bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic organization of visual cortical networks inferred from massive spiking datasets
Authors: Graber Colin , Vlasov Yurii , Schwing Alexander 
Published: August 2023

ABSTRACTComplex cognitive functions in a mammalian brain are distributed across many anatomically and functionally distinct areas and rely on highly dynamic routing of neural activity across the network. While modern electrophysiology methods enable recording of spiking activity from increasingly large neuronal populations at a cellular level, development of probabilistic methods to extract these dynamic inter-area interactions is lagging. Here, we introduce an unsupervised machine learning model that infers dynamic connectivity across the recorded neuronal population from a synchrony of their spiking activity. As opposed to traditional population decoding models that reveal dynamics of the whole population, the model produces cellular-level cell-type specific dynamic functional interactions that are otherwise omitted from analysis. The model is evaluated on ground truth synthetic data and compared to alternative methods to ensure quality and quantification of model predictions. Our strategy incorporates two sequential stages – extraction of static connectivity structure of the network followed by inference of temporal changes of the connection strength. This two-stage architecture enables detailed statistical criteria to be developed to evaluate confidence of the model predictions in comparison with traditional descriptive statistical methods. We applied the model to analyze large-scale in-vivo recordings of spiking activity across mammalian visual cortices. The model enables the discovery of cellular-level dynamic connectivity patterns in local and long-range circuits across the whole visual cortex with temporally varying strength of feedforward and feedback drives during sensory stimulation. Our approach provides a conceptual link between slow brain-wide network dynamics studied with neuroimaging and fast cellular-level dynamics enabled by modern electrophysiology that may help to uncover often overlooked dimensions of the brain code.
Early Deprivation Impairs Perforant Pathway Connectivity and Contextual Memory in Adolescent Male Mice
Authors: Islam Rafiad , White Jordon D. , Arefin Tanzil M. , Mehta Sameet , Liu Xinran , Polis Baruh , Giuliano Lauryn , Ahmed Sahabuddin , Bowers Christian , Zhang Jiangyang , Kaffman Arie 
Published: August 2023

ABSTRACTEarly-life adversity causes reduced hippocampal volume and abnormal hippocampal connectivity and function, with evidence indicating more prominent deficits in males compared to females. Reelin-positive projections from the lateral entorhinal cortex (LEC) to the dorsal hippocampus are essential for encoding contextual and semantic memories in diverse mammalian species, including humans and rodents. However, the impact of early-life adversity on these projections and their contribution to hippocampal-dependent deficits have not been reported. Using a modified limited bedding (LB) mouse model of early adversity that extends the impoverished conditions from birth to postnatal day 25 (P25), we found severe impairment in contextual fear conditioning for adolescent LB male but not LB female mice. Using retrograde tracing, we found that the number of reeling-positive projections from the LEC to the dorsal hippocampus is significantly reduced in LB males but not LB females. Further, the number of projections was highly correlated with deficits in contextual memory and hypomyelination in perforant pathway terminals located in the dorsal hippocampus. Ex vivo high-resolution diffusion magnetic resonance imaging confirmed reduced structural connectivity between the entorhinal cortex and the dorsal hippocampus and revealed extensive cortical atrophy that resembled abnormalities reported in children exposed to severe deprivation. Given the essential role that reelin-positive projections play in contextual memory, these findings suggest a novel mechanism to explain the pronounced contextual memory deficits seen in LB males.
Post-COVID conditions during Delta and early-Omicron SARS-CoV-2 variant periods among adults in the United States
Authors: Edwards Deja , Logan Pamela , Feldstein Leora R. , Fairlie Tarayn , Accorsi Emma , Saydah Sharon 
Published: August 2023

AbstractBackgroundPost-COVID conditions after infection with new SARS-CoV-2 variants have been incompletely described. We compared the prevalence and risk factors for ongoing symptoms lasting 4 weeks or longer (often referred to as post-COVID Conditions) among adults who had tested positive vs. negative during the Delta and early-Omicron periods.MethodsSelf-reported survey data regarding symptoms and previous SARS-CoV 2 test results were collected from May 31 – July 6, 2022, from a probability sampling of United States adults. Respondents were classified according to their test result, predominant circulating variant when respondents first tested positive (Delta vs early-Omicron), and demographic risk factors.ResultsAmong 2,421 respondents, 256 tested positive during Delta, 460 during early-Omicron, and 1,705 always tested negative. Nearly one-fourth (22.3%) of negative respondents reported ≥1symptom that lasted ≥4 weeks, compared to 60.6% (p<0.05) of respondents who tested positive during the Delta period and 47.8% (p<0.05) during the early-Omicron period. Fatigue, change in smell/taste, and cough were commonly reported by respondents who tested positive. Demographic risk factors associated with ongoing symptoms were being female and unemployed (aOR 1.28, 95% CI 1.06–1.55; aOR 1.48, 95% CI: 1.17–1.87).ConclusionThe reported occurrence of ongoing symptoms associated with post-COVID conditions was reduced during the early-Omicron period, compared with Delta.
Assessing clinical acuity in the Emergency Department using the GPT-3.5 Artificial Intelligence Model
Authors: Williams Christopher Y.K. , Zack Travis , Miao Brenda Y. , Sushil Madhumita , Wang Michelle , Butte Atul J. 
Published: August 2023

AbstractThis paper evaluates the performance of the Chat Generative Pre-trained Transformer (ChatGPT; GPT-3.5) in accurately identifying higher acuity patients in a real-world clinical context. Using a dataset of 10,000 pairs of patient Emergency Department (ED) visits with varying acuity levels, we demonstrate that GPT-3.5 can successfully determine the patient with higher acuity based on clinical history sections extracted from ED physician notes. The model achieves an accuracy of 84% and an F1 score of 0.83, with improved performance for more disparate acuity scores. Among the 500 pair subsample that was also manually classified by a resident physician, GPT-3.5 achieved similar performance (Accuracy = 0.84; F1 score = 0.85) compared to the physician (Accuracy = 0.86, F1 score = 0.87). Our results suggest that, in real-world settings, GPT-3.5 can perform comparably to physicians on the clinical reasoning task of ED acuity determination.
High 3-hydroxybutyrate concentrations in the placenta-produced amniotic fluid in the human uterus
Authors: Satoh Takumi , Shibata Takeo , Takata Emi , Takakura Masahiro , Han Jia , Yamada Sohsuke 
Published: August 2023

ABSTRACTIn this study, we report first high concentrations of a ketone body, 3-hydroxybutyrate (3HB) in the amniotic fluid in humans. Although 3HB concentrations in the maternal blood are approximately 0.1, those in the amniotic fluid are approximately 0.6 mM. High placental 3HB production is potentially key for producing and maintaining high 3HB levels in the amniotic fluid. The rate-limiting enzyme, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), is highly expressed in the cells of the chorionic plate and responsible for 3HB production. Therefore, high HMGCS2 expression maintenance is supposed to be pivotal for maintaining the 3HB supply for the human fetus. Here, we propose that humans display two pathways, an amniotic fluid- and another umbilical vein-mediated, for supplying 3HB to the human fetus. These supply pathways are supposedly essential for human brain development during the late phase of pregnancy.Graphical abstractHuman fetuses are supported by 3HB from the amniotic fluid for their brain development.HIGHLIGTS3-Hydroxybutyrate concentrations are high in the amniotic fluid in the human uterus.The chorionic plate of the placenta highly expresses 3-hydroxy-3-methylglutaryl-CoA synthase 2.Human fetuses may be supplied with 3HB for brain development through the amniotic fluid.
Epigenome-wide association study of incident type 2 diabetes in Black and White participants from the Atherosclerosis Risk in Communities Study
Authors: Venkataraghavan Sowmya , Pankow James S. , Boerwinkle Eric , Fornage Myriam , Selvin Elizabeth , Ray Debashree 
Published: August 2023

ABSTRACTDNA methylation studies of incident type 2 diabetes in US populations are limited, and to our knowledge none included individuals of African descent living in the US. We performed an epigenome-wide association analysis of blood-based methylation levels at CpG sites with incident type 2 diabetes using Cox regression in 2,091 Black and 1,029 White individuals from the Atherosclerosis Risk in Communities study. At an epigenome-wide significance threshold of 10−7, we detected 7 novel diabetes-associated CpG sites inC1orf151(cg05380846: HR= 0.89,p= 8.4 × 10−12),ZNF2(cg01585592: HR= 0.88,p= 1.6 × 10−9),JPH3(cg16696007: HR= 0.87,p= 7.8 × 10−9),GPX6(cg02793507: HR= 0.85,p= 2.7 × 10−8and cg00647063: HR= 1.20,p= 2.5 × 10−8), chr17q25 (cg16865890: HR= 0.8,p= 6.9 × 10−8), and chr11p15 (cg13738793: HR= 1.11,p= 7.7 × 10−8). The CpG sites atC1orf151,ZNF2, JPH3andGPX6, were identified in Black adults, chr17q25 was identified in White adults, and chr11p15 was identified upon meta-analyzing the two groups. The CpG sites atJPH3andGPX6were likely associated with incident type 2 diabetes independent of BMI. All the CpG sites, except atJPH3, were likely consequences of elevated glucose at baseline. We additionally replicated known type 2 diabetes-associated CpG sites including cg19693031 atTXNIP, cg00574958 atCPT1A, cg16567056 atPLBC2, cg11024682 atSREBF1, cg08857797 atVPS25, and cg06500161 atABCG1, 3 of which were replicated in Black adults at the epigenome-wide threshold. We observed modest increase in type 2 diabetes variance explained upon addition of the significantly associated CpG sites to a Cox model that included traditional type 2 diabetes risk factors and fasting glucose (increase from 26.2% to 30.5% in Black adults; increase from 36.9% to 39.4% in White adults). We examined if groups of proximal CpG sites were associated with incident type 2 diabetes using a gene-region specific and a gene-region agnostic differentially methylated region (DMR) analysis. Our DMR analyses revealed several clusters of significant CpG sites, including a DMR consisting of a previously discovered CpG site atADCY7and promoter regions ofTP63which were differentially methylated across all race groups. This study illustrates improved discovery of CpG sites/regions by leveraging both individual CpG site and DMR analyses in an unexplored population. Our findings include genes linked to diabetes in experimental studies (e.g.,GPX6,JPH3,andTP63), and future gene-specific methylation studies could elucidate the link between genes, environment, and methylation in the pathogenesis of type 2 diabetes.
Immunogenicity of mRNA-1273 and BNT162b2 in Immunocompromised Patients: Systematic Review and Meta-Analysis Using GRADE
Authors: Kavikondala Sushma , Haeussler Katrin , Wang Xuan , Spellman Anne , Bausch-Jurken Mary T. , Sharma Pawana , Amiri Mohammadreza , Krivelyova Anna , Vats Sonam , Nassim Maria , Kumar Nitendra , Van de Velde Nicolas 
Published: August 2023

ABSTRACTAimImmunocompromised (IC) patients mount poor immune responses to vaccination. Higher-dose COVID-19 vaccines may offer increased immunogenicity.Materials & methodsA pairwise meta-analysis of 98 studies reporting comparisons of mRNA-1273 (50 or 100 mcg/dose) and BNT162b2 (30 mcg/dose) in IC adults was performed. Outcomes were seroconversion, total and neutralizing antibody titers, and cellular immune responses.ResultsmRNA-1273 was associated with a significantly higher seroconversion likelihood (relative risk, 1.11 [95% CI, 1.08, 1.14];P<0.0001;I2=66.8%) and higher total antibody titers (relative increase, 50.45% [95% CI, 34.63%, 66.28%];P<0.0001;I2=89.5%) versus BNT162b2. mRNA-1273 elicited higher but statistically nonsignificant relative increases in neutralizing antibody titers and cellular immune responses versus BNT162b2.ConclusionHigher-dose mRNA-1273 had increased immunogenicity versus BNT162b2 in IC patients.
Dopamine D2 receptor upregulation in dorsal striatum in theLRRK2-R1441C rat model of early Parkinson’s disease revealed byin vivoPET imaging
Authors: Delgado-Goñi Teresa , Connor-Robson Natalie , Cioroch Milena , Paisey Stephen , Marshall Christopher , Lane Emma L. , Hauton David , McCullagh James , Magill Peter J. , Cragg Stephanie J. , Mackay Clare E. , Wade-Martins Richard , Klein Johannes C. 
Published: August 2023

AbstractLRRK2mutations are the most common cause of dominantly inherited Parkinson’s disease (PD). Here, we conducted PET imaging in aged transgenic rats carrying human pathogenicLRRK2R1441C or G2019S mutations with [18F]FDOPA and dopamine D2/3 receptor ligand [18F]fallypride. We interrogate presynaptic integrity and postsynaptic dopamine receptor availability, and compared these to non-transgenic rats.LRRK2mutant rats displayed similar [18F]FDOPA uptake to non-transgenic animals, consistent with intact dopamine synthesis in striatal axons. However,LRRK2-R1441C rats demonstrated greater binding of [18F]fallypride thanLRRK2-G2019S or non-transgenic controls, exhibiting regionally selective binding increase in the dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors inLRRK2-R1441C than other genotypes restricted to the dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit observed in this genotype.These results show that [18F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in theLRRK2-R1441C rat, detecting upregulation of D2 receptors that parallels observations in early human sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.
Actomyosin-II Proactively Shields Axons of the Central Nervous System from Mild Mechanical Stress
Authors: Pan Xiaorong , Lei Gaowei , Li Jie , Luan Tongshu , Hu Yiqing , Chu Yuanyuan , Feng Yu , Zhan Wenrong , Zhao Chunxia , Meunier Frédéric A. , Liu Yifan , Li Yi , Wang Tong 
Published: August 2023

AbstractSummaryPanet alfound that actomyosin-II-driven radial contractility underpins the resilience of central axons to mild mechanical stress by suppressing the propagation and firing of injurious Ca2+waves. Boosting actomyosin-II activity alleviates axon degeneration in mice with traumatic brain injury.Traumatic brain injury (TBI) remains a significant and unmet health challenge. However, our understanding of how neurons, particularly their fragile axons, withstand the abrupt mechanical impacts within the central nervous system remains largely unknown. Using a microfluidic device applying discrete levels of transverse forces to axons, we identified the stress levels that most axons could resist and explored their instant responses at nanoscale resolution. Mild stress induces rapid and reversible axon beading, driven by actomyosin-II-dependent radial contraction, which restricts the spreading and bursting of stress-induced Ca2+waves. More severe stress causes irreversible focal swelling and Ca2+overload, ultimately leading to focal axonal swelling and degeneration. Up-regulating actomyosin-II activity prevented the progression of initial injuryin vivo, protecting commissural axons from degeneration in a mice TBI model. Our study established a scalable axon injury model and uncovered the critical roles of actomyosin-II in shielding neurons against detrimental mechanical stress.
Small fibre neuropathy in Fabry disease: a human-derived neuronalin vitrodisease model
Authors: Klein Thomas , Grüner Julia , Breyer Maximilian , Schlegel Jan , Schottmann Nicole Michelle , Hofmann Lukas , Gauss Kevin , Mease Rebecca , Erbacher Christoph , Finke Laura , Klein Alexandra , Klug Katharina , Karl-Schöller Franziska , Vignolo Bettina , Reinhard Sebastian , Schneider Tamara , Günther Katharina , Fink Julian , Dudek Jan , Maack Christoph , Klopocki Eva , Seibel Jürgen , Edenhofer Frank , Wischmeyer Erhard , Sauer Markus , Üçeyler Nurcan 
Published: August 2023

AbstractAcral burning pain triggered by fever, thermal hyposensitivity, and skin denervation are hallmarks of small fibre neuropathy in Fabry disease, a life-threatening X-linked lysosomal storage disorder. Variants in the gene encoding alpha-galactosidase A may lead to impaired enzyme activity with cellular accumulation of globotriaosylceramide (Gb3). To study the underlying pathomechanism of Fabry-associated small fibre neuropathy, we generated a neuronalin vitrodisease model using patient-derived induced pluripotent stem cells from three Fabry patients and one healthy control. We further generated an isogenic control line via CRISPR/Cas9 gene editing. We subjected iPSC to targeted peripheral neuronal differentiation and observed intra-lysosomal Gb3 accumulations in somas and neurites of Fabry sensory neurons using super-resolution microscopy. At functional level, patch-clamp analysis revealed a hyperpolarizing shift of voltage-gated sodium channel steady-state inactivation kinetics in Fabry cell lines as compared to the healthy control. Moreover, we demonstrate a drastic increase in Fabry sensory neuron Ca2+levels at 39°C mimicking clinical fever (p < 0.001). This pathophysiological phenotype was accompanied by thinning of neurite calibres in sensory neurons obtained from Fabry patients compared to healthy control cells (p < 0.001). Linear-Nonlinear cascade models fit to spiking responses revealed that Fabry cell lines exhibit altered single neuron encoding properties relative to control. We further observed jam of mitochondrial trafficking at sphingolipid accumulations within Fabry sensory neurites utilizing a click-chemistry approach together with mitochondrial dysmorphism compared to healthy control cells. We pioneer insights into the cellular mechanisms contributing to pain, thermal hyposensitivity, and denervation in Fabry small fibre neuropathy, and pave the way for further mechanisticin vitrostudies in Fabry disease and the development of novel treatment approaches.
Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy
Authors: Wang Lei , Xiao Yufeng , Luo Yuewan , Master Rohan P , Mo Jiao , Kim Myung-Chul , Liu Yi , Patel Urvi M , Li Xiangming , Shaffer Donald , Guertin Kevin R , Moser Emily , Smalley Keiran S. , Zhou Daohong , Zheng Guangrong , Zhang Weizhou 
Published: August 2023

AbstractAn effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple tumor-promoting cell types and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatmentin vitroand sustains for at least 4 daysin vivo, exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti- cancer immune responses and offers a new avenue for treating various types of cancer.
SCI-VCF: A cross-platform GUI solution to Summarise, Compare, Inspect, and Visualise the Variant Call Format
Authors: Kamaraj Venkatesh , Sinha Himanshu 
Published: August 2023

ABSTRACTAs genomics advances swiftly and its applications extend to diverse fields, bioinformatics tools must enable researchers and clinicians to work with genomic data irrespective of their programming expertise. We developed SCI-VCF, a Shiny-based comprehensive analysis utility to summarise, compare, inspect, analyse, and design interactive visualisations of the genetic variants from the variant call format. With an intuitive GUI, SCI-VCF aims to bridge the approachability gap in genomics that arises from the existing predominantly command-line utilities. SCI-VCF is written with R and is freely available athttps://github.com/HimanshuLab/SCI-VCF. For installation-free access, users can avail of an online version athttps://ibse.shinyapps.io/sci-vcf-online/.
Sustained Generation of Neurons Destined for Neocortex with Oxidative Metabolic Upregulation upon Filamin Abrogation
Authors: Kopsidas Caroline A. , Lowe Clara C. , McDaniel Dennis P. , Zhou Xiaoming , Feng Yuanyi 
Published: August 2023

SummaryNeurons in the neocortex are generated during embryonic development. While the adult ventricular-subventricular zone (V-SVZ) contains cells with neural stem/progenitors’ characteristics, it remains unclear whether it has the capacity of producing neocortical neurons. Here we show that the generation of neurons exhibiting transcriptomic resemblance to neurons of the upper cortical layers continues in the V-SVZ of mouse models of a human condition known as periventricular heterotopia by abrogating filamin. We found such surplus neurogenesis was associated with V-SVZ’s transcriptional upregulation of oxidative phosphorylation, mitochondrial biogenesis, and increased vascularization. Our spatial transcriptomics analysis also showed that the neurogenic activation of V-SVZ was coupled with enriched expression of genes in diverse pathways for energetics, signaling, neuronal activities, and metabolic turnovers of nucleic acids and proteins in upper cortical layers. These findings support the potential of generating neocortical neurons in adulthood through enhancing brain-wide vascular circulation, aerobic ATP synthesis, and neuronal vitality.