bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel, high throughput, and low-cost method for the detection of 40 amines relevant to inborn errors of metabolism, in under 60 minutes, using reverse phase high performance liquid chromatography
Authors: Wilson Kirkland A , Zhou Yun , Cunningham Gary , Chapman Kimberly , Summar Marshall , Regier Debra
Published: May 2024

Objectives

An assessment of amino acid and amine concentrations is important for the diagnosis and management of inborn errors of metabolism (IEMs). Methods exist that measure these biologically important metabolites but are cost-prohibitive and/or time consuming. We therefore sought to develop a novel methodology, applicable to IEMs, that is both high-throughput and low cost.

Methods

Previously, we developed a methodology for rapid, repeatable, and cost-efficient separation of approximately 20 amines as a proof of concept and now expand it to amines relevant to IEMs. We describe our separation methodology using reverse phase high performance liquid chromatography with ultraviolet-visible spectrum absorbance paired with precolumn derivatization witho-phthaladehyde.

Results

We show reproducibility via concentration assessments, in triplicate, for each amine. We assess amines in prepared standard solutions and in biologic samples from patients with IEMs. We also detected and assessed the amino group containing compounds oxidized and reduced glutathione and ammonia. Validation was established using absolute area under the curve (AUC) and via comparison using a single internal standard.

Conclusions

We report good separation of 40 primary amino group containing metabolites, in a single, less than 60-minute run. This rapid, low cost, and accurate methodology only requires a small volume of sample and can greatly increase availability and access. Finally, the numerous disease associated amines (ie homocitrulline, trimethyllysine, alloisoleucine) and unique compounds detected in our single run has broad research and clinical utility and can increase efficiency, important as the need for analysis of amines grows globally.
Single unit-derived connectivity networks in tuberous sclerosis complex reveal propensity for network hypersynchrony driven by tuber-tuber interactions
Authors: Chari Aswin , Hernan Amanda E , Mahoney J Matthew , Thornton Rachel , Tahir M Zubair , Tisdall Martin M , Scott Rod C
Published: May 2024

Network hypersynchrony is emerging as an important system-level mechanism underlying seizures, as well as cognitive and behavioural impairments, in children with structural brain abnormalities. We investigated patterns of single neuron action potential behaviour in 206 neurons recorded from tubers, transmantle tails of tubers and normal looking cortex in 3 children with tuberous sclerosis. The patterns of neuronal firing, on a neuron-by-neuron (autocorrelation) basis did not reveal any differences as a function of anatomy. However, at the level of functional networks (cross-correlation), there is a much larger propensity towards hypersynchrony of tuber-tuber neurons that in neurons from any other anatomical site. This suggests that tubers are the primary drivers of adverse outcomes in children with tuberous sclerosis.
Posttraumatic stress symptoms in chronic pain: impacts on brain morphology
Authors: Quidé Yann , Hesam-Shariati Negin , Norman-Nott Nell , McAuley James H , Gustin Sylvia M
Published: May 2024

Background. Posttraumatic stress symptoms (PTSS) are commonly experienced by people with chronic pain. Although PTSS and chronic pain are associated with similar effects on brain morphology, the present study aimed to clarify the relationship between chronic pain and PTSS on the brain. Methods. Fifty-two people with chronic pain and 38 pain-free healthy controls (HC) underwent T1-weighted magnetic resonance imaging. Severity of PTSS was measured using the civilian version of the posttraumatic stress disorder checklist (PCL-C). A series of multiple linear regressions determined the main effects of group, PTSS severity (PCL-C total score and symptom-specific scores) and their interaction on grey matter volume of selected regions-of-interest. Results. The interaction term was significantly associated with variations in grey matter volume in the left and right putamen, the left middle cingulate cortex (MCC) and the right posterior insula. Results showed significantly smaller left and right putamen when reporting higher PTSS levels, and significantly larger left MCC and right posterior insula at lower PTSS levels in people with chronic pain compared to HCs. In addition, increasing PTSS severity was significantly associated with larger left and right putamen in HCs, and significantly associated with smaller left MCC and right posterior insula, in people with chronic pain. Conclusions. Severity of PTSS moderated chronic pain-related grey matter alterations. More severe PTSS, especially avoidance, was associated with smaller left MCC, a core region of the pain matrix. The MCC is strongly linked with the somatosensory network, and critical for empathy, especially toward pain-related stimuli.
Housing instability among young men who have sex with men in a US national sample
Authors: Sisselman-Borgia Amanda , Patel Viraj V , Grov Christian
Published: May 2024

Background

Youth, including those experiencing housing instability, are among the fastest growing groups of individuals with new STI diagnoses, including HIV. The unpredictable nature of the lives of youth experiencing housing instability often leads to inconsistent or non-existent health care and preventive follow up, leaving gaps in our knowledge about the most prominent needs for intervention.

Methods

Using data from theTogether 5000(T5K) study, we examined factors associated with housing instability in a sample of 2,228 youth between the ages of 16-24 who identified as sexual and gender minority (SGM) men having sex with men. Logistic regression was used to assess the most prominent factors associated with housing instability. The model included seven significant factors - former peer victimization, gender, age, sex work, IPV, social support, and health insurance status.

Findings

Participants who reported more behavioral risk factors for STI and those who reported sex work in the last three months were more likely to experience housing instability (OR = 2.5 and 2.76 respectively). Youth with higher levels of reported social support, health insurance, and older age were more likely to report stable housing (OR = .98, 1.61, and 1.13 respectively). Surprisingly, youth with stable housing were more likely to report intimate partner violence than those experiencing housing instability (OR = .89).

Discussion

Implications for addressing STIs among adolescent SGM men having sex with men are discussed including bolstering support systems and addressing basic needs deficits and trauma associated with sex work and behavioral risk factors for STI.

Implications and contributions statement

The study examines correlates of housing instability among a sample of young sexual and gender minority men who have sex with other men. Correlates of housing instability included behavioral risk factors for sexually transmitted infection and reporting sex work in the last three months. Health insurance, older age, and higher levels of social support were correlated with more stable housing.
One way or another, you’re not going to fit: Trans and gender diverse people’s perspectives on sexual health services in the United Kingdom
Authors: Witney Tom , Rait Greta , Saunders John , Hobbes Lorna , Mitchell Laura , Stewart Jay , McDonagh Lorraine
Published: May 2024

Objectives

Trans and/or gender diverse (T/GD) people in the UK are less likely to access sexual health services (SHS) than cisgender people but are more likely to report negative experiences. The British Association for Sexual Health and HIV (BASHH) developed expert recommendations for T/GD-inclusive SHS, but these lack service user perspectives. This study addressed this gap by asking T/GD people how SHS could be T/GD-inclusive.

Methods

Semi-structured interviews (n=31) and focus groups (n=21) were conducted with T/GD people aged 17-71 years old recruited through community organisations and social media, exploring experiences of SHS and inclusivity. Study design, materials, and analysis were informed by T/GD people and an advisory committee of charities and sexual health clinicians. Data were analysed using thematic analysis, managed using NVivo.

Results

Participants often expected that SHS were not set up for T/GD people. This was reinforced by poor experiences in other healthcare settings and the lack of information on NHS websites. Some participants had been denied care because they were ‘too complex.’ Participants wanted to know that SHS had engaged with the needs of T/GD people and looked for hallmarks of inclusivity, such as Trans Pride flags in reception areas. Some participants wanted specialist T/GD services, but others preferred to access general SHS. Staff attitudes were a key factor underpinning inclusivity. Anticipating having their identity questioned or needs dismissed, participants sought kindness and openness. Although the needs of T/GD people are diverse and different from cisgender service users, participants stressed that SHS staff already had the skills to deliver sensitive person-centred care and emphasised the value of inclusive SHS.

Conclusion

These findings provide insight into what a sample of T/GD people in the UK consider important for T/GD-inclusive SHS. Participants’ suggestions aligned with and reinforce BASHH expert recommendations. Importantly, they highlight the need for ongoing engagement to deliver T/GD-inclusive SHS.

Key messages

What is already known on this topic

Trans and/or gender diverse people are less likely to engage with sexual health services than cis-gender people

The British Association for Sexual Health and HIV (BASHH) Gender and Sexual Minority Special Interest Group (GSM SIG) has developed expert recommendations for trans-inclusive sexual health services, but user perspectives are missing

What this study adds

Participant suggestions and preferences for inclusive services support BASHH GSM recommendations

Participants looked for inclusive SHS thatrecognise, understand and affirmtheir needs

How this study might affect research, practice or policy

Enhancing T/GD inclusivity involvesactive engagementwithclinical spaces, processes and delivery
Association of immunoglobulin E levels with glioma risk and survival
Authors: Guerra Geno , Nakase Taishi , Kachuri Linda , McCoy Lucie , Hansen Helen M. , Rice Terri , Wiemels Joseph. L. , Wiencke John K. , Molinaro Annette M. , Wrensch Margaret , Francis Stephen S.
Published: May 2024

Background

Previous epidemiologic studies have reported an association of serum immunoglobulin E (IgE) levels with reduced glioma risk, but the association between IgE and glioma prognosis has not been characterized. This study aimed to examine how sex, tumor subtype, and IgE class modulate the association of serum IgE levels with glioma risk and survival.

Methods

We conducted a case-control study using participants from the University of California, San Francisco Adult Glioma Study (1997-2010). Serum IgE levels for total, respiratory and food allergy were measured in adults diagnosed with glioma (n=1319) and cancer-free controls (n=1139) matched based on age, sex, and race and ethnicity. Logistic regression was adjusted for patient demographics to assess the association between IgE levels and glioma risk. Multivariable Cox regression adjusted for patient-specific and tumor-specific factors compared survival between the elevated and normal IgE groups. All statistical tests were 2-sided.

Results

Elevated total IgE was associated with reduced risk of IDH-wildtype (RR=0.78, 95% CI: 0.71-0.86) and IDH-mutant glioma (RR=0.73, 95% CI: 0.63-0.85). In multivariable Cox regression, positive respiratory IgE was associated with improved survival for IDH-wildtype glioma (RR=0.79, 95% CI: 0.67-0.93). The reduction in mortality risk was significant in females only (RR=0.75, 95% CI: 0.57-0.98) with an improvement in median survival of 6.9 months (P<.001).

Conclusion

Elevated serum IgE was associated with improved prognosis for IDH-wildtype glioma, with a more pronounced protective effect in females than males, which has implications for the future study of IgE-based immunotherapies for glioma.
Optimal Donor Selection Across Multiple Outcomes For Hematopoietic Stem Cell Transplantation By Bayesian Nonparametric Machine Learning
Authors: Sparapani Rodney A , Maiers Martin , Spellman Stephen R. , Shaw Bronwen E , Laud Purushottam W , Devine Steven M. , Logan Brent R
Published: May 2024

Allogeneic hematopoietic cell transplantation (HCT) is one of the only curative treatment options for patients suffering from life-threatening hematologic malignancies; yet, the possible adverse complications can be serious even fatal. Matching between donor and recipient for 4 of the HLA genes is widely accepted and supported by the literature. However, among 8/8 allele matched unrelated donors, there is less agreement among centers and transplant physicians about how to prioritize donor characteristics like additional HLA loci (DPB1 and DQB1), donor sex/parity, CMV status, and age to optimize transplant outcomes. This leads to varying donor selection practice from patient to patient or via center protocols. Furthermore, different donor characteristics may impact different post transplant outcomes beyond mortality, including disease relapse, graft failure/rejection, and chronic graft-versus-host disease (components of event-free survival, EFS). We develop a general methodology to identify optimal treatment decisions by considering the trade-offs on multiple outcomes modeled using Bayesian nonparametric machine learning. We apply the proposed approach to the problem of donor selection to optimize overall survival and event-free survival, using a large outcomes registry of HCT recipients and their actual and potential donors from the Center for International Blood and Marrow Transplant Research (CIBMTR). Our approach leads to a donor selection strategy that favors the youngest male donor, except when there is a female donor that is substantially younger.
Development and Iterative Design of Peer-based Discussions about Heart Health for Women
Authors: Spatz Erica S , Park Tina , Breslin Maggie
Published: May 2024

Objective

To support women in their health journeys around cardiovascular risk reduction, providing: access to information; space to discuss complex and personal issues that may factor into decision making; and skills to support conversations with healthcare providers.

Methods

We used a participatory design approach to develop peer sessions led by a non-clinical facilitator and a cardiologist, for women to learn, think, and discuss information and decision-making around cardiovascular risk. These sessions took place in-person and over video. A host invited her friends, family or network to the events. Sessions were designed to bring information to women at all stages of cardiovascular risk, including women with no prior experiences with heart health and women with established cardiovascular disease. The sessions provided information about cardiovascular risk and facilitated discussion around risk factors and treatment. Sessions were recorded, transcribed and analyzed using a grounded theory approach to identify emerging themes.

Results

We conducted 12 groups, with an average of 6 women per group. Women were of all ages and spectrums of cardiovascular risk. The three major themes that emerged were: Starting Place (attitudes, beliefs, and behaviors toward cardiovascular care are informed by a blend of one’s family history, personal interactions with their health and the health system, and approach to managing uncertainty); Lack of Sense-Making (seemingly simple recommendations to support heart health were much more complicated when related to their own risk and experience), and Self-Judgement and Judgement by Others (without support or validation, women may feel judged by others for not doing enough).

Conclusion

Peer sessions can illuminate the complicated issues women face when approaching decisions regarding cardiovascular health. These sessions may offer an alternative to the healthcare setting, for women to wrestle with complex issues that relate to their risk, and better prepare for visits with their healthcare providers.

Highlights

Peer-based sessions designed to support cardiovascular risk reduction conversations can support women in their healthcare journeys.

Women approach cardiovascular risk from different starting places and are challenged with sense-making of conflicting data.

Women are often judged by themselves, and others, about doing ‘enough’ to prevent cardiovascular disease.

Peer-based sessions offer a space for women to think, feel, and discuss issues most relevant to them, which may help support conversations with their healthcare providers.
Genetic correlation and causality between smoking and 42 neuropsychiatric and gastrointestinal diseases
Authors: Xiong Jiayi , Wang Zheng , Huang Yuanfeng , Zhang Shiyu , Yang Guang , Yang Jiaqi , Gao Shuo , Wang Tianyang , Li Jinchen , Zhao Guihu , Li Bin
Published: May 2024

Background

Previous investigations have elucidated epidemiological associations linking smoking to neuropsychiatric and gastrointestinal diseases, yet the underlying causal relationships remain enigmatic. To shed light on this matter, we undertook a Mendelian randomisation(MR) study with the aim of gauging the potential causal association between smoking and the susceptibility to neuropsychiatric and gastrointestinal tract diseases.

Methods

We meticulously collected and preprocessed genome-wide association study (GWAS) data encompassing smoking (280,508 cases and 180,558 controls) as well as neuropsychiatric and gastrointestinal phenotypes (n = 6,681 to 87,3341). To investigate the genetic correlation between smoking and diseases, we employed linkage disequilibrium score regression. We further applied multi-trait analysis of GWAS to identify the shared risk single-nucleotide polymorphisms (SNPs) implicated in both smoking and diseases. Pleiotropic genes were annotated by enrichment analysis. Subsequently, bidirectional MR analysis was performed to infer causality.

Results

Our findings, supported by robust evidence derived from an expansive sample size, demonstrate that smoking exerts a causal influence on merely six of these diseases, while no disease was found to causally impact smoking. Intriguingly, we discovered 513 pleiotropic genes enriched in pathways such as the regulation of growth and synapses, suggesting a potential shared genetic basis between smoking and these diseases, leading to aberrant neural development. Remarkably, among the 42 diseases scrutinized, a significant genetic correlation was exclusively observed with gastroesophageal reflux disease (GRED). Furthermore, we identified risk SNPs shared by smoking and GRED.

Conclusions

This study revealed the shared genetic basis and causal effects connecting smoking to neuropsychiatric and gastrointestinal diseases, thereby providing novel etiological insights into the role of smoking in these diseases.
A cross-sectional study to evaluate access to antenatal care services in Twifo Hemang Lower Denkyira district of Ghana
Authors: Hammond John , Adjei-Gyamfi Silas , Daniels Doreen Brew , Sarpong Godfred Kwabena , Aiga Hirotsugu , Aoki Tsunenori
Published: May 2024

Background

Antenatal care (ANC) which is an essential component of the reproductive, maternal, newborn, and child health continuum of care is found to positively correlate with supervised delivery and the reduction of maternal deaths. In Ghana, few studies have explored how ANC is influenced by the community-based health planning and services (CHPS) policy, and in the Central Region, evidence is non-existent. This study aimed to determine factors that influence access to ANC services provided through the CHPS policy in the Twifo Hemang Lower Denkyira district in the Central Region of Ghana.

Methods

A cross-sectional study examined 310 women aged 15-49 years, having children less than 12 months, and interviewed using a structured questionnaire. Univariate and multivariate logistic regression analyses were conducted using STATA 17 and results were reported as odds ratios at a confidence level of 95%.

Results

ANC coverage and proportion of early ANC initiation were 93.9% and 69.1% respectively.

Being unmarried (AOR=0.125, 95%CI=0.012,0.926), and home delivery (AOR=0.013; 95%CI: 0.001,0.176) were associated with decreased odds of at least one ANC visit during pregnancy. Larger (≥11) household size (AOR=3.848; 95%CI=1.914,16.21), lesser (<4) ANC contacts (AOR=6.332; 95%CI=2.049,19.57), and home visitation by CHPS staff (AOR=1.813; 95%CI=1.014,3.243) were associated with higher odds of late ANC initiation while average monthly income (AOR=0.123; 95%CI=0.024,0.630) was associated with reduced odds of late ANC initiation. Interestingly, knowledge about ANC and pregnancy, and geographical variables like receiving ANC services from CHPS zones, and distance to CHPS zones were not statistically significant with either ANC attendance or time of ANC initiation after controlling for the effect of other variables.

Conclusion

Though ANC and early ANC initiation coverages were relatively high, the complexities in the given correlates of ANC accessibility require a multi-sectoral approach to strengthen community-based services to increase the survival of pregnant women and unborn babies.
Delineating neural contributions to electroencephalogram-based speech decoding
Authors: Sato Motoshige , Kabe Yasuo , Nobe Sensho , Yoshida Akito , Inoue Masakazu , Shimizu Mayumi , Tomeoka Kenichi , Sasai Shuntaro
Published: May 2024

Speech Brain-computer interfaces (BCIs) have emerged as a pivotal technology in facilitating communication for individuals with speech impairments. Utilizing electroencephalography (EEG) for noninvasive speech BCIs offers an accessible and affordable solution, potentially benefiting a broader audience. However, EEG-based speech decoding remains controversial especially for overt speech, due to difficulties in separating speech-related neural activities from myoelectric potential artifacts generated during articulation. Here we aim to delineate the extent of the neural contributions by employing Explainable AI techniques to a convolutional neural network predicting spoken words based on signals obtained by ultra-high-density (uhd)-EEG. We found that electrode-wise contributions to the decoding cannot be explained by their mutual information with electromyography (EMG). Furthermore, contributing periods of speech to EEG-based decoding are distinct from those to decoding solely relying on EMG. In contrast, there are significant overlaps in signal timings contributing to EEG-based decoding, regardless of vocal conditions such as overt or covert speech. Notably, the denoising process successfully enhanced the decoding contribution from electrodes within speech-related brain areas for all speech conditions. Altogether, our findings support the idea that, with appropriate preprocessing, EEG becomes a valuable tool for decoding spoken words based on underlying neural activities.
Revealing the taxonomy and functional potential of urban soil microbiomes
Authors: Stohel Izabel L. , Song Young , Turetcaia Anna , Wilson Andrew J. , Schmidt Dietrich Epp , Yarwood Stephanie A. , Townsend Andrew , Graham Emily B.
Published: May 2024

Urbanization is a leading cause of global biodiversity loss, but its impact on soil microorganisms and biogeochemistry remains uncertain. To address this gap, we investigate urban soil microbiome composition using metagenomic sequences from the Global Urban Soil Environment Ecology Network (GLUSEEN). We seek to reveal (1) changes in taxonomic composition and functional potential and (2) ubiquitous (core) taxa and metabolisms across the urban soil microbiome. We hypothesize that soil taxonomic and functional diversity are correlated due to the unique selective pressures of the urban ecosystem, and that the potential for carbon, nutrient, and pollutant cycling is a key feature of the urban soil microbiome. We find that Baltimore soil microbiomes are distinct from all other cities, displaying the highest taxonomic and lowest functional diversity. Only 66.3% of taxonomic and functional composition is correlated across all cities, highlighting differing functional potential within similar soil microbial taxa. Metabolic processes involving carbon and nitrogen cycling are abundant, as well as xenobiotic degradation. Core urban microbiota include many common soil bacteria and methane- and nitrogen-cycling archaea. Understanding the predominant characteristics of microbial taxonomy and functional potential in urban soils will aid in understanding feedback between growing metropolitan areas and processes driving climate change.
USP14 regulates pS129 α-synuclein levels and oxidative stress in human SH-SY5Y dopaminergic cells
Authors: Srinivasan Vignesh , Soliymani Rabah , Ivanova Larisa , Eriksson Ove , Peitsaro Nina , Lalowski Maciej , Karelson Mati , Lindholm Dan
Published: May 2024

Ubiquitin specific protease-14 (USP14) is critical for controlling protein homeostasis disturbed in human disorders like Parkinsońs disease (PD). Here we investigated the role of USP14 in regulating proteasome and autophagy pathways, and their influence on α-synuclein (α-syn) degradation. Data showed that α-syn and phosphorylated serine129 α-syn (pS129 α-syn) were elevated inUSP14gene-deleted SH-SY5Y dopaminergic cells with concomitant reduction in proteasome activity. Inhibition of proteasomes using MG132 particularly elevated pS129 α-syn in these cells, but the levels were not influenced by inhibiting autophagy using chloroquine. In contrast, autophagy and the CLEAR (Coordinated Lysosomal Expression and Regulation) pathways were elevated in USP14 lacking cells with an upregulation of the transcription factor TFEB. USP14-ablated cells also exhibited increases in reactive oxidative species (ROS) and elongation of mitochondria. The addition of N-Acetylcysteine amide (NACA) to counteract oxidative stress, reduced pS129 α-syn and α-syn levels in USP14 deficient cells. Phospho-proteomic analyses revealed that USP14 is phosphorylated at S143 affecting its function and structure as shown by molecular modeling, and protein interaction studies. Re-expression of wild-type and the phospho-mimetic S143D-USP14 mutant decreased ROS, pS129 α-syn, and α-syn in USP14 lacking cells. These results demonstrate that pS129 α-syn levels are sensitive to oxidative stress in SH-SY5Y dopaminergic cells. USP14 by stimulating the proteasome activity and reducing oxidative stress is a promising factor for targeting α-syn and its pathogenic variants in PD.
Spatial domains identification in spatial transcriptomics by domain knowledge-aware and subspace-enhanced graph contrastive learning
Authors: Gui Yang , Li Chao , Xu Yan
Published: May 2024

Spatial transcriptomics (ST) technologies have emerged as an effective tool to identify the spatial architecture of the tissue, facilitating a comprehensive understanding of organ function and tissue microenvironment. Spatial domain identification is the first and most critical step in ST data analysis, which requires thoughtful utilization of tissue microenvironment and morphological priors. To this end, we propose a graph contrastive learning framework, GRAS4T, which combines contrastive learning and subspace module to accurately distinguish different spatial domains by capturing tissue microenvironment through self-expressiveness of spots within the same domain. To uncover the pertinent features for spatial domain identification, GRAS4T employs a graph augmentation based on histological images prior, preserving information crucial for the clustering task. Experimental results on 8 ST datasets from 5 different platforms show that GRAS4T outperforms five state-of-the-art competing methods in spatial domain identification. Significantly, GRAS4T excels at separating distinct tissue structures and unveiling more detailed spatial domains. GRAS4T combines the advantages of subspace analysis and graph representation learning with extensibility, making it an ideal framework for ST domain identification.
Endogenous retrovirus ERV-DC8 highly integrated in domestic cat populations is a replication-competent provirus
Authors: Pramono Didik , Muto Yutaro , Shimazu Yo , Deshapriya R.M.C. , Makundi Isaac , Arnal MaríaCruz , de Luco Daniel Fernández , Ngo Minh Ha , Miyake Ariko , Nishigaki Kazuo
Published: May 2024

Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections in vertebrate genomes and are inherited by offspring. ERVs can produce pathogenic viruses through gene mutations or recombination. ERVs in domestic cats (ERV-DCs) generate feline leukemia virus subgroup D (FeLV-D) through viral recombination. Herein, we characterized the locus ERV-DC8, on chromosome B1, as an infectious replication-competent provirus. ERV-DC8 infected several cell lines, including human cells. Transmission electron microscopy of ERV-DC8 identified the viral release as aGammaretrovirus. ERV-DC8 was identified as the FeLV-D viral interference group, with feline copper transporter 1 as its viral receptor. Insertional polymorphism analysis showed high ERV-DC8 integration in domestic cats. This study highlights the role, pathogenicity, and evolutionary relationships between ERVs and their hosts.
Contraction-induced endocardial id2b plays a dual role in regulating myocardial contractility and valve formation
Authors: Chen Shuo , Yin Jie , Liang Jinxiu , Zhang Weijia , Jiang Peijun , Wang Wenyuan , Chen Xiaoying , Zhou Yuanhong , Xia Peng , Yang Fan , Gu Ying , Zhang Ruilin , Han peidong
Published: May 2024

Biomechanical cues play an essential role in sculpting organ formation. Comprehending how cardiac cells perceive and respond to biomechanical forces is a biological process with significant medical implications that remains poorly understood. Here we show that biomechanical forces activate endocardial id2b (inhibitor of DNA binding 2b) expression, thereby promoting cardiac contractility and valve formation. Taking advantage of the unique strengths of zebrafish, particularly the viability of embryos lacking heartbeats, we systematically compared the transcriptomes of hearts with impaired contractility to those of control hearts. This comparison identified id2b as a gene sensitive to blood flow. By generating a knockin reporter line, our results unveiled the presence of id2b in the endocardium, and its expression is sensitive to both pharmacological and genetic perturbations of contraction. Furthermore, id2b loss-of-function resulted in progressive heart malformation and early lethality. Combining RNA-seq analysis, electrophysiology, calcium imaging, and echocardiography, we discovered profound impairment in atrioventricular (AV) valve formation and defective excitation-contraction coupling in id2b mutants. Deletion of id2b cell-autonomously reduced AV endocardial cell proliferation and led to a progressive increase in retrograde blood flow. Moreover, id2b also played a non-cell-autonomous role in maintaining cardiomyocyte function. Mechanistically, id2b directly interacted with the bHLH component tcf3b (transcription factor 3b) to restrict its activity. Inactivating id2b unleashed its inhibition on tcf3b, resulted in enhanced repressor activity of tcf3b, which subsequently suppressed the expression of nrg1 (neuregulin 1), an essential mitogen for heart development. Overall, our findings identify id2b as an endocardial cell-specific, biomechanical signaling-sensitive gene, which mediates intercellular communications between endocardium and myocardium to sculpt heart morphogenesis and function.
3-nitrotyrosine shortens axons of a non-dopaminergic neuron by inhibiting mitochondrial motility
Authors: Hirai Masahiro , Suzuki Kohei , Kassai Yusuke , Konishi Yoshiyuki
Published: May 2024

3-nitrotyrosine (3-NT), a byproduct of oxidative/nitrosative stress, is implicated in age-related neurodegenerative disorders. Existing literature indicates that free 3-NT becomes integrated into the carboxy-terminal domain of α-tubulin through the tyrosination/detyrosination cycle. Independently of this integration, 3-NT has been linked to the cell death of dopaminergic neurons. Given the critical role of tyrosination/detyrosination in governing axonal morphology and function, the substitution of tyrosine with 3-NT in this process may potentially disrupt axonal homeostasis, although this aspect remains underexplored. In this study, we examined the impact of 3-NT on the axons of cerebellar granule neurons, representing non-dopaminergic neurons. Our observations revealed axonal shortening, which correlated with the incorporation of 3-NT into α-tubulin. Importantly, this axonal effect was observed prior to the onset of cellular death. Furthermore, 3-NT was found to diminish mitochondrial motility within the axon, resulting in a subsequent reduction in mitochondrial membrane potential. The suppression of syntaphilin, a protein responsible for anchoring mitochondria to microtubules, reversed the 3-NT-induced decrease in mitochondrial motility, consequently restoring axonal elongation. These findings underscore the inhibitory role of 3-NT in axonal elongation by impeding mitochondrial movement, implying its potential involvement in axonal dysfunction within non-dopaminergic neurons.
Stem cell culture conditions affect in vitro differentiation potential and efficiency of mouse gastruloid development
Authors: Blotenburg Marloes , Suurenbroek Lianne , Bhardwaj Vivek , Zeller Peter
Published: May 2024

By aggregating low numbers of mouse embryonic stem cells (mESCs) followed by exposure to Wnt activation, structures termed gastruloids are produced that display an anteroposterior organisation of cell types derived from all three germ layers. Since current gastruloid protocols display considerable heterogeneity between experiments in terms of morphology, elongation efficiency, and cell type composition, we investigated whether an optimised mESC pluripotency state would provide more consistent results. By growing mESCs in different intervals of ESLIF and 2i medium the pluripotency state of cells was modulated, and mESC culture as well as the resulting gastruloids were analysed. Microscopy analysis showed a pre-culture-specific effect on gastruloid formation, in terms of efficiency, elongation index and reproducibility. RNA-seq analysis of the mESC start population confirmed that short-term pulses of 2i and ESLIF modulate the pluripotency state, and result in different cellular states. With multiple epigenetic regulators among the top differentially expressed genes we further analysed genome-wide DNA methylation and H3K27me3 distributions. We observed the same divergence between conditions, most dominantly displayed in the promoter regions of developmental regulators. Lastly, when we investigated the cell type composition of gastruloids grown from these different pre-cultures, we observed that mESCs subjected to 2i-ESLIF preceding aggregation generated gastruloids more consistently, including more complex mesodermal contributions as compared to the ESLIF-only control. This indicates that optimisation of the mESCs pluripotency state allows the modulation of cell differentiation during gastruloid formation.
Natural phasic inhibition of dopamine neurons signals cognitive rigidity
Authors: Burwell Sasha C.V. , Yan Haidun , Lim Shaun S.X. , Shields Brenda C. , Tadross Michael R.
Published: May 2024

When animals unexpectedly fail, their dopamine neurons undergo phasic inhibition that canonically drives extinction learning—a cognitive-flexibility mechanism for discarding outdated strategies. However, the existing evidence equates natural and artificial phasic inhibition, despite their spatiotemporal differences. Addressing this gap, we targeted a GABAA-receptor antagonist precisely to dopamine neurons, yielding three unexpected findings. First, this intervention blocked natural phasic inhibition selectively, leaving tonic activity unaffected. Second, blocking natural phasic inhibition accelerated extinction learning—opposite to canonical mechanisms. Third, our approach selectively benefitted perseverative mice, restoring rapid extinction without affecting new reward learning. Our findings reveal that extinction learning is rapid by default and slowed by natural phasic inhibition—challenging foundational learning theories, while delineating a synaptic mechanism and therapeutic target for cognitive rigidity.
A comparison among EL-FAME, PLFA, and quantitative PCR methods to detect changes in the abundance of soil bacteria and fungi
Authors: Siles José A. , Gómez-Pérez Roberto , Vera Alfonso , García Carlos , Bastida Felipe
Published: May 2024

EL-FAME (ester-linked fatty acid methyl ester), PLFA (phospholipid fatty acid) and qPCR (quantitative PCR) of ribosomal genes are three of the most common methods used to quantify soil microbial communities. The reliability of these three methods has not been simultaneously compared in situations of rapid changes in soil microbial abundances. For this purpose, we (i) incubated badland, cropland, and forest soils with nutrients or antibiotics for 2, 7, 14, and 28 days, (ii) quantified total, bacterial, and fungal abundances through EL-FAME, PLFA, and qPCR methods, and (iii) measured soil basal respiration. The general dynamic patterns of the three soil microbial fractions in response to soil addition of nutrients and antibiotics were captured by the three methods, which led to strong and positive associations between the abundances of total microorganisms, bacteria, and fungi measured by the three techniques. However, these relationships were found to be stronger between the EL-FAME and PLFA results, indicating that reliability of the fatty-acid based methods is higher than that of the qPCR. Further, soil basal respiration was associated to a higher extent with total, bacterial, and fungal abundances captured by EL-FAME and PLFA analyses than with those measured by qPCR, which suggests that the first two methods are most closely related to the soil living microbial community. In general, dynamics in the abundance of total and bacterial communities were better captured than those of fungi. The PLFA analysis seems to perform better than the EL-FAME method in forest soil and in detecting the small antibiotic-induced decreases in microbial abundances. Since the EL-FAME method is cheaper and allows a much faster processing of samples than the PLFA method, and the reliability of both methods is similar in detecting rapid changes of soil microbial abundances, choosing EL-FAME over PLFA may be advantageous in most cases.
Structural and functional analyses of SARS-CoV-2 Nsp3 and its specific interactions with the 5’ UTR of the viral genome
Authors: Lemak Sofia , Skarina Tatiana , Flick Robert , Patel Deepak T. , Stogios Peter J. , Savchenko Alexei
Published: May 2024

Non-structural protein 3 (Nsp3) is the largest open reading frame encoded in the SARS-CoV-2 genome, essential for formation of double-membrane vesicles (DMV) wherein viral RNA replication occurs. We conducted an extensive structure-function analysis of Nsp3 and determined the crystal structures of the Ubiquitin-like 1 (Ubl1), Nucleic Acid Binding (NAB), β-coronavirus-Specific Marker (βSM) domains and a sub-region of the Y domain of this protein. We show that the Ubl1, ADP-ribose phosphatase (ADRP), human SARS Unique (HSUD), NAB, and Y domains of Nsp3 bind the 5’ UTR of the viral genome and that the Ubl1 and Y domains possess affinity for recognition of this region, suggesting high specificity. The Ubl1-Nucleocapsid (N) protein complex binds the 5’ UTR with greater affinity than the individual proteins alone. Our results suggest that multiple domains of Nsp3, particularly Ubl1 and Y, shepherd the 5’ UTR of viral genome during translocation through the DMV membrane, priming the Ubl1 domain to load the genome onto N protein.
Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases
Authors: Sokratian Arpine , Zhou Ye , Tatli Meltem , Burbidge Kevin J. , Xu Enquan , Viverette Elizabeth , Duda Addison M. , Yuan Yuan , Strader Samuel , Patel Nirali , Shiell Lauren , Malankhanova Tuyana , Chen Olivia , Mazzulli Joseph R. , Perera Lalith , Stahlberg Henning , Borgnia Mario , Bartesaghi Alberto , Lashuel Hilal A. , West Andrew B.
Published: May 2024

Short Abstract

The intricate process of α-synuclein aggregation and fibrillization hold pivotal roles in Parkinson’s disease (PD) and multiple system atrophy (MSA). While mouse α-synuclein can fibrillizein vitro, whether these fibrils commonly used in research to induce this process or form can reproduce structures in the human brain remains unknown. Here we report the first atomic structure of mouse α-synuclein fibrils, which was solved in parallel by two independent teams. The structure shows striking similarity to MSA-amplified and PD-associated E46K fibrils. However, mouse α-synuclein fibrils display altered packing arrangements, reduced hydrophobicity, heightened fragmentation sensitivity, and evoke only weak immunological responses. Furthermore, mouse α-synuclein fibrils exhibit exacerbated pathological spread in neurons and humanized α-synuclein mice. These findings provide new insights into the structural underpinnings of α-synuclein pathogenicity and emphasize a need to reassess the role of mouse α-synuclein fibrils in the development of related diagnostic probes and therapeutic interventions.
Bacterial heterozygosity promotes survival under multidrug selection
Authors: Shitut Shraddha , van Dijk Thomas , Claessen Dennis , Rozen Daniel
Published: May 2024

Although bacterial cells typically contain a single chromosome, some species are naturally polyploid and carry multiple copies of their chromosome. Polyploid chromosomes can be identical or heterogeneous, the latter giving rise to bacterial heterozygosity. While the benefits of heterozygosity are well studied in eukaryotes, its consequences in bacteria are unknown. Here we examine this question in the context of antibiotic resistance to understand how bacterial heterozygosity affects bacterial survival. Using a cell wall deficient model system in the actinomyceteKitasatospora viridifaciens, we found that heterozygous cells containing different chromosomes expressing different antibiotic resistance markers persist across a broader range of antibiotic concentrations. Recombinant cells containing the same resistance genes on a single chromosome also survive these conditions, but these cells pay a significant fitness cost due to constitutive expression of these genes. By contrast, heterozygous cells mitigate these costs by flexibly adjusting the ratio of their different chromosomes, thereby allowing rapid responses in temporally and spatially variable environments. Our results provide evidence that bacterial heterozygosity can increase adaptive plasticity in bacterial cells, in a similar manner to the evolutionary benefits provided by multicopy plasmids in bacteria.

Graphical abstract

Heterozygotic bacterial cells (polyploid with multiple chromosome types) can persist across a wider range of conditions than homozygotic cells.

Heterozygous cells can adaptively adjust chromosomal frequencies in response to external conditions

Flexibly adjusting chromosome ratios enables heterozygous cells to mitigate the costs of antibiotic resistance and allows rapid responses to temporally and spatially variable environments

Heterozygosity can increase adaptive plasticity in bacterial cells, in a similar manner to the evolutionary benefits provided by multicopy plasmids.
A meta reinforcement learning account of behavioral adaptation to volatility in recurrent neural networks
Authors: Tuzsus D. , Pappas I. , Peters J.
Published: May 2024

Natural environments often exhibit various degrees of volatility, ranging from slowly changing to rapidly changing contingencies. How learners adapt to changing environments is a central issue in both reinforcement learning theory and psychology. For example, learners may adapt to changes in volatility by increasing learning if volatility increases, and reducing it if volatility decreases. Computational neuroscience and neural network modeling work suggests that this adaptive capacity may result from a meta-reinforcement learning process (implemented for example in the prefrontal cortex), where past experience endows the system with the capacity to rapidly adapt to environmental conditions in new situations. Here we provide direct evidence for a meta-reinforcement learning account of adaptation to environmental volatility. Recurrent neural networks (RNNs) were trained on a restless four-armed bandit reinforcement learning problem under three different training regimes (low volatility training only, medium volatility training only, or meta-volatility training across a range of volatilities). We show that, in contrast to RNNs trained in the low volatility regime, RNNs trained under the medium or meta-volatility regimes exhibited a superior adaption to environmental volatility. This was reflected in a better performance, and computational modeling of the network’s behavior revealed a more adaptive adjustment of learning and exploration to varying levels of volatility during test. Results extend the meta-RL account to volatility adaptation and confirm past experience as a crucial factor of adaptive decision-making.
Dopamine transporter threonine-53 phosphorylation dictates kappa opioid receptor mediated locomotor suppression and conditioned place aversion via transporter upregulation
Authors: Varman Durairaj Ragu , Jayanthi Lankupalle D. , Ramamoorthy Sammanda
Published: May 2024

Dynorphin (DYN)/kappa opioid receptor (KOR) activation contributes to aversion, dysphoria, sedation, depression, and enhanced psychostimulant-rewarding effects, which have been attributed to the inhibition of dopamine (DA) release. DYN fibers synapse onto DA terminals which express both KOR and dopamine transporter (DAT). DAT activity is critical in the regulation of DA dynamics and dopaminergic neurotransmission. Previously, we demonstrated that KOR agonists upregulate DAT activity via ERK1/2 signaling involving phospho-Thr53 DAT (pT53-DAT). However, whether pT53-DAT is involved in KOR-mediated DAT regulation in-vivo and whether such phenomenon contributes to the behavioral effects of KOR agonism are unknown. Here, we investigated the role of endogenous pT53-DAT in KOR-mediated DAT regulation and the effect of KOR agonists on locomotor suppression and aversive behaviors using DAT-Ala53 knock-in mice expressing DAT carrying non-phosphorylatable Ala at position 53 replacing Thr. Acute systemic administration of KOR agonist, U69593 resulted in KOR antagonist-sensitive increases in DAT activity in parallel to increases in pT53-DAT, and DAT Vmaxand surface expression in the ventral and dorsal striatum (containing the nucleus accumbens and caudate putamen respectively) of WT, but not DAT-Ala53 mice. KOR agonists produced conditioned place aversion (CPA) and locomotor suppression in WT but not DAT-Ala53 mice. However, both WT and DAT-Ala53 mice exhibited similar lithium chloride-induced CPA and morphine-induced conditioned place preference (CPP). These findings provide the first evidence that locomotor suppression and aversive responses to KOR agonists manifest due to the modulation of DAT activity via DAT-T53 phosphorylation establishing a causal relationship of pT53-DAT in KOR-mediated DAT regulation and KOR agonist-induced adverse effects.