhao Naisi , Koestler Devin C. , Boerwinkle Eric , Bressler Jan , Buchsbaum Rachel J. , Kelsey Karl T. , Platz Elizabeth A. , Michaud Dominique S.
Published: May 2024

Prior cohort studies assessing cancer risk based on immune cell subtype profiles have predominantly focused on White populations. This limitation obscures vital insights into how cancer risk varies across race. Immune cell subtype proportions were estimated using deconvolution based on leukocyte DNA methylation markers from blood samples collected at baseline on participants without cancer in the Atherosclerosis Risk in Communities (ARIC) Study. Over a mean of 17.5 years of follow-up, 668 incident cancers were diagnosed in 2,467 Black participants. Cox proportional hazards regression was used to examine immune cell subtype proportions and overall cancer incidence and site-specific incidence (lung, breast, and prostate cancers). Higher T regulatory cell proportions were associated with statistically significantly higher lung cancer risk (hazard ratio = 1.22, 95% confidence interval = 1.06-1.41 per percent increase). Increased memory B cell proportions were associated with significantly higher risk of prostate cancer (1.17, 1.04-1.33) and all cancers (1.13, 1.05-1.22). Increased CD8+ naïve cell proportions were associated with significantly lower risk of all cancers in participants ≥55 years (0.91, 0.83-0.98). Other immune cell subtypes did not display statistically significant associations with cancer risk. These results in Black participants align closely with prior findings in largely White populations. Findings from this study could help identify those at high cancer risk and outline risk stratifying to target patients for cancer screening, prevention, and other interventions. Further studies should assess these relationships in other cancer types, better elucidate the interplay of B cells in cancer risk, and identify biomarkers for personalized risk stratification.