bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison between EEG and MEG of static and dynamic resting-state networks
Authors: Cho SungJun , van Es Mats , Woolrich Mark , Gohil Chetan
Published: May 2024

The characterisation of resting state networks (RSNs) using neuroimaging techniques has significantly contributed to our understanding of the organisation of brain activity. Prior work has demonstrated the electrophysiological basis of RSNs and their dynamic nature, revealing transient activations of brain networks with millisecond timescales. While previous research has confirmed the comparability of RSNs identified by electroencephalography (EEG) to those identified by magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI), most studies have utilised static analysis techniques, ignoring the dynamic nature of brain activity. Often, these studies use high-density EEG systems, which limit their applicability in clinical settings. Addressing these gaps, our research studies RSNs using medium-density EEG systems (61 sensors), comparing both static and dynamic brain network features to those obtained from a high-density MEG system (306 sensors). We assess the qualitative and quantitative comparability of EEG-derived RSNs to those from MEG, including their ability to capture age-related effects, and explore the reproducibility of dynamic RSNs within and across the modalities. Our findings suggest that both MEG and EEG offer comparable static and dynamic network descriptions, albeit with MEG offering some increased sensitivity and reproducibility. Such RSNs and their comparability across the two modalities remained consistent qualitatively but not quantitatively when the data were reconstructed without subject-specific structural MRI images.
High glucose treatment induced nuclei aggregation of microvascular endothelial cells via foxo1a-klf2a pathway
Authors: Wang Xiaoning , Kang Xinyi , Li Bowen , Chen Changshen , Chen Liping , Liu Dong
Published: May 2024

BACKGROUND

Hyperglycemia is a major contributor to endothelial dysfunction and blood vessel damage, leading to severe diabetic microvascular complications. Despite the growing body of research on the underlying mechanisms of endothelial cell dysfunction, the available drugs based on current knowledge fall short of effectively alleviating these complications. Therefore, our endeavor to explore novel insights into the cellular and molecular mechanisms of endothelial dysfunction is crucial for the field.

METHODS

In this study, we carried out a high-resolution imaging and time-lapse imaging analysis of the behavior of endothelial cellsin Tg(kdrl:ras-mCherry::fli1a:nEGFP)zebrafish embryos upon high glucose treatment. Genetic manipulation and chemical biology approaches were utilized to analyze the underlying mechanism of high-glucose-induced nuclei aggregation and aberrant migration of zebrafish endothelial cells and cultured human endothelial cells. Bioinformatical analysis of single-cell RNA sequencing data and molecular biological techniques to identify the target genes of Foxo1a.

RESULTS

In this study, we observed that the high glucose treatment resulted in nuclei aggregation of endothelial cells in zebrafish intersegmental vessels (ISVs). Additionally, the aberrant migration of microvascular endothelial cells in high glucose-treated embryos, which might be a cause of nuclei aggregation, was discovered. High glucose-induced aggregation of vascular endothelial nuclei via foxo1a downregulation in zebrafish embryos. Then, we revealed that high glucose resulted in the downregulation of foxo1a expression and increased the expression of its direct downstream effector, klf2a, through which the aberrant migration and aggregation of vascular endothelial nuclei were caused.

CONCLUSIONS

High glucose treatment caused the nuclei of endothelial cells to aggregatein vivo, which resembles the crowded nuclei of endothelial cells in microaneurysms. High glucose suppresses foxo1a expression and increases the expression of its downstream effector, klf2a, thereby causing the aberrant migration and aggregation of vascular endothelial nuclei. Our findings provide a novel insight into the mechanism of microvascular complications in hyperglycemia.
Sex-dependant differences in the ability of nicotine to modulate discrimination learning and cognitive flexibility in mice
Authors: Aomine Yoshiatsu , Shimo Yuto , Sakurai Koki , Abe Mayuka , Macpherson Tom , Ozawa Takaaki , Hikida Takatoshi
Published: May 2024

1

Nicotine, an addictive compound found in tobacco, functions as an agonist of nicotinic acetylcholine receptors (nAChRs) in the brain. Interestingly, nicotine has been reported to act as a cognitive enhancer in both human subjects and experimental animals. However, its effects in animal studies have not always been consistent, and sex differences have been identified in the effects of nicotine on several behaviors. Specifically, the role that sex plays in modulating the effects of nicotine on discrimination learning and cognitive flexibility in rodents is still unclear. Here, we evaluated sex-dependent differences in the effect of daily nicotine administration at various doses (0.125, 0.25, and 0.5 mg/kg) on visual discrimination (VD) learning and reversal (VDR) learning in mice. In male mice, nicotine significantly improved performance in VDR, but not VD, task, while, in female mice, nicotine significantly worsened performance in the VD, but not VDR, task. Next, to investigate the cellular mechanisms that underlie the sex differences in the effects of nicotine on cognition, transcriptomic analyses were performed on prefrontal cortex tissue samples from male and female mice that had undergone VD and VDR tasks. Pathway enrichment analysis and Protein-protein interaction (P-PI) analysis using gene sets with altered gene expression found three types of effects of nicotine: those common to both sexes, those in males only, and those in females only. Decreased expression of postsynaptic-related genes in males and increased expression of innate immunity-related genes in females were identified as possible molecular mechanisms related to sex differences in the effects of nicotine on cognition in discrimination learning and cognitive flexibility.
Data Resource Profile: Whole Blood DNA Methylation Resource in Generation Scotland (MeGS)
Authors: Walker Rosie M. , McCartney Daniel L. , Carr Kevin , Barber Michael , Shen Xueyi , Campbell Archie , Bernabeu Elena , Aitken Emma , Fawkes Angie , Wrobel Nicola , Murphy Lee , Whalley Heather C. , Howard David M. , Adams Mark J. , Rawlik Konrad , Navarro Pau , Tenesa Albert , Sudlow Cathie L , Porteous David J , Marioni Riccardo , McIntosh Andrew M. , Evans Kathryn L.
Published: May 2024

We have generated whole-blood DNA methylation profiles from 18,869 Generation Scotland Scottish Family Health Study (GS) participants, resulting in, at the time of writing, the largest single-cohort DNA methylation resource for basic biological and medical research: Methylation in Generation Scotland (MeGS). GS is a community- and family-based cohort, which recruited over 24,000 participants from Scotland between 2006 and 2011. Comprehensive phenotype information, including detailed data on cognitive function, personality traits, and mental health, is available for all participants. The majority (83%) have genome-wide SNP genotype data (Illumina HumanOmniExpressExome-8 array v1.0 and v1.2), and over 97% of GS participants have given consent for health record linkage and re-contact. At baseline, blood-based DNA methylation was characterised at ∼850,000 sites across four batches using the Illumina EPICv1 array. MeGS participants were aged between 17 and 99 years at the time of enrolment to GS. Blood-based DNA methylation EPICv1 array profiles collected at a follow-up appointment that took place 4.3-12.2 years (mean=7.1 years) after baseline are also available for 796 MeGS participants. Access to MeGS for researchers in the UK and international collaborators is via application to the GS Access Committee (access@generationscotland.org).
Hepatic Toxicity Assessment in HIV’s Interaction with Reverse Transcriptase and Integrase Strand Transfer Inhibitors at a Military Hospital, Southsouth Nigeria
Authors: Odegbemi Odekunle Bola , Olaniyan Mathew Folaranmi , Muhibi Musa Abidemi
Published: May 2024

Introduction

The use of Anti-retroviral therapy (ART) has made HIV a manageable condition, but there are risks associated with medications like Reverse Transcriptase Inhibitors (RTIs) and Integrase Strand Transfer Inhibitors (INSTIs), such as liver and renal toxicity. It is essential to understand these risks for effective treatment and case management. Investigating liver toxicity related to RTIs and INSTIs in Nigeria is crucial for optimizing HIV treatment. This study aimed to assess the impact of Tenofovir Lamivudine Dolutegravir (TLD) on the liver function of HIV patients at Nigerian Navy Hospital (NNH) Warri.

Methods

The liver function of 170 participants was assessed, with 120 on ART and the remainder being HIV-negative attendees at NNH Warri. The study used a cross-sectional design and selected participants through random sampling. We collected data using a semi-structured questionnaire. Blood samples were taken through venipuncture and stored at –20°C before analysis. Ethical approval was obtained, and data analysis was conducted using SPSS Statistical Software Version 23, with significance set at p < 0.05.

Results

The study found significant differences in AST, TP, Alb, and GST levels between HIV-positive subjects receiving TLD and HIV-negative individuals. HIV-positive subjects had lower AST and Alb levels but higher TP and GST levels. Further analysis revealed correlations between age, gender, and liver enzymes, highlighting the complex relationship between HIV, liver function, and treatment outcomes.

Conclusion

The study suggests that decreased AST levels may have a protective effect, while ALT activity had minimal impact. Changes in TP, Alb, and GSTs emphasize the importance of monitoring hepatic synthetic function and detoxification pathways in HIV patients taking TLD.
Dynamics of the blood plasma proteome during hyperacute HIV-1 infection
Authors: Nazziwa Jamirah , Freyhult Eva , Hong Mun-Gwan , Johansson Emil , Årman Filip , Hare Jonathan , Gounder Kamini , Rezeli Melinda , Mohanty Tirthankar , Kjellström Sven , Kamali Anatoli , Karita Etienne , Kilembe William , Price Matt A , Kaleebu Pontiano , Allen Susan , Hunter Eric , Ndung’u Thumbi , Gilmour Jill , Rowland-Jones Sarah L. , Sanders Eduard , Hassan Amin S. , Esbjörnsson Joakim
Published: May 2024

HIV-1 remains incurable and there is no effective vaccine towards the infection. A main challenge for this is the lack of a holistic understanding of the myriad of complex virus-host interactions during hyperacute HIV-1 infection (hAHI), and how these contribute to tissue damage and pathogenesis. Here, 1293 blood plasma proteins were quantified from 157 linked plasma samples collected before, during, and after hAHI of 54 volunteers from four sub-Saharan African countries. Six distinct longitudinal expression profiles were identified, of which four demonstrated a consistent decrease in protein levels following HIV-1 infection. Differentially expressed proteins were involved in inflammation, innate immunity, cell motility, and actin cytoskeleton reorganisation. Specifically, decreased levels of Zyxin, Secretoglobin family 1A member 1, and Pro-platelet basic protein were associated with acute retroviral syndrome; Rho GTPase activating protein 18, Annexin A1, and Lipopolysaccharide binding protein with viral load; and Hepsin, Protein kinase C beta, and Integrin subunit beta 3 with disease progression. This is the first holistic characterisation of within-patient blood plasma proteome dynamics during the first weeks of HIV-1 infection and presents multiple potential blood biomarkers and targets for prophylactic and therapeutic HIV-1 interventions.
Holistic antenatal care during pregnancy: A systematic review
Authors: Chewe Violet Manonyana , Mathibe-Neke Johanna Mmabojalwa
Published: May 2024

Background

Pregnancy outcomes are determined by the type of antenatal care a woman receives. The purpose of this review was to conduct a critical analysis of the literature on the provision of holistic antenatal care to pregnant women.

Design

A systematic research review was employed for the study.

Data Sources

A search of EBSCO Host, Google Scholar, Sabinet, and Science Direct databases was performed. After reviewing 150 paper titles and abstracts, 14 studies were found to meet the final criteria for quality assessment. Included were only English-language papers published from 2020 to 2023.

Eligibility Criteria for Selecting Studies

Quantitative, Qualitative, Review studies, Quasi-experimental, and cohort studies. Papers had to include adults (>18 years old), and pregnant women attending antenatal care at different health facilities worldwide and published in peer-reviewed journals from 2020 onwards.

Results

Four of the fourteen analysed articles focused on socioeconomic status, three on staff attitudes, age, parity, and religion, and one on infrastructure. Six studies focused on midwives ’role in providing holistic antenatal care. These factors impacted pregnant women’s ability to receive comprehensive antenatal care. Three studies on woman-centered care and three on focused antenatal care have also come to light to enhance midwives’ capacity to deliver comprehensive prenatal care.

Conclusion

Healthcare facilities should offer an environment where communities may learn about the importance of antenatal care visits and how to ensure pregnant women obtain acceptable treatments.

Implications

This study demonstrates the necessity for healthcare providers to be resourceful about offering holistic antenatal care to pregnant women to enhance outcomes for both mothers and newborns.
Distress and factors for maintaining good mental health among general practitioners during the SARS-CoV-2 pandemic: Results from the cross-sectional PRICOV-19 study in Austria
Authors: Hoffmann Kathryn , Stummer Florian O. , van Poel Esther , Willems Sara , Wojczewski Silvia
Published: May 2024

Background

The COVID-19 pandemic has had a significant negative impact on the physical and mental health of healthcare workers worldwide. The aim of the paper is to measure the frequency of distress and wellbeing among general practitioners (GPs) in Austria during the pandemic and to identify key levers that could mitigate the risks of distress.

Methods

Data were collected as part of the international PRICOV-19 study. In Austria, 500 GPs were randomly selected for participation in a survey between December 2020 and July 2021. For analysis, all dependent and independent variables were described using descriptive statistical methods. Subgroup analyses were conducted using cross-tables and Fisher’s exact tests. A binary logistic regression model was also applied. Open text question was analysed via content analysis.

Results

In total, 130 GPs completed the relevant questions for this analysis of the online survey. More than 40% of GPs felt burned out or stated that their work schedules did not leave enough time for personal/family life. Half of the GPs were found to be in distress, with 14.3% in (very) strong distress. More than 40% of the respondents thought that government support was insufficient for the proper functioning of their practice. Working in rural areas was a protective factor against distress, as were sport and exercise, particularly outdoor activity. Connecting with family and friends and adjustments to the work environment to reduce workload were shown to be important.

Discussion

Our results show that GPs in Austria suffered from distress during the first two years of the pandemic. To protect GPs as our first-line healthcare workers in pandemic or high-stress situations, several factors are required for a functioning healthcare system: support of GPs regarding work-life balance, support in terms of collaboration between colleagues and the team and easy access to green outdoor spaces for sports and exercise. By identifying key factors that promote good mental health among GPs, healthcare organizations and policymakers can take targeted action to alleviate the negative impact of stress and burnout on this critical sector of the healthcare workforce.
Large language models to help appeal denied radiotherapy services
Authors: Kiser Kendall , Waters Mike , Reckford Jocelyn , Lundeberg Christopher , Abraham Christopher
Published: May 2024

Background

Large language model (LLM) artificial intelligences have potential to perform myriad healthcare tasks but should be validated in specific clinical use cases before deployment. One use case is to help physicians appeal insurer denials of prescribed medical services, a task that delays patient care and contributes to burnout. We evaluated LLM performance at this task for denials of radiotherapy services.

Methods

We evaluated generative pre-trained transformer 3.5 (GPT-3.5) (OpenAI, San Francisco, CA), GPT-4, GPT-4 with internet search functionality (GPT-4web), and GPT-3.5ft. The latter was developed by fine-tuning GPT-3.5 via an OpenAI application programming interface with 53 examples of appeal letters written by radiation oncologists. Twenty test prompts with simulated patient histories were programmatically presented to the LLMs, and output appeal letters were scored by three blinded radiation oncologists for language representation, clinical detail inclusion, clinical reasoning validity, literature citations, and overall readiness for insurer submission.

Results

Interobserver agreement between radiation oncologists’ scores was moderate or better for all domains (Cohen’s kappa coefficients: 0.41 – 0.91). GPT-3.5, GPT-4, and GPT-4web wrote letters that were on average linguistically clear, summarized provided clinical histories without confabulation, reasoned appropriately, and were scored useful to expedite the insurance appeal process. GPT-4 and GPT-4web letters demonstrated superior clinical reasoning and were readier for submission than GPT-3.5 letters (p < 0.001). Fine-tuning increased GPT-3.5ft confabulation and compromised performance compared to other LLMs across all domains (p < 0.001). All LLMs, including GPT-4web, were poor at supporting clinical assertions with existing, relevant, and appropriately cited primary literature.

Conclusions

When prompted appropriately, three commercially available LLMs drafted letters that physicians deemed would expedite appealing insurer denials of radiotherapy services. LLMs may decrease this task’s clerical workload on providers. However, LLM performance worsened when fine-tuned with a task-specific, small training dataset.
Causal Machine Learning Analysis of Radiation-Induced Leukemia and Solid Tumor Incidence in Japanese Atomic Bomb Survivors
Authors: Shuryak Igor , Liu Zhenqiu , Wang Eric , Ullrich Robert L. , Brenner David J.
Published: May 2024

Uncertainty in low-dose ionizing radiation-induced health risks stems from several factors. The complex biological pathways leading to diseases like cancer are not fully understood, making it difficult to distinguish the contribution of radiation, particularly at low doses which induce only small perturbations to background disease risks. Additionally, traditional dose-response models, such as the Linear No-Threshold formalism and competing threshold or hormesis models, impose rigid assumptions on dose response shapes, causing controversy and increasing model selection uncertainty. Furthermore, these modeling strategies operate on the level of correlations/associations, and are not designed to directly address the ultimate goal of radiation epidemiology – assessing causal links between radiation and disease. A promising and rapidly-developing approach for addressing some of these challenges is causal machine learning (CML), such as double/debiased machine learning (DML), which is designed to model causal effects in multi-dimensional data sets. Our study employs DML to elucidate the causal impacts of radiation exposure on the incidence of leukemia, all solid tumors, and stomach tumors among Japanese atomic bomb survivors. Its goal was not to produce a definitive re-analysis of these data sets, but to provide a useful example of implementing CML in radiation epidemiology, which can advance the field by supplementing traditional modeling approaches. The results revealed robust positive causal effects of radiation for all three tumor types, especially for leukemia and stomach tumors. The effect magnitudes, and uncertainties, were not dramatically different at low doses than at higher doses. The influences of age at exposure, attained age, sex and other covariates on the causal effects of radiation were assessed using Shapley Additive Explanations (SHAP) values. We believe that this analysis, based on a flexible machine learning framework with a causal inference motivation and without strict dose response assumptions, provides an important contribution to radiation epidemiology.
Notable transmitted HIV drug resistance among people who inject drugs in Pakistan
Authors: Melnychuk Stephanie , Thompson Laura H. , Archibald Chris , Blanchard James F. , Emmanuel Faran , Reza Tahira , Dar Nosheen , Sandstrom Paul , Shaw Souradet Y. , Becker Marissa L. , Cholette François
Published: May 2024

Transmission of drug-resistant HIV strains to treatment-naïve patients can compromise antiretroviral therapy (ART) effectiveness and lead to treatment failure. In Pakistan, transmitted HIV drug resistance among people who inject drugs (PWID) is fuelled by a lack of ART, poor drug adherence, and unsafe injection practices, resulting in efficient transmission in large injecting networks. A cross-sectional study was conducted among PWID recruited in the Pakistani cities of Karachi, Larkana, Peshawar, Quetta and Hyderabad (August 2014 to January 2015). A portion of the HIVpolgene was amplified from HIV-reactive dried blood spot specimens (n=282/367) and sequenced using an in-house Sanger sequencing assay for HIV drug resistance mutation genotyping. Drug resistance mutations (DRMs) were identified using the Stanford University HIV Drug Resistance Database HIVdb algorithm (https://hivdb.stanford.edu/hivdb). Overall, HIV subtype A1 was dominant (78.0%;n=220), followed by CRF02_AG (15.6%;n=44), CRF35_AD (2.5%n=7), recombinants (3.5%;n=10), and subtype C (0.4%n=1). DRM analysis identified over half (63.8%) of participants harbored at least one DRM, of which 28.9% reported using help from a professional injector. Nearly all (99.4%) participants were not actively receiving ART because most (88.7%) had never undergone HIV testing and were unaware of their status. Findings suggest significant transmitted HIV drug resistance present among PWID, exacerbated by unsafe injection practices, particularly professional injection. Low testing rates signal a need for more comprehensive testing programs to improve HIV status awareness and ART coverage in Pakistan. Given most treatment-naïve participants had evidence of drug resistance, drug resistance genotyping prior to ART initiation might aid in ensuring effective treatment to prevent transmission of resistant HIV strains.
Leveraging haplotype information in heritability estimation and polygenic prediction
Authors: Meisner Jonas , Benros Michael Eriksen , Rasmussen Simon
Published: May 2024

Polygenic prediction has yet to make a major clinical breakthrough in precision medicine and psychiatry, where the application of polygenic risk scores are expected to improve clinical decision-making. Most widely used approaches for estimating polygenic risk scores are based on summary statistics from external large-scale genome-wide association studies, which relies on assumptions of matching data distributions. This may hinder the impact of polygenic risk scores in modern diverse populations due to small differences in genetic architectures. Reference-free estimators of polygenic scores are instead based on genomic best linear unbiased predictions and models the population of interest directly. We introduce a framework, namedhapla, with a novel algorithm for clustering haplotypes in phased genotype data to estimate heritability and perform reference-free polygenic prediction in complex traits. We utilize inferred haplotype clusters to compute accurate SNP heritability estimates and polygenic scores in a simulation study and the iPSYCH2012 case-cohort for depression disorders and schizophrenia. We demonstrate that our haplotype-based approach robustly outperforms standard genotype-based approaches, which can help pave the way for polygenic risk scores in the future of precision medicine and psychiatry.haplais freely available athttps://github.com/Rosemeis/hapla.
Influence of aversive cue detection sensitivity on extinction in adult male rats
Authors: Cahill Emma N , Sherman Emily R , Jollans Joseph , Deiana Serena , Hengerer Bastian
Published: May 2024

Threat detection prompts reactions classified either as fear (obvious, predictable, immediate threat) or anxiety (ambiguous, sustained, distant threat). Hypervigilance is a state of sensitivity to threatening stimuli and an attentional bias symptomatic of anxiety disorders. In rodents, threat detection can be measured by freezing behaviour and production of ultrasonic vocalisation (USV) alarm calls. The amygdala is classically associated with fear-like responses, whereas the bed nucleus of the stria terminalis (BNST) has been proposed to be preferentially recruited by anxiogenic stimuli. The conditioned responses triggered by aversive cues can be extinguished through repeated exposure of a subject to the threat stimulus but without any aversive reinforcement. The extent of extinction acquisition and consolidation are notedly variable across individuals. It has been reported that NMDA-type glutamate receptor co-agonists, like D-cycloserine, can enhance extinction consolidation. In the experiments herein, the salience of a threat cue was modified to compare the relative activation of the brain vigilance networks to an obvious cue, and to test whether sensitivity to the aversive cue at such a ‘vigilance screen’ might predict subsequent ability to extinguish conditioned responses. We demonstrated activation of the BNST by a low salience aversive cue. Rats that had the propensity to make alarm ultrasonic vocalisation calls reacted more strongly to aversive cues and had deficits in conditioned freezing extinction. Finally, we demonstrated the potential to enhance extinction consolidation by targeting glycine transmission. Taken together these results demonstrate how threat detection and responses are sensitive to cue salience and can be manipulated by combined pharmacological and behavioural interventions.

HIGHLIGHTS:

-Auditory cue at low salience revealed attentional bias unrelated to maze behaviour

-Low salience cue recruited activation of the BNST

-Alarm call vocaliser rats had deficit in extinction consolidation

-GlyT1 inhibition enhanced extinction consolidation
Hippocampal sharp wave ripples mediate generalization and subsequent fear attenuation via closed-loop brain stimulation in rats
Authors: Pedraza Lizeth Katherine , Sierra Rodrigo Ordoñez , Barcsai Lívia , Li Qun , Pejin Andrea , Gellért Levente , Lőrincz Magor , Berenyi Antal
Published: May 2024

The balance between stimulus generalization and discrimination is essential in modulating behavioral responses across different contexts. Excessive fear generalization is linked to neuropsychiatric disorders such as generalized anxiety disorder (GAD) and PTSD. While hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are central to the consolidation of contextual memories, their involvement in non-hippocampal dependent memories remains poorly understood. Here we show that closed-loop disruption of SWRs, after the consolidation of a cued fear conditioning, leads to atypical memory discrimination that would normally be generalized. Furthermore, SWR-triggered closed-loop stimulation of the basolateral amygdala (BLA) during memory reconsolidation inhibits fear generalization and enhances subsequent extinction. Comparable effects were observed when stimulating the infralimbic cortex either post-training or after a brief memory reactivation. A consistent increase in gamma incidence within the amygdala was identified in animals subjected to closed-loop BLA or infralimbic cortex neuromodulation. Our findings highlight the functional role of hippocampal SWRs in modulating the qualitative aspects of amygdala-dependent memories. Targeting the amygdala activity via prefrontal cortex with closed-loop SWR triggered stimulation presents a potential foundation of a non-invasive therapy for GAD and PTSD.
Nuclear Translocation of SIRT4 Mediates Deacetylation of U2AF2 to Modulate Renal Fibrosis Through Alternative Splicing-mediated Upregulation of CCN2
Authors: Yang Guangyan , Xiang Jiaqing , Yang Xiaoxiao , Liu Xiaomai , Li Yanchun , Li Lixing , Kang Lin , Liang Zhen , Yang Shu
Published: May 2024

TGF-β stimulates CCN2 expression which in turn amplifies TGF-β signaling. This process promotes extracellular matrix production and accelerates the pathological progression of fibrotic diseases. Alternative splicing plays an important role in multiple disease development, while U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an essential factor in the early steps of pre-mRNA splicing. However, the molecular mechanism underlying abnormalCCN2expression upon TGF-β stimulation remains unclear. This study elucidates that SIRT4 acts as a master regulator for CCN2 expression in response to TGF-β by modulating U2AF2-mediated alternative splicing. Analyses of renal biopsy specimens from patients with CKD and mouse fibrotic kidney tissues revealed marked nuclear accumulation of SIRT4. The tubulointerstitial fibrosis was alleviated by global deletion or tubular epithelial cell (TEC)-specific knockout ofSirt4, and aggravated by adeno-associated virus-mediated SIRT4 overexpression in TECs. Furthermore, SIRT4 was found to translocate from the mitochondria to the cytoplasm through the BAX/BAK pore under TGF-β stimulation. In the cytoplasm, TGF-β activated the ERK pathway and induced the phosphorylation of SIRT4 at Ser36, which further promoted its interaction with importin α1 and subsequent nuclear translocation. In the nucleus, SIRT4 was found to deacetylate U2AF2 at K413, facilitating the splicing of CCN2 pre-mRNA to promote CCN2 protein expression. Importantly, exosomes containing anti-SIRT4 antibodies were found to effectively mitigate the UUO-induced kidney fibrosis in mice. Collectively, these findings indicated that SIRT4 plays a role in kidney fibrosis by regulating CCN2 expression via the pre-mRNA splicing.
Accurate localization of cortical and subcortical sources of M/EEG signals by a convolutional neural network with a realistic head conductivity model: Validation with M/EEG simulation, evoked potentials, and invasive recordings
Authors: Yokoyama Hikaru , Kaneko Natsuko , Usuda Noboru , Kato Tatsuya , Ming Khoo Hui , Fukuma Ryohei , Oshino Satoru , Tani Naoki , Kishima Haruhiko , Yanagisawa Takufumi , Nakazawa Kimitaka
Published: May 2024

While electroencephalography (EEG) and magnetoencephalography (MEG) are well-established non-invasive methods in neuroscience and clinical medicine, they suffer from low spatial resolution. Particularly challenging is the accurate localization of subcortical sources of M/EEG, which remains a subject of debate. To address this issue, we propose a four-layered convolutional neural network (4LCNN) designed to precisely locate both cortical and subcortical source activity underlying M/EEG signals. The 4LCNN was trained using a vast dataset generated by forward M/EEG simulations based on a realistic head volume conductor model. The 4LCNN implicitly learns the characteristics of M/EEG and their sources from the training data without need for explicitly formulating and fine-tuning optimal priors, a common challenge in conventional M/EEG source imaging techniques. We evaluated the efficacy of the 4LCNN model on a validation dataset comprising forward M/EEG simulations and two types of real experimental data from humans: 1) somatosensory evoked potentials recorded by EEG, and 2) simultaneous recordings from invasive electrodes implanted in the brain and MEG signals. Our results demonstrate that the 4LCNN provides robust and superior estimation accuracy compared to conventional M/EEG source imaging methods, aligning well with established neuroscience knowledge. Notably, the accuracy of the subcortical regions was as accurate as that of the cortical regions. The 4LCNN method, as a data-driven approach, enables accurate source localization of M/EEG signals, including in subcortical regions, suggesting future contributions to various research endeavors such as contributions to the clinical diagnosis, understanding of the pathophysiology of various neuronal diseases and basic brain functions.
Layer 6 corticocortical neurons are a major route for intra and interhemispheric feedback
Authors: Weiler Simon , Teichert Manuel , Margrie Troy W.
Published: May 2024

The mouse neocortex contains at least ninety distinctly defined yet interconnected areas that are symmetrically located across the two hemispheres. Determining the logic of this long range circuitry is necessary for understanding how inter-areal integration enables high level brain function involving multiple sensory, motor and cognitive processes. To address this we have performed a systematic anatomical analysis of the areal and laminar organization of the ipsilateral and contralateral cortical projection onto the primary visual (VISp), primary somatosensory barrel field (SSp-bfd) and primary motor (MOp) cortices. The resultant input maps reveal that although the ipsilateral hemisphere is the primary source of cortical input, there is substantial bilateral symmetry regarding the relative contribution and areal identity of contralateral input. Laminar analysis of these input areas show that excitatory Layer 6 corticocortical cells (L6 CCs) are a major projection pathway from both within and across the two hemispheres. Based on cortical hierarchy analysis that compares the relative contribution of inputs from supra-(feedforward) and infra-granular (feedback) layers, we find that contra-hemispheric projections reflect a dominant feedback organization compared to their ipsi-cortical counterpart. The magnitude of the interhemispheric difference in hierarchy was largest for sensory and motor projection areas compared to frontal, medial or lateral brain areas and can be explained by a proportional increase in input from L6 neurons. L6 CCs therefore not only mediate long-range cortical communication but also reflect its inherent feedback organization.
Emergence and interstate spread of highly pathogenic avian influenza A(H5N1) in dairy cattle
Authors: Nguyen Thao-Quyen , Hutter Carl , Markin Alexey , Thomas Megan , Lantz Kristina , Killian Mary Lea , Janzen Garrett M. , Vijendran Sriram , Wagle Sanket , Inderski Blake , Magstadt Drew R. , Li Ganwu , Diel Diego G. , Frye Elisha Anna , Dimitrov Kiril M. , Swinford Amy K. , Thompson Alexis C. , Snevik Kevin R. , Suarez David L. , Spackman Erica , Lakin Steven M. , Ahola Sara C. , Johnson Kammy R. , Baker Amy L. , Robbe-Austerman Suelee , Torchetti Mia Kim , Anderson Tavis K.
Published: May 2024

Highly pathogenic avian influenza (HPAI) viruses cross species barriers and have the potential to cause pandemics. In North America, HPAI A(H5N1) viruses related to the goose/Guangdong 2.3.4.4b hemagglutinin phylogenetic clade have infected wild birds, poultry, and mammals. Our genomic analysis and epidemiological investigation showed that a reassortment event in wild bird populations preceded a single wild bird-to-cattle transmission episode. The movement of asymptomatic cattle has likely played a role in the spread of HPAI within the United States dairy herd. Some molecular markers in virus populations were detected at low frequency that may lead to changes in transmission efficiency and phenotype after evolution in dairy cattle. Continued transmission of H5N1 HPAI within dairy cattle increases the risk for infection and subsequent spread of the virus to human populations.
Identification of Fibrinogen as a Plasma Protein Binding Partner for Lecanemab Biosimilar IgG: Implications for Alzheimer’s Disease Therapy
Authors: Bellier Jean-Pierre , Román Viera Andrea M. , Christiano Caitlyn , Anzai Juliana A. U. , Moreno Stephanie , Campbell Emily C. , Godwin Lucas , Li Amy , Chen Alan Y. , Alam Sarah , Saba Adriana , Yoo Han bin , Yang Hyun-Sik , Chhatwal Jasmeer P. , Selkoe Dennis J. , Liu Lei
Published: May 2024

Objective

Recombinant monoclonal therapeutic antibodies like lecanemab, which target amyloid beta in Alzheimer’s disease, offer a promising approach for modifying the disease progression. Due to its relatively short half-life, Lecanemab, administered as a bi-monthly infusion (typically 10mg/kg) has a relatively brief half-life. Interaction with abundant plasma proteins binder in the bloodstream can affect pharmacokinetics of drugs, including their half-life. In this study we investigated potential plasma protein binding interaction to lecanemab using lecanemab biosimilar.

Methods

Lecanemab biosimilar used in this study was based on publicly available sequences. ELISA and Western blotting were used to assess lecanemab biosimilar immunoreactivity in the fractions human plasma sample obtained through size exclusion chromatography. The binding of lecanemab biosimilar to candidate binders was confirmed by Western blotting, ELISA, and surface plasmon resonance analysis.

Results

Using a combination of equilibrium dialysis, ELISA, and Western blotting in human plasma, we first describe the presence of likely plasma protein binding partner to lecanemab biosimilar, and then identify fibrinogen as one of them. Utilizing surface plasmon resonance, we confirmed that lecanemab biosimilar does bind to fibrinogen, although with lower affinity than to monomeric amyloid beta.

Interpretation

In the context of lecanemab therapy, these results imply that fibrinogen levels could impact the levels of free antibodies in the bloodstream and that fibrinogen might serve as a reservoir for lecanemab. More broadly, these results indicate that plasma protein binding may be an important consideration when clinically utilizing therapeutic antibodies in neurodegenerative disease.
Early life growth and cellular heterogeneity in the short-lived African turquoise killifish telencephalon
Authors: Zandecki Caroline , Mariën Valerie , Ayana Rajagopal , Van houcke Jolien , Arckens Lutgarde , Seuntjens Eve
Published: May 2024

The African turquoise killifish (Nothobranchius furzeri) is becoming a favorable model for neurobiological research. The combination of a short lifespan and a declining neuroregenerative capacity upon aging makes the killifish ideally suited for research on brain aging and regeneration. A remarkable cellular diversity makes up the young-adult killifish telencephalon, characterized by highly proliferative non-glial progenitors and four spatially distinct radial glia subtypes. In contrast to a relatively slow embryonic development, hatching is followed by a period of accelerated growth in the short-lived N. furzeri strain; GRZ. Accordingly, the brain of this teleost experiences a period of rapid expansion and maturation. In this study, we charted the growth progression of the killifish telencephalon during early post-embryonic development. We identified a dynamic cellular buildup of the neurogenic niches sustaining this explosive growth. Spatial data revealed specific differences between pallial and subpallial regions in terms of growth pace and cellular output. Spatial signatures comparable to zebrafish were identified for excitatory and inhibitory neuronal lineages, already present at hatching.
The diel disconnect between cell growth and division inAureococcusis interrupted by giant virus infection
Authors: Truchon Alexander R. , Chase Emily E. , Stark Ashton R. , Wilhelm Steven W.
Published: May 2024

Viruses of eukaryotic algae have become an important topic due to their roles in nutrient cycling and top-down control of algal blooms. Omics-based studies have identified a boon of genomic and transcriptional potential among theNucleocytoviricota, a phylum of large dsDNA viruses which have been shown to infect algal and non-algal eukaryotes. However, little is still understood regarding the infection cycle of these viruses, particularly in how they take over a metabolically active host and convert it into a virocell state. Of particular interest are the roles light and the diel cycle in virocell development. Yet despite such a large proportion ofNucleocytoviricotainfecting phototrophs, little work has been done to tie infection dynamics to the presence, and absence, of light. Here, we examine the role of the diel cycle on the physiological and transcriptional state of the pelagophyteAureococcus anophagefferenswhile undergoing infection byKratosvirus quantuckense. Our observations demonstrate how infection by the virus interrupts the diel growth and division of this cell line, and that infection further complicates the system by enhancing export of cell biomass.
Cryo-EM Reveals the Mechanochemical Cycle of Reactive Full-length Human Dynein-1
Authors: Chai Pengxin , Yang Jun , Geohring Indigo C. , Markus Steven M. , Wang Yue , Zhang Kai
Published: May 2024

Dynein-driven cargo transport plays pivotal roles in diverse cellular activities, central to which is dynein’s mechanochemical cycle. Here, we performed a systematic cryo-electron microscopic investigation of the conformational landscape of full-length human dynein-1 in reaction, under various nucleotide conditions, on and off microtubules. Our approach reveals over 40 high-resolution structures, categorized into eight states, providing a dynamic and comprehensive view of dynein throughout its mechanochemical cycle. The novel intermediate states reveal important mechanistic insights into dynein function, including a ‘backdoor’ phosphate release model that coordinates linker straightening, how microtubule binding enhances ATPase activity through a two-way communication mechanism, and the crosstalk mechanism between AAA1 and the regulatory AAA3 site. Our findings also lead to a substantially revised model for the force-generating powerstroke and reveal a means by which dynein exhibits unidirectional stepping. These results substantially improve our understanding of dynein and provide a more complete model of its mechanochemical cycle.
Dorsomedial Striatum CB1R signaling is required for Pavlovian outcome devaluation in male Long Evans rats and reduces inhibitory synaptic transmission in both sexes
Authors: Stapf Catherine A. , Keefer Sara E. , McInerney Jessica M , Cheer Joseph F. , Calu Donna J.
Published: May 2024

Cannabinoid-1 receptor (CB1R) signaling in the dorsal striatum regulates the shift from flexible to habitual behavior in instrumental outcome devaluation. Based on prior work establishing individual, sex, and experience-dependent differences in Pavlovian behaviors, we predicted a role for dorsomedial striatum CB1R signaling in driving rigid responding in Pavlovian autoshaping and outcome devaluation. We trained male and female Long Evans rats in Pavlovian Lever Autoshaping (PLA). We gave intra-dorsomedial striatum (DMS) infusions of the CB1R inverse agonist, rimonabant, before satiety-induced outcome devaluation test sessions, where we sated rats on training pellets or home cage chow and tested them in brief nonreinforced Pavlovian Lever Autoshaping sessions. Overall, inhibition of DMS CB1R signaling prevented Pavlovian outcome devaluation but did not affect behavior in reinforced PLA sessions. Males were sensitive to devaluation while females were not and DMS CB1R inhibition impaired devaluation sensitivity in males. We then investigated how DMS CB1R signaling impacts local inhibitory synaptic transmission in male and female Long Evans rats. We recorded spontaneous inhibitory postsynaptic currents (sIPSC) from DMS neurons at baseline and before and after application of a CB1R agonist, WIN 55,212-2. We found that male rats showed decreased sIPSC frequency compared to females, and that CB1R activation reduced DMS inhibitory transmission independent of sex. Altogether our results demonstrate that DMS CB1Rs regulate Pavlovian devaluation sensitivity and inhibitory synaptic transmission and suggest that basal sex differences in inhibitory synaptic transmission may underly sex differences in DMS function and behavioral flexibility.
Brain rewiring during developmental transitions: A Comparative Analysis of Larva and AdultDrosophila melanogaster
Authors: Yadav Prateek , Shinde Pramod , Singh Aradhana
Published: May 2024

The brain’s ability to adapt through structural rewiring during developmental transitions is a fundamental aspect of neuroscience. Our study conducts a detailed comparison ofDrosophila melanogaster‘s brain networks during larval and adult stages, revealing significant changes in neuronal wiring during developmental phases. The degree distribution of the larval brain deviates significantly from power-law behavior and fits well with the Weibull distribution. In contrast, the adult brain exhibits power-law behavior in its degree distribution, with the exponent for the out-degree distribution lying in the scale-free regime and the exponent for the in-degree distribution being close to this regime. This difference reflects a change in the robustness of brain development from larval to adult phases. The core of these networks also changes during development in terms of their cell composition and topological influence. The larval core comprises Mushroom Body neurons, while the adult core mainly has Antennal Lobe neurons. Moreover, all the core neurons in the larval brain are also part of the rich-club neurons, a group of neurons with high in/out degrees that are well connected, whereas the same is not true for the adult brain network. Additionally, the core of the larval brain displays a more heterogeneous connectivity profile in its second-order neighbors compared to adult brain neurons, indicating greater diversity in larval brain connectivity. Our work stands as a step forward in understanding the rewiring of brain networks across the life stages ofDrosophila melanogaster.
Two-Metal Ion Mechanism of DNA Cleavage by Activated, Filamentous SgrAI
Authors: Shan Zelin , Rivero-Gamez Andres , Lyumkis Dmitry , Horton N. C.
Published: May 2024

Enzymes that form filamentous assemblies with modulated enzymatic activities have gained increasing attention in recent years. SgrAI is a sequence specific type II restriction endonuclease that forms polymeric filaments. SgrAI filamentation increases enzymatic activity by up to three orders of magnitude and additionally expands its DNA sequence specificity. Prior studies have suggested a mechanistic model linking the structural changes accompanying SgrAI filamentation to its accelerated DNA cleavage activity. In this model, the conformational changes that are specific to filamentous SgrAI maximize contacts between different copies of the enzyme within the filament and create a second divalent cation binding site in each subunit, which in turn facilitates the DNA cleavage reaction. However, our understanding of the atomic mechanism of catalysis is incomplete. Herein, we present two new structures of filamentous SgrAI solved using cryo-electron microscopy (cryo-EM). The first structure, resolved to 3.3 Å, is of filamentous SgrAI containing an active site mutation that is designed to stall the DNA cleavage reaction, which reveals the enzymatic configuration prior to DNA cleavage. The second structure, resolved to 3.1 Å, is of WT filamentous SgrAI containing cleaved substrate DNA, which reveals the enzymatic configuration at the end of the enzymatic cleavage reaction. Both structures contain the phosphate moiety at the cleavage site and the biologically relevant divalent cation cofactor Mg2+and define how the Mg2+cation reconfigures during enzymatic catalysis. The data support a model for the activation mechanism that involves binding of a second Mg2+in the SgrAI active site as a direct result of filamentation induced conformational changes.