bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects
Authors: Bozon Kayleigh , Cuny Hartmut , Sheng Delicia Z. , Martin Ella M. M. A. , Sipka Alena , Young Paul , Humphreys David T. , Dunwoodie Sally L.
Published: May 2024

Congenital malformations can originate from numerous genetic or non-genetic factors but in most cases the causes are unknown. Genetic disruption of nicotinamide adenine dinucleotide (NAD)de novosynthesis causes multiple malformations, collectively termed Congenital NAD Deficiency Disorder (CNDD), highlighting the necessity of this pathway during embryogenesis. Previous work in mice shows that NAD deficiency perturbs embryonic development specifically when organs are forming. While the pathway is predominantly active in the liver postnatally, the site of activity prior to and during organogenesis is unknown.

Here, we used a mouse model of human CNDD and assessed pathway functionality in embryonic livers and extraembryonic tissues via gene expression, enzyme activity and metabolic analyses. We found that the extra-embryonic visceral yolk sac endoderm exclusively synthesises NADde novoduring early organogenesis before the embryonic liver takes over this function. Under CNDD-inducing conditions, visceral yolk sacs had reduced NAD levels and altered NAD-related metabolic profiles, affecting embryo metabolism. Expression of requisite pathway genes is conserved in the equivalent yolk sac cell type in humans.

Our findings show that visceral yolk sac-mediated NADde novosynthesis activity is essential for mouse embryogenesis and its perturbation causes CNDD. As mouse and human yolk sacs are functionally homologous, our data improve the understanding of human congenital malformation causation.
Daily Acute Intermittent Hypoxia Elicits Age & Sex-Dependent Changes in Molecules Regulating Phrenic Motor Plasticity
Authors: Nair Jayakrishnan , Marciante Alexendria B. , Lurk Carter , Kelly Mia N. , Mitchell Gordon S.
Published: May 2024

Acute intermittent hypoxia (AIH) elicits a form of respiratory motor plasticity known as phrenic long-term facilitation (LTF). Repetitive daily AIH (dAIH) exposure enhances phrenic LTF, demonstrating a form of metaplasticity. Two additional factors impacting phrenic LTF are age and sex. For example, moderate AIH-induced phrenic LTF decreases with age in males, but increases in middle-aged females. However, little is known concerning cellular mechanisms of dAIH effects or age-dependent sexual dimorphism in phrenic LTF. Moderate AIH elicits distinct signaling cascades within phrenic motor neurons initiated by 5HT2 receptors (Q pathway)versusadenosine 2A or 5HT7 receptors (S pathway), respectively. The Q and S pathways interactviamutual crosstalk inhibition, a powerful regulator of phrenic LTF. To test the hypothesis that dAIH, age and sex effects on phrenic LTF are associated with differential expression of molecules known to regulate the Q and S pathways, we assessed mRNA of key regulatory molecules in ventral cervical homogenates from spinal segments containing the phrenic motor nucleus from young (3 month) and middle-aged (12 month) male and female Sprague-Dawley rats. Since CNS estrogen levels impact molecules regulating the Q and/or S pathways, mRNA was correlated with serum estradiol. Rats (n=8/group) were exposed to sham (21% O2) or dAIH (15, 1 min episodes of 10.5% inspired O2per day) for 14 days, and sacrificed 24 hours post-dAIH. mRNA for molecules known to regulate phrenic LTF were assessedviaRT PCR, including: brain derived neurotrophic factor (Bdnf); serotonin 2A (Htr2a); 2B (Htr2b); and (Htr7) receptors; adenosine 2a (Adora2a) receptors; exchange protein activated by cAMP (Epac1); p38 MAP kinase [Mapk14(α) &Mapk11(β)]; PKA catalytic subunit (Prkaa1); PKA regulatory subunit (Prkar1a); fractalkine (Cx3cl1); phosphodiesterase type 4 (Pde4b); NAPDH–gp91 (Cybb) and p47 (ncf1); and the PKCδ isoform (Prkcd). Significantly higherPde4b,Adora2a, andPrkcdmRNA were found in young and middle-aged femalesversusage-matched males;Epac1was elevated, but only in young females (p<0.001).Ncf1was increased in middle-aged versus young adult rats of both sexes (p<0.01).Ncf1, Cx3cl1,Adora2aandPrkcdmRNA were reduced by dAIH in middle-aged females (p<0.01), but not other groups. Serum estradiol levels positively correlated withEpac1(r2=0.29, p=0.002),Mapk14(r2=0.31, p=0.001),Mapk11(r2=0.20, p=0.014), andPrkar1a(r2=0.20 p=0.013) mRNA. With higher serum estradiol levels, dAIH decreasedMapk14mRNA (slope difference p=0.001). Thus, age, sex and dAIH preconditioning influence molecules known to regulate the Q and S pathways to phrenic motor facilitation. These novel findings advance our understanding of phrenic LTF, and inform translational research concerning the therapeutic potential of dAIH to treat breathing deficits in individuals of different ages or sex.
Spectrograms of Ivory-billed Woodpecker (Campephilus principalis) kent sounds from seven expeditions show 587 Hertz as a pattern
Authors: Williams John D ,   Mission Ivorybill
Published: May 2024

Although the Ivory-billed Woodpecker is widely considered to be extinct, expeditions led by professional ornithologists have acquired visual, video, and audio evidence since 1968, with increases in data since 2000. Audio evidence for “kent” sounds (n=150) were examined for commonality; this was found to be true with a pattern at 587 Hz that suggests a morphological basis. Differences from other species were found on spectrograms. The patterns extend to different states and years and reinforces that the species persists.
Survival, Movement, and Lifespan: Decoding the Roles ofPatched-Related(Ptr) inDrosophila melanogaster
Authors: Parada Cristina , Prieto Daniel
Published: May 2024

Patched-related (Ptr) is a transmembrane protein implicated in developmental processes inDrosophila melanogaster, yet its precise role remains incompletely understood. Here, we usePtr23cnull mutants to investigate the functional significance of Ptr through the entire life cycle monitoring survival during embryonic, larval, pupal and adult development, and studying larval locomotion and muscle structure. We report thatPtr23clarvae displayed impaired hatching, indicative of defective embryonic development. Moreover, mutant larvae exhibited reduced mobility and lethargy, suggesting a potential involvement of Ptr in neuromuscular function. Morphological analysis of somatic muscles in mutant larvae revealed enlarged cell nuclei. Despite high pre-adult mortality, a subset ofPtr23cmutant adults display an unexpected extension in lifespan compared to controls, implicating Ptr in the regulation of longevity. Our findings provide critical insights into the multifaceted role of Ptr inDrosophiladevelopment, highlighting its contributions to post-embryonic survival, neuromuscular function, and lifespan regulation. This study underscores the significance of exploring broader genetic networks to unravel the complexities of developmental processes.

Highlights

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Loss of Ptr elicits impaired embryonic hatching, reduced mobility, and lethargy.

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Ptr23c mutants display nuclear enlargement in somatic muscles.

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Ptr23c individuals that survive to adulthood demonstrate extended longevity.
Effect of interhemispheric zero-phase entrainment of the intrinsic mu-rhythm on behavioral and neural markers of predictive coding
Authors: Heise Kirstin-Friederike , Albouy Geneviève , Dolfen Nina , Peeters Ronald , Mantini Dante , Swinnen Stephan P.
Published: May 2024

Goal-directed behavior requires the integration of information from the outside world and internal (somatosensory) sources about our own actions. Expectations (or ‘internal models’) are generated from prior knowledge and constantly updated based on sensory feedback. This optimized information integration (’predictive coding’) results in a global behavioral advantage of anticipated action in the presence of uncertainty. Our goal was to probe the effect of phase entrainment of the sensorimotor mu-rhythm on visuomotor integration. Participants received transcranial alternating current stimulation over bilateral motor cortices (M1) while performing a visually-guided force adjustment task during functional magnetic resonance imaging. Inter-hemispheric zero-phase entrainment resulted in effector-specific modulation of performance precision and effector-generic minimization of force signal complexity paralleled by BOLD activation changes in bilateral caudate and increased functional connectivity between the right M1 and contralateral putamen, inferior parietal, and medial temporal regions. While effector-specific changes in performance precision were associated with contralateral caudate and hippocampal activation decreases, only the global reduction in force signal complexity was associated with increased functional M1 connectivity with bilateral striatal regions. We propose that zero-phase synchronization represents a neural mode of optimized information integration related to internal model updating within the recursive perception-action continuum associated with predictive coding.
Artesunate, EDTA and colistin work synergistically against MCR-negative and -positive colistin-resistantSalmonella
Authors: Zhai Yajun , Liu Peiyi , Hu Xueqin , Fan Changjian , Cui Xiaodie , He Qibiao , He Dandan , Ma Xiaoyuan , Hu Gongzheng , Zhai Yajun
Published: May 2024

Discovering new strategies to combat the multi-drug resistance bacteria constitutes a major medical challenge of our time. Previously, artesunate (AS) has been reported to exert antibacterial enhancement activity in combination with β-lactam antibiotics, via inhibition of the efflux pump AcrB. However, combination of AS and colistin (COL) revealed weak synergistic effect against a limited number of strains, and few studies have further explored its possible mechanism of synergistic action. In this paper, we found that AS and EDTA could strikingly enhance the antibacterial effects of COL againstmcr-1-andmcr-1+Salmonellastrains eitherin vitroorin vivo, when used in triple combination. The excellent bacteriostatic effect was primarily related to the increased cell membrane damage, accumulation of toxic compounds and inhibition of MCR-1. The potential binding sites of AS to MCR-1 (THR283, SER284, and TYR287) were critical for its inhibition of MCR-1 activity. Additionally, we also demonstrated that the CheA of chemosensory system and virulence-related protein SpvD were critical for the bacteriostatic synergistic effects of the triple combination. Selectively targeting CheA, SpvD or MCR using the natural compound AS could be further investigated as an attractive strategy for treatment ofSalmonellainfection. Collectively, our work opens new avenues towards the potentiation of COL and revealed an alternative drug combination strategy to overcome COL resistant bacterial infections.
Endothelial deletion ofp53generates transitional endothelial cells and improves lung development during neonatal hyperoxia
Authors: Ellis Lisandra Vila , Bywaters Jonathan D , Chen Jichao
Published: May 2024

Bronchopulmonary dysplasia (BPD), a prevalent and chronic lung disease affecting premature newborns, results in vascular rarefaction and alveolar simplification. Although the vasculature has been recognized as a main player in this disease, the recently found capillary heterogeneity and cellular dynamics of endothelial subpopulations in BPD remain unclear. Here, we show Cap2 cells are damaged during neonatal hyperoxic injury, leading to their replacement by Cap1 cells which, in turn, significantly decline. Single-cell RNA-seq identifies the activation of numerous p53 target genes in endothelial cells, includingCdkn1a (p21). While global deletion ofp53results in worsened vasculature, endothelial-specific deletion ofp53reverses the vascular phenotype and improves alveolar simplification during hyperoxia. This recovery is associated with the emergence of a transitional EC state, enriched for oxidative stress response genes and growth factors. These findings implicate the p53 pathway in EC type transition during injury-repair and highlights the endothelial contributions to BPD.
Exercising with virtual reality is potentially better for the working memory and positive mood than cycling alone
Authors: Ochi Genta , Ohno Ken , Kuwamizu Ryuta , Yamashiro Koya , Fujimoto Tomomi , Ikarashi Koyuki , Kodama Naoki , Onishi Hideaki , Sato Daisuke
Published: May 2024

Although virtual reality (VR) exercise has attracted attention as a factor in exercise habituation due to its mood-enhancing effects, its impact on brain function remains unclear. This study, involving 23 healthy university students, used functional magnetic resonance imaging (fMRI) to explore how VR exercise affects working memory, a key executive function, and its underlying neural mechanisms. Our findings indicate that a 10-min VR exercise session improved mood (arousal and vitality level) and working memory task performance (3-back task) more effectively than exercise or rest alone. Furthermore, the results confirmed that increased vitality from exercise and VR exercise interventions was associated with improved 3-back task performance. However, specific brain regions contributing to this enhancement remain unidentified. These results highlight VR exercise as the optimal exercise program for enhancing working memory function by increasing vitality level. These insights underscore VR’s potential as a novel exercise modality with benefits extending beyond exercise adherence to potentially preventing dementia and depression.
α-Synuclein Conformations in Plasma Distinguish Parkinson’s Disease from Dementia with Lewy Bodies
Authors: Kannarkat George T. , Zack Rebecca , Skrinak R. Tyler , Morley James F. , Davila-Rivera Roseanne , Arezoumandan Sanaz , Dorfmann Katherine , Luk Kelvin , Wolk David A. , Weintraub Daniel , Tropea Thomas F. , Lee Edward B. , Xie Sharon X. , Chandrasekaran Ganesh , Lee Virginia M.-Y. , Irwin David , Akhtar Rizwan S. , Chen-Plotkin Alice S.
Published: May 2024

Abstract

Spread and aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). While evidence exists for multiple aSyn protein conformations, often termed “strains” for their distinct biological properties, it is unclear whether PD and DLB result from aSyn strain differences, and biomarkers that differentiate PD and DLB are lacking. Moreover, while pathological forms of aSyn have been detected outside the brain (e.g.,in skin, gut, blood), the functional significance of these peripheral aSyn species is unclear. Here, we developed assays using monoclonal antibodies selective for two different aSyn species generatedin vitro– termed Strain A and Strain B – and used them to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma, through immunohistochemistry, enzyme-linked immunoassay, and immunoblotting. Surprisingly, we found that plasma aSyn species detected by these antibodies differentiated individuals with PD vs. DLB in a discovery cohort (UPenn, n=235, AUC 0.83) and a multi-site replication cohort (Parkinson’s Disease Biomarker Program, or PDBP, n=200, AUC 0.72). aSyn plasma species detected by the Strain A antibody also predicted rate of cognitive decline in PD. We found no evidence for aSyn strains in CSF, and ability to template aSyn fibrillization differed for species isolated from plasma vs. brain, and in PD vs. DLB. Taken together, our findings suggest that aSyn conformational differences may impact clinical presentation and cortical spread of pathological aSyn. Moreover, the enrichment of these aSyn strains in plasma implicates a non-central nervous system source.
Prefrontal 5α-reductase 2 mediates male-specific acute stress response
Authors: Cadeddu Roberto , Braccagni Giulia , Floris Gabriele , Branca Caterina , Corridori Eleonora , Salviati Sara , Sánchez Pilar , Santovito Luca Spiro , Torres Jesus M , Ortega Esperanza , Pinna Graziano , Moos Philip J. , Scheggi Simona , Bortolato Marco
Published: May 2024

A key response to acute stress is the increased brain synthesis of the neurosteroid allopregnanolone (AP). While the rate-limiting step of this reaction is catalyzed by 5α-reductase (5αR), the role of its two primary isoenzymes, 5αR1 and 5αR2, in stress reactivity remains unclear. Here, we found that acute stress led to increased levels of 5αR2, but not 5αR1, in the medial prefrontal cortex (mPFC) of male, but not female, rats. Downregulation of 5αR2 in the mPFC significantly reduced stress response in males, and similar sexual dimorphic effects were observed in a novel line of 5αR2 knockout rats. Notably, 5αR1 regulated baseline AP synthesis, while 5αR2 enabled AP production under stress. Acute AP administration restored stress response in 5αR2 knockdown rats. Single-nucleus transcriptomics showed that 5αR2 enabled stress-induced protein translation in neurons and glia. These results highlight the crucial role of 5αR2 in mediating sex-specific differences in acute stress reactivity.
Wearable neuroprosthesis improves mobility and reduces pain in neuropathic participants
Authors: Gozzi Noemi , Chee Lauren , Odermatt Ingrid , Kikkert Sanne , Preatoni Greta , Valle Giacomo , Pfender Nikolai , Beuschlein Felix , Wenderoth Nicole , Zipser Carl , Raspopovic Stanisa
Published: May 2024

Peripheral neuropathy (PN) is the most common complication of diabetes. It is characterized by sensory loss which often causes major health consequences including foot ulceration, chronic pain, poor mobility and increased risk of falls. However, present treatments do not counteract the cause of the disease, namely lack of sensory feedback, but rather aim at partial and temporal symptoms relief (e.g. analgesics for pain or creams for ulcers healing). Electrical stimulation is a promising solution for sensory restoration, but it is yet unknown if it can elicit perceivable sensations in PN damaged nerves and whether it could lead to any health or functional benefits. To this aim, we designed a wearable sensory neuroprosthesis providing targeted neurostimulation at the ankle level (NeuroStep) restoring feet lost sensations. We tested it in 14 participants with PN, evaluating its effects on functional outcomes and pain, and the cortical activation related to the restored sensations. Our system was able to restore lost sensations in all participants. The nerves of PN participants resulted significantly less excitable and sensitive than healthy individuals (N=22). Thanks to the neurostimulation, participants improved cadence and functional gait, with even stronger improvements in individuals with higher risk of falls. A full day of NeuroStep use led to a clinically significant reduction of 30.4% ± 9.2% in neuropathic pain. Restored sensations activated cortical patterns, as measured via fMRI, similar to the naturally located foot sensations, thus not requiring training by the user. NeuroStep restores intuitive sensations in PN participants, improving mobility and decreasing pain, possibly replacing multiple inefficient treatments. It holds potential to drastically improve patients’ quality of life thanks to functional and health benefits, while paving the way to new effective neuromodulation treatments.
Occupation Recognition and Exploitation in Rheumatology Clinical Notes: Employing Deep Learning Models for Named Entity Recognition and Knowledge Discovery in Electronic Health Records
Authors: Madrid-García Alfredo , Pérez-Sancristóbal Inés , Leticia-Leon  , Lydia-Abásolo  , Fernández-Gutiérrez Benjamín , Rodríguez-Rodríguez Luis
Published: May 2024

Occupation is considered a Social Determinant of Health (SDOH) and its effects have been studied at multiple levels. Although the inclusion of such data in the Electronic Health Record (EHR) is vital for the provision of clinical care, specially in rheumatology where work disability prevention is essential, occupation information is often either not routinely documented or captured in an unstructured manner within conventional EHR systems. Encouraged by recent advances in natural language processing and deep learning models, we propose the use of novel architectures (i.e., transformers) to detect occupation mentions in rheumatology clinical notes of a tertiary hospital, and to whom those occupations belongs. We also aimed to evaluate the clinical and demographic characteristics that influence the collection of this SDOH; and the association between occupation and patients’ diagnosis. Bivariate and multivariate logistic regression analysis were conducted for this purpose.

A Spanish pre-trained language model, RoBERTa, fine-tuned with biomedical texts was used to detect occupations. The best model achieved a F1-score of 0.725 identifying occupation mentions. Moreover, highly disabling mechanical pathology diagnoses (i.e., back pain, muscle disorders) were associated with a higher probability of occupation collection. Ultimately, we determined the professions most closely associated with more than ten categories of muscu-loskeletal disorders.

Highlights

Deep learning models hold significant potential for structuring and leveraging information in rheumatology

Diagnoses related to highly disabling mechanical pathology were associated with a higher probability of occupation collection

Cleaners, helpers, and social workers occupations are linked to mechanical pathologies such as back pain
Reduced Likelihood of Hospitalization with the JN.1 or HV.1 SARS-CoV-2 Variants Compared to the EG.5 Variant
Authors: Levy Matthew E. , Chilunda Vanessa , Davis Richard E. , Heaton Phillip R. , Pawloski Pamala A. , Goldman Jason D. , Schandl Cynthia A. , McEwen Lisa M. , Cirulli Elizabeth T. , Wyman Dana , Rossi Andrew Dei , Dai Hang , Isaksson Magnus , Washington Nicole L. , Basler Tracy , Tsan Kevin , Nguyen Jason , Ramirez Jimmy , Sandoval Efren , Lee William , Lu James , Luo Shishi
Published: May 2024

Within a multi-state viral genomic surveillance program, proportions of SARS-CoV-2 infections attributed to the JN.1 and HV.1 variants, compared to EG.5, were each lower among inpatients versus outpatients (aOR=0.33 [95% CI: 0.20-0.55] and aOR=0.62 [95% CI: 0.44-0.86], respectively). JN.1 and HV.1 variants may be associated with a lower risk of severe illness.
Novel Deep CNNs Explore Regions, Boundaries, and Residual Learning for COVID-19 Infection Analysis in Lung CT
Authors: Alshemaimri Bader Khalid , Khan Saddam Hussain
Published: May 2024

COVID-19 poses a global health crisis, necessitating precise diagnostic methods for timely containment. However, accurately delineating COVID-19 affected regions in Lung CT scans is challenging due to contrast variations and significant texture diversity. In this regard, this study introduces a novel two-stage classification and segmentation CNN approach for COVID-19 lung radiological pattern analysis. A novel Residual-BRNet is developed to integrate boundary and regional operations with residual learning, capturing key COVID-19 radiological homogeneous regions, texture variations, and structural contrast patterns in the classification stage. Subsequently, infectious CT images undergo lesion segmentation in the second stage using the newly proposed RESeg segmentation CNN. The RESeg leverages both average and max-pooling implementations to simultaneously learn region homogeneity and boundary-related patterns. Furthermore, novel pixel attention (PA) blocks are integrated into RESeg to effectively address mildly infected regions. The evaluation of the proposed Residual-BRNet CNN demonstrates promising performance metrics, achieving an accuracy of 97.97%, F1-score of 98.01%, sensitivity of 98.42%, and MCC of 96.81%. Meanwhile, PA-RESeg achieves optimal segmentation performance with an IoU score of 98.43% and a Dice Similarity score of 95.96% of the lesion region. These findings highlight the potential of the proposed diagnosis framework to assist radiologists in identifying and analyzing COVID-19 affected lung regions. The CAD GUI diagnosis tool is provided athttps://github.com/PRLAB21/COVID-19-Diagnostic-System.
Risk of common psychiatric disorders, suicidal behaviours and premature mortality following violent victimisation: A matched cohort and sibling-comparison study of 127,628 people who experienced violence in Finland and Sweden
Authors: Sariaslan Amir , Pitkänen Joonas , Forsman Jonas , Kuja-Halkola Ralf , Brikell Isabell , D’Onofrio Brian M. , Aaltonen Mikko , Larsson Henrik , Martikainen Pekka , Lichtenstein Paul , Fazel Seena
Published: May 2024

Background

Associations between violent victimisation and psychiatric disorders are hypothesised to be bidirectional, but the role of violent victimisation in the aetiologies of psychiatric disorders and other adverse outcomes remains unclear. We aimed to estimate associations between violent victimisation and subsequent common psychiatric disorders, suicidal behaviours, and premature mortality whilst accounting for unmeasured familial confounders.

Methods and Findings

Using nationwide registers, we identified a total of 127,628 individuals born in Finland (1987-2004) and Sweden (1973-2004) who had experienced violent victimisation, defined as either hospital admissions or secondary care outpatient visits for assault-related injuries. These were age- and sex-matched with up to 10 individuals in the general population (n=1,276,215) and their unaffected siblings (n=132,408). Outcomes included depression, anxiety, personality disorders, substance use disorders, suicidal behaviours, and premature mortality. Participants were followed from the victimisation date until the date of the outcome, emigration, death, or December 31, 2020, whichever occurred first. Country-specific associations were estimated using stratified Cox regression models, which also accounted for unmeasured familial confounders via sibling comparisons. The country-specific associations were then pooled using meta-analytic models.

Among 127,628 patients (69.0% men) who had experienced violent victimisation, the median age at first violent victimisation was 21 (interquartile range: 18-26) years. Absolute risks of all outcomes were larger in those who were exposed to violent victimisation compared to population controls (2.3-22.5 vs. 0.6-7.3 per 1000 person-years). In adjusted models, people who had experienced violent victimisation were between two to three times as likely as their siblings to develop any of the outcomes (adjusted hazard ratios [aHRs]: 1.7-3.0). Risks remained elevated two years post-victimisation (aHRs: 1.4-2.3).

Conclusions

Improving clinical assessment, management and aftercare psychosocial support could potentially reduce rates of common psychiatric disorders, suicidality and premature in individuals experiencing violent victimisation.
The Relationship Between Triglyceride to High-Density Lipoprotein Cholesterol Ratio and Cardiovascular High-Risk: A Cross-Sectional Investigation
Authors: Li Yapeng , Shi Huiting , Liang Cui , Xie Qiaotao , Hu Haowei , Wang Haoran , Li Pengcheng
Published: May 2024

Aims

The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio reflects the balance between atherogenic and anti-atherogenic lipid fractions. The study aims to investigate the utility of the TG/HDL-C ratio in identifying high-risk groups for cardiovascular disease (CVD) within the general population.

Methods

The current study was a branch of the ChinaHEART cohort in middle China that involved a total of 6,593 community-dwelling adults. We examine the association between TG/HDL-C and CVD high-risk in a cross-sectional investigation.

Results

Results from restricted cubic spline and ROC analyses revealed a significant relationship between higher TG/HDL-C levels and increased odds of cardiovascular high-risk, with the ratio exhibiting good discriminatory power (AUC=0.819 in the fully adjusted model). Logistic regression further supported this association, indicating a 1.21-fold rise in the odds of high-risk for each unit increase in TG/HDL-C.

Conclusions

The TG/HDL ratio demonstrates potential as a valuable clinical tool for CVD prevention. By incorporating the TG/HDL ratio into risk assessment models, healthcare professionals can enhance risk stratification and identify high-risk individuals who may benefit from targeted interventions.
Unraveling the “indirect effects” of interventions against malaria endemicity: A systematic scoping review
Authors: Ko Yura K. , Kagaya Wataru , Chan Chim W. , Kanamori Mariko , Mbugua Samuel M. , Rotich Alex K. , Kanoi Bernard N. , Ngara Mtakai , Gitaka Jesse , Kaneko Akira
Published: May 2024

There is an urgent need to maximize the effectiveness of existing malaria interventions and optimize the deployment of novel countermeasures. When assessing the effects of interventions against malaria, it is imperative to consider the interdependence of people and the resulting indirect effects, without which the impact on health outcomes and their cost-effectiveness may be miscalculated. Here, we conducted a scoping review of existing literature on the indirect effects of malaria interventions. We observed a recent increase in both the number of reports and the variety of terms used to denote indirect effects. We further classified eight categories of comparative analysis to identify the indirect effects, proposed common terms for the indirect effects, and highlighted the potential benefits of mathematical models in estimating indirect effects. Improving the study design and reporting the indirect effects of malaria interventions will lead to better informed decisions by policymakers.
Genomics-informed Neuropsychiatric Care for Neurodevelopmental Disorders: Results from A Multidisciplinary Clinic
Authors: Besterman Aaron D. , Adams David J. , Wong Nicole R. , Schneider Benjamin N. , Mehta Sunil , DiStefano Charlotte , Wilson Rujuta B. , Martinez-Agosto Julian A. , Jeste Shafali S.
Published: May 2024

Background

Patients with neurodevelopmental disorders (NDDs) have high rates of neuropsychiatric comorbidities that can be highly impairing and treatment refractory. Genomic medicine may help guide care, as pathogenic variants are identified in up to 50% of patients with NDDs. We evaluate the impact of a genomics-informed, multidisciplinary, neuropsychiatric specialty clinic on the diagnosis and management of patients with NDDs.

Methods

We performed a retrospective study of 316 patients from the UCLA Care and Research in Neurogenetics Clinic, a genomics-informed multidisciplinary clinic composed of psychiatry, neurology, medical genetics, psychology, and social work.

Results

We observed high rates of psychiatric and medical comorbidity. Among the 246 patients that underwent genetic testing, 41.8% had a pathogenic or likely pathogenic (P/LP) variant. Patients had 62 different genetic diagnoses, with 12 diagnoses shared by two or more patients, including Duplication 15q syndrome (9.18%), Tuberous Sclerosis Complex (3.48%), and Angelman syndrome (1.27%), while 50 diagnoses were found in only single patients. Genetic diagnosis resulted in direct changes to clinical management in all patients with a P/LP variant, including high rates of cascade testing (30.6%), family counseling (22.2%), medication changes (13.9%), clinical trial referral (2.8%), medical surveillance (30.6%), and specialty referrals (69.4%).

Conclusions

A genomics-informed model can provide significant clinical benefits to patients with NDDs, directly impacting management across multiple domains for most diagnosed patients. As precision treatments for NDDs advance, establishing a genetic diagnosis will be critical for proper management. With the growing number of rare neurogenetic disorders, clinician training should emphasize core principles of genomic medicine over individual syndromes.
Sex differences in change-of-mind neuroeconomic decision-making is modulated by LINC00473 in medial prefrontal cortex
Authors: Cuttoli Romain Durand-de , Issler Orna , Yakubov Benjamin , Jahan Nusrat , Abid Aisha , Kasparov Susanna , Granizo Kastalia , Ahmed Sanjana , Russo Scott J. , Nestler Eric J. , Sweis Brian M.
Published: May 2024

Changing one’s mind is a complex cognitive phenomenon involving a continuous re-appraisal of the trade-off between past costs and future value. Recent work modeling this behavior across species has established associations between aspects of this choice process and their contributions to altered decision-making in psychopathology. Here, we investigated the actions in medial prefrontal cortex (mPFC) neurons of long intergenic non-coding RNA, LINC00473, known to induce stress resilience in a striking sex-dependent manner, but whose role in cognitive function is unknown. We characterized complex decision-making behavior in male and female mice longitudinally in our neuroeconomic foraging paradigm, Restaurant Row, following virus-mediated LINC00473 expression in mPFC neurons. On this task, mice foraged for their primary source of food among varying costs (delays) and subjective value (flavors) while on a limited time-budget during which decisions to accept and wait for rewards were separated into discrete stages of primary commitments and secondary re-evaluations. We discovered important differences in decision-making behavior between female and male mice. LINC00473 expression selectively influenced multiple features of re-evaluative choices, without affecting primary decisions, in female mice only. These behavioral effects included changing how mice (i) cached the value of the passage of time and (ii) weighed their history of economically disadvantageous choices. Both processes were uniquely linked to change-of-mind decisions and underlie the computational bases of distinct aspects of counterfactual thinking. These findings reveal a key bridge between a molecular driver of stress resilience and psychological mechanisms underlying sex-specific decision-making proclivities.
Functional Resilience of the Neural Visual Recognition System Post-Pediatric Occipitotemporal Resection
Authors: Granovetter Michael C. , Maallo Anne Margarette S. , Ling Shouyu , Robert Sophia , Freud Erez , Patterson Christina , Behrmann Marlene
Published: May 2024

In the typically developing (TD) brain, neural representations for visual stimulus categories (e.g., faces, objects, and words) emerge in bilateral occipitotemporal cortex (OTC), albeit with weighted asymmetry; in parallel, recognition behavior continues to be refined. A fundamental question is whether two hemispheres are necessary or redundant for the emergence of neural representations and recognition behavior typically distributed across both hemispheres. The rare population of patients undergoing unilateral OTC resection in childhood offers a unique opportunity to evaluate whether neural computations for visual stimulus individuation suffice for recognition with only a single developing OTC. Here, using functional magnetic resonance imaging, we mapped category selectivity (CS) and neural representations for individual stimulus exemplars using repetition suppression (RS) in the non-resected hemisphere of pediatric OTC resection patients (n= 9) and control patients with resection outside of OTC (n= 12), as well as in both hemispheres of TD controls (n= 21). There were no univariate group differences in the magnitude of CS or RS or any multivariate differences (per representational similarity analysis) in neural activation to faces, objects, or words across groups. Notwithstanding their comparable neural profiles, accuracy of OTC resection patients on face and object recognition, but not word recognition, was statistically inferior to that of controls. The comparable neural signature of the OTC resection patients’ preserved hemisphere and the other two groups highlights the resilience of the system following damage to the contralateral homologue. Critically, however, a single OTC does not suffice for normal behavior, and, thereby, implicates the necessity for two hemispheres.
Cell-surface receptor-mediated regulation of synaptic organelle distribution controls dendritic spine maturation
Authors: Verpoort Ben , Amado Luísa , Vandensteen Jeroen , Leysen Elke , Dascenco Dan , Vandenbempt Joris , Lemmens Irma , Wauman Joris , Vennekens Kristel , Escamilla-Ayala Abril , Nogueira Freitas Ana Cristina , Voets Thomas , Munck Sebastian , Tavernier Jan , de Wit Joris
Published: May 2024

The spine apparatus (SA), an endoplasmic reticulum-related organelle present in a subset of mature dendritic spines, plays a key role in postsynaptic development and has been implicated in various neurological disorders. However, the molecular mechanisms that dictate SA localization at selected synapses remain elusive. Here, we identify a postsynaptic signaling complex comprising the GPCR-like receptor GPR158 and a largely uncharacterized phospholipase C (PLC), PLCXD2, that controls SA abundance. Sparse genetic manipulationsin vivodemonstrate that in the absence of GPR158, unrestrained PLCXD2 activity impedes postsynaptic SA incorporation and hampers dendritic spine maturation. Finally, we show that extracellular heparan sulfate proteoglycan (HSPG) binding modulates the GPR158-PLCXD2 interaction. Together, our findings reveal how a postsynaptic receptor signaling complex regulates the local lipid microenvironment to control SA abundance required for the proper maturation of dendritic spines.
autoMEA: Machine learning-based burst detection for multi-electrode array datasets
Authors: Hernandes Vinicius , Heuvelmans Anouk M. , Gualtieri Valentina , Meijer Dimphna H. , van Woerden Geeske M. , Greplova Eliska
Published: May 2024

Neuronal activity in the highly organized networks of the central nervous system is the vital basis for various functional processes, such as perception, motor control, and cognition. Understanding interneuronal connectivity and how activity is regulated in the neuronal circuits is crucial for interpreting how the brain works. Multi-electrode arrays (MEAs) are particularly useful for studying the dynamics of neuronal network activity and their development as they allow for real-time, high-throughput measurements of neural activity. At present, the key challenge in the utilization of MEA data is the sheer complexity of the measured datasets. Available software offers semi-automated analysis for a fixed set of parameters that allow for the definition of spikes and bursts. However, this analysis remains time-consuming, user-biased, and limited by pre-defined parameters. Here, we present autoMEA, software for machine learning-based automated burst detection in MEA datasets. We exemplify autoMEA efficacy on neuronal network activity of primary hippocampal neurons from wild-type mice monitored using 24-well multiwell MEA plates. To validate and benchmark the software, we showcase its application using wild-type neuronal networks and two different neuronal networks modeling neurodevelopmental disorders to assess network phenotype detection. Detection of network characteristics typically reported in literature, such as synchronicity and rhythmicity, could be accurately detected compared to manual analysis using the autoMEA software. Additionally, autoMEA could detect reverberations, a more complex burst dynamic present in hippocampal cultures. Furthermore, autoMEA burst detection was sufficiently sensitive to detect changes in the synchronicity and rhythmicity of networks modeling neurodevelopmental disorders as well as detecting changes in their burst dynamics. Thus, we show that autoMEA reliably analyses neural networks measured with the multi-well MEA setup with the precision and accuracy compared to that of a human expert.
Unraveling the complexity of rat object vision requires a full convolutional network - and beyond
Authors: Muratore Paolo , Alemi Alireza , Zoccolan Davide
Published: May 2024

Despite their prominence as model systems to dissect visual cortical circuitry, it remains unclear whether rodents are capable of truly advanced processing of visual information. Here, we considered several psychophysical studies of rat object vision, and we used a deep convolutional neural network (CNN) to measure the computational complexity required to account for the patterns of rat performances reported in these studies, as well as for the animals’ perceptual strategies. We found that at least half of the CNN depth was required to match the modulation of rat classification accuracy in tasks where objects underwent variations of size, position and orientation. However, the full network was needed to equal the tolerance of rat perception to more severe image manipulations, such as partial occlusion and reduction of objects to their outlines. Finally, rats displayed a perceptual strategy that was way more invariant than that of the CNN, as they more consistently relied on the same set of diagnostic features across object transformations. Overall, these results reveal an unexpected level of sophistication of rat object vision, while reinforcing the intuition that, despite their proficiency in solving challenging image classification tasks, CNNs learn solutions that only marginally match those of biological visual systems.
Coxsackievirus group B3 regulates ASS1-mediated metabolic reprogramming and promotes macrophage inflammatory polarization in viral myocarditis
Authors: Liu Qiong , Shang Yinpan , Tao Ziwei , Li Xuan , Shen Lu , Zhang Hanchi , Liu Zhili , Rao Zhirong , Yu Xiaomin , Cao Yanli , Zeng Lingbing , Huang Xiaotian
Published: May 2024

Coxsackievirus group B3 (CVB3) belongs to the genusEnterovirusesof the familyPicornaviridaeand is the main pathogen underlying viral myocarditis (VMC). No specific therapeutic is available for this condition. Argininosuccinate synthase 1 (ASS1) is a key enzyme in the urea cycle that converts citrulline and aspartic acid to argininosuccinate. Here, we found that CVB3 and its capsid protein VP2 inhibit the autophagic degradation of ASS1 and that CVB3 consumes citrulline to upregulate ASS1, triggers urea cycle metabolic reprogramming, then activates macrophages to develop pro-inflammatory polarization, thereby promoting the occurrence and development of VMC. Conversely, citrulline supplementation to prevent depletion can downregulate ASS1, rescue macrophage polarization, and alleviate the pathogenicity of VMC. These findings provide a new perspective on the occurrence and development of VMC, revealing ASS1 as a potential new target for the treatment of this disease.

IMPORTANCE

Viral myocarditis (VMC) is a common and potentially life-threatening myocardial inflammatory disease, most commonly caused by CVB3 infection. So far, the pathogenesis of VMC caused by CVB3 is mainly focused on two aspects: one is the direct myocardial injury caused by a large number of viral replication in the early stage of infection, and the other is the local immune cell infiltration and inflammatory damage of the myocardium in the adaptive immune response stage. There are few studies on the early innate immunity of CVB3 infection in myocardial tissue, but the appearance of macrophages in the early stage of CVB3 infection suggests that they can play a regulatory role as early innate immune response cells in myocardial tissue. Here, we discovered a possible new mechanism of VMC caused by CVB3, revealed new drug targets for anti-CVB3 and discovered the therapeutic potential of citrulline for VMC.
Generating gnotobiotic bivalves: a new method on Manila clam (Ruditapes philippinarum)
Authors: Gallo Marialaura , Quagliariello Andrea , Rovere Giulia Dalla , Maietti Federica , Cardazzo Barbara , Peruzza Luca , Bargelloni Luca , Martino Maria Elena
Published: May 2024

The microbiome, which encompasses microbial communities associated with animal hosts, exerts a profound impact on host physiology and ecosystem dynamics. The application of advanced sequencing technologies has enabled researchers to investigate the composition of microbiomes across a range of hosts and environments. While correlating microbial composition with health outcomes has been a priority, interpreting such data requires caution to avoid overemphasizing the roles of microbes. Understanding microbial influence demands mechanistic insights, which are often elucidated through gnotobiology. Despite their limitations in representing animal diversity, model organisms offer the advantage of reproducibility and experimental tractability. However, the marine realm, especially bivalves, which are crucial for ecosystem functioning and aquaculture, lacks gnotobiotic models. In this study, we present a method for generating microbiome-depleted and gnotobiotic clams (Ruditapes philippinarum), one of the most widely farmed molluscs in the world and a sentinel organism for climate change. This model expands gnotobiotic research into marine invertebrates, thereby enabling investigations into the impact of microbes on such key animal species.
Electroacupuncture regulates microglia activation through the STING/NF-κB pathway to reduce pain in bone cancer pain model
Authors: Liang Ying , Liu Wenhao , Shen Zhiyi , Yan Xu , He Yihan , Xu Nenggui
Published: May 2024

Cancer pain is a global public health problem. The mechanism of cancer pain is complex, and opioid analgesics, which are widely used clinically, have obvious addiction and side effects, which seriously affect patients’life functions and may aggravate their anxiety, depression and other negative emotions. Acupuncture has a history of thousands of years in China, and acupuncture analgesia has been confirmed by many studies. This study investigated whether electroacupuncture can alleviate abnormal pain in bone cancer pain (BCP) mouse models and its possible central mechanism. A bone cancer pain model was established by injecting Lewis lung cancer cells into the left femoral cavity of adult male mice. Mechanical paw withdrawal threshold was tested baseline before surgery and 1, 4, 7, 10, 14 and 21 days after surgery. On day 21, behaviours related to depression emotions were tested. After the behaviours, the femurs were removed to observe pathological changes, the neck was broken and brain tissue was collected from the basal lateral amygdala (BLA) area for subsequent Western Blot and ELISA experiments were performed to verify the expression of (stimulator of interferon genes, STING) STING/NF-κB pathway proteins and the expression of inflammatory factors. Immunofluorescence of Ionized calcium-binding adapter molecule-1 (Iba-1) and STING in the basal lateral amygdala (BLA) brain region was also performed. The results show that electroacupuncture can increase the pain threshold of the bone cancer pain model and alleviate the depressive-like emotional phenotype. Electroacupuncture inhibited the expression of STING/NF-κB pathway proteins, activation of microglia and release of inflammatory factors in the basal lateral amygdala (BLA) area. Therefore, this study shows that electroacupuncture may relieve bone cancer pain by regulating microglial activation and inflammatory factor release through the STING/NF-κB pathway.