bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-wide identification of loss of heterozygosity generated by mitotic homologous recombination reveals its possible association with spatial positioning of chromosomes
Authors: Kim Hyeonjeong , Suyama Mikita 
Published: June 2022

AbstractLoss of heterozygosity (LOH) is a genetic alteration that results from the loss of one allele at a heterozygous locus. Some LOH events are generated by mitotic homologous recombination after monoallelic defection, then the novel homozygous locus has two copies of the normal counterpart allele. This phenomenon can serve as a source of genome diversity and is associated with various diseases. To clarify the nature of the LOH such as the frequency, genomic distribution, and inheritance pattern, we made use of whole-genome sequencing data of the three-generation CEPH/Utah family cohort, with the pedigree consisting of grandparents, parents, and offspring. We identified an average of 40.7 LOH events per individual taking advantage of 285 healthy individuals from 33 families in the cohort. On average 65% of them were classified as gonosomal-mosaicism-associated LOH, which exists in both germline and somatic cells. We also confirmed that the incidence of the LOH has little to do with the parents’ age and sex. Furthermore, through the analysis of the genomic region including the LOH, we found that the chance of the occurrence of the LOH tends to increase at the GC-rich locus and/or on the chromosome having a relatively close inter-homolog distance. We expect that these results provide significant insights into the association between genetic alteration and spatial position of chromosomes as well as the intrinsic genetic property of the LOH.Author SummaryLoss of heterozygosity (LOH) is a common genetic alteration that a heterozygous locus becomes a homozygous locus. In some cases, if a monoallelic defection accompanying homologous recombination between inter-homolog occurs, it results in copy-neutral LOH having two copies of the allele. Although the LOH is potentially important in understanding pathogenesis of various diseases, its fundamental features have received scant attention. To characterize the nature of the LOH, data from single individuals and their parents are required. This is because it would be difficult to discriminate between the LOH and a normal homozygous allelic state using genomic data obtained only from a single individual. Whole-genome sequencing data of 33 CEPH/Utah families, which comprise large three-generation family units, motivated us to perform a genome-wide identification of the LOH. Using this dataset, we successfully identified the LOH and analyzed its frequency, genomic distribution, and inheritance pattern. Moreover, we revealed that the occurrence of the LOH was affected by the inter-homolog distances, which reflect the chromosome territory. Our findings pertaining to the LOH provide insight into the association between genetic alteration and spatial positioning of chromosomes.
Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis
Authors: Maserumule Charlotte , Passemar Charlotte , Oh Olivia S H , Hegyi Kriztina , Brown Karen , Weimann Aaron , Dinan Adam , Davila Sonia , Klapholz Catherine , Bryant Josephine , Verma Deepshikha , Gadwa Jacob , Krishnananthasivam Shivankari , Vongtongsalee Kridakorn , Kendall Edward , Trelles Andres , Hibberd Martin L , Prados-Rosales Rafael , Andi Kaliappan , Kumar S Siva , Ordway Diane , MacAry Paul A , Floto R. Andres 
Published: June 2022

AbstractGenetic determinants of susceptibility to Mycobacterium tuberculosis (Mtb) are poorly understood but could provide insights into critical pathways involved in infection, informing host-directed therapies and enabling risk stratification at individual and population levels. Through a genome-wide forward genetic screen, we identify the Toll-like Receptor 8 (TLR8), as a key regulator of intracellular killing of Mtb. Pharmacological TLR8 activation enhances killing of phylogenetically diverse clinical isolates of drug-susceptible and multidrug-resistant Mtb by macrophages and during in vivo infection in mice. TLR8 is activated by phagosomal mycobacterial RNA released by extracellular membrane vesicles, and enhances xenophagy-dependent Mtb killing. We find that the TLR8 variant, M1V, common in far eastern populations, enhances intracellular killing of Mtb through preferential signal-dependent trafficking to phagosomes. TLR8 signalling may therefore both regulate susceptibility to tuberculosis and provide novel drug targets.Single sentence summaryRNA released from Mycobacterium tuberculosis in the macrophage phagosome is sensed by the pattern recognition receptor TLR8 controlling host susceptibility to tuberculosis and revealing a druggable pathway for host-directed therapy.
Temporally and regionally distinct morphogenetic processes govern zebrafish tail fin blood vessel network expansion
Authors: Leonard Elvin V. , Hasan Sana Safatul , Siekmann Arndt F. 
Published: June 2022

AbstractBlood vessels form elaborate networks depending on tissue-specific signalling pathways and anatomical structures to guide their growth. However, it is not clear which morphogenetic principles organize the stepwise assembly of the vasculature. We thus performed a longitudinal analysis of zebrafish tail fin vascular assembly, revealing the existence of temporally and spatially distinct morphogenetic processes. Initially, vein-derived endothelial cells (ECs) generated arteries in a reiterative process requiring Vascular Endothelial Growth Factor (VEGF), Notch and cxcr4a signalling. Subsequently, veins produced veins in more proximal fin regions, transforming pre-existing artery-vein loops into a three-vessel pattern consisting of an artery and two veins. A distinct set of vascular plexuses formed at the base of the fin. They differed by virtue of diameter, flow magnitude and marker gene expression. At later stages, intussusceptive angiogenesis occurred from veins in distal fin regions. In proximal fin regions, we observed new vein sprouts crossing the inter-ray tissue through sprouting angiogenesis. Together, our results reveal a surprising diversity among the mechanisms generating the mature fin vasculature and suggest that these might be driven by separate local cues.
Therapeutic activation of endothelial sphingosine 1-phosphate receptor-1 by chaperone-bound S1P suppresses proliferative retinal vasculopathy
Authors: Niaudet Colin , Jung Bongnam , Kuo Andrew , Swendeman Steven , Bull Edward , Seno Takahiro , Crocker Reed , Fu Zhongjie , Smith Lois E. H. , Hla Timothy 
Published: June 2022

AbstractSphingosine-1-phosphate (S1P), a bioactive lipid mediator that signals via G protein-coupled S1P receptors (S1PR), is required for normal vascular development. The role of this signaling axis in vascular retinopathies is largely unexplored. Here we show in a mouse model of oxygen-induced retinopathy (OIR) that endothelial overexpression of S1pr1 suppresses while endothelial knockout (KO) of S1pr1 worsens neovascular tuft formation. Furthermore, neovascular tufts are increased in Apom KO mice which lack HDL-bound S1P while they are suppressed in Apom TG mice which has more circulating HDL-S1P. These results suggest that circulating HDL-S1P activation of endothelial S1PR1 specifically suppresses proliferative retinal vasculopathy. Moreover, systemic administration of ApoM-Fc-bound S1P or a small molecule Gi-biased S1PR1 agonist suppressed neovascular tuft formation. Circulating HDL-S1P activation of endothelial S1PR1 may be a key protective mechanism to guard against neovascular retinopathies that occur not only in premature infants but also in diabetes and aging.
Automatic Sleep Stage Classification with Optimized Selection of EEG Channels
Authors: Stenwig Håkon , Soler Andres , Furuki Junya , Suzuki Yoko , Abe Takashi , Molinas Marta 
Published: June 2022

AbstractVisual inspection of Polysomnography (PSG) recordings by sleep experts based on established guidelines has been the gold standard in sleep stage classification. This approach is expensive, time consuming and mostly limited to experimental research and clinical cases of major sleep disorders. Various automatic approaches to sleep scoring have been emerging in the past years and are opening the way to a quick computational assessment of sleep architecture that may find its way to the clinics. With the hope to make sleep scoring a fully automated process in the clinics, we report here an ensemble algorithm that aims at not only predicting sleep stages but of doing so with an optimized minimal number of EEG channels. For that, we combine a genetic algorithm based optimization with a classification framework that minimizes the number of channels used by the machine learning algorithm to quantify sleep stages. This resulted in a scoring with an F1 score of 0.793 for the fully automatic model and 0.806 for the model trained on 10 percent of the unseen subject, both with only 3 EEG channels. The ensemble algorithm is based on a combination of extremely randomized trees and MiniRocket classifiers. The algorithm was trained, validated and tested on night sleep PSG data collected from 7 subjects. The novelty of our approach lies on the use of the minimum information needed for automated sleep scoring, based on a systematic search that concurrently selects the optimal-minimum number of EEG channels and the best performing features for the machine learning classifier. The optimization framework presented in this work may enable new designs for sleep scoring devices suited to studies in the comfort of the homes, easily and inexpensively and in this way facilitate experimental and clinical studies in large populations.
Sparse Dimensionality Reduction Approaches in Mendelian Randomization with highly correlated exposures
Authors: Karageorgiou Vasilios , Gill Dipender , Bowden Jack , Zuber Verena 
Published: June 2022

ABSTRACTMultivariable Mendelian randomization (MVMR) is an instrumental variable technique that generalizes the MR framework for multiple exposures. Framed as a linear regression problem, it is subject to the pitfall of multi-collinearity. The bias and efficiency of MVMR estimates thus depends on the correlation of exposures. Dimensionality reduction techniques such as principal component analysis (PCA) provide transformations of all the included variables that are effectively uncorrelated. We propose the use of sparse PCA (sPCA) algorithms that create principal components of subsets of the exposures and may provide more interpretable and reliable MR estimates. The approach consists of three steps. We first apply a sparse dimension reduction method and transform the variant-exposure summary statistics to principal components. We then choose a subset of the principal components based on data-driven cutoffs, and estimate their strength as instruments with an adjusted F-statistic. Finally, we perform MR with these transformed exposures. This pipeline is demonstrated in a simulation study of highly correlated exposures and an applied example using summary data from a genome-wide association study of 118 highly correlated lipid metabolites. As a positive control, we tested the causal associations of the transformed exposures on CHD. Compared to the conventional inverse-variance weighted MVMR method and a weak-instrument robust MVMR method (MR GRAPPLE), sparse component analysis achieved a superior balance of sparsity and biologically insightful grouping of the lipid traits.Key MessagesIn multivariable MR, investigation of multiple highly correlated exposures can hinder the efficiency of the estimators and mask true associations.Dimensionality reduction approaches such as principal component analysis (PCA) appear to be effective in summarising the variant-exposure summary statistics data in an example of correlated metabolite data.Sparse PCA approaches have the additional benefit of providing interpretable PCs as only a few exposures contribute to each. This benefit is shown in simulation studies where there is a gain in accuracy over PCA.In a positive control analysis, the sparse PCs were representing biologically meaningful groups of metabolites (VLDL, LDL, HDL) and in general were associated with coronary heart disease in an anticipated mannert.
Important Role of Hematopoietic Proteoglycan Serglycin in Liver Hepatocellular Carcinoma Associated with Tumor Microenvironment
Authors: Zou Zengcheng , Xie Heping , Guo Wenhai , Li Yue , Zhang Jiongshan , Li Yongwei 
Published: June 2022

AbstractBackgroundSerglycin (SRGN) is a prominent hematopoietic proteoglycan that regulates tumorigenesis; however, its role in tumor immunity is unclear.Materials and methodsWe investigated the expression and prognostic potential of SRGN in liver hepatocellular cancer (LIHC) in the context of pan-cancer (for showing the similarity and heterogeneity) using the PrognoScan, GEPIA, Kaplan–Meier Plotter, and TIMER bioinformatics databases. HepG2 cells were transfected with an SRGN over-expression vector, and their proliferation, invasion, sorafenib resistance, and vasculature were examinedin vitro. A subcutaneous xenograft tumor model was created in nude mice.ResultsSRGN expression was prominent in M2 macrophages in LIHC. The Kaplan–Meier Plotter indicated that SRGN RNA was a favorable prognostic factor after correcting for clinical factors. TIMER 2.0 showed that the immune infiltrates of CD8+ T cells, M1 and M2 macrophages, and endothelial cells were strongly correlated with SRGN RNA expression (r=0.552, P=5.79e-29; r=0.517, P=5.84e-25; r=0.696, P=3.26e51; and r=0.522, P=1.67e-25, respectively), and had prognostic potential in LIHC in patients with low or high levels of SRGN, in addition to resting memory CD4+ T cells, hematopoietic stem cells (HSCs), and myeloid-derived suppressor cells (MDSCs). SRGN promoted the proliferation of HepG2 cellsin vitroandin vivo, and was associated with weak sorafenib resistance, invasion, and vasculature. CD206 and CD80 were up-regulated and down-regulated, respectively, in subcutaneous tumor tissues.ConclusionsThe results comprehensively revealed relationships between SRGN and tumor microenvironment(TME)-infiltrating cells, especially monocyte/macrophage subsets. These may constitute an important TME because the pro-tumorigenicity of SRGN in liver cancer.
Comparison between an exact and a heuristic neural mass model with second order synapses
Authors: Clusella Pau , Köksal-Ersöz Elif , Garcia-Ojalvo Jordi , Ruffini Giulio 
Published: June 2022

AbstractNeural mass models (NMMs) are designed to reproduce the collective dynamics of neuronal populations. A common framework for NMMs assumes heuristically that the output firing rate of a neural population can be described by a static nonlinear transfer function (NMM1). However, a recent exact mean-field theory for quadratic integrate-and-fire (QIF) neurons challenges this view by showing that the mean firing rate is not a static function of the neuronal state but follows two coupled non-linear differential equations (NMM2). Here we analyze and compare these two descriptions in the presence of second-order synaptic dynamics. First, we derive the mathematical equivalence between the two models in the infinitely slow synapse limit, i.e., we show that NMM1 is an approximation of NMM2 in this regime. Next, we evaluate the applicability of this limit in the context of realistic physiological parameter values by analyzing the dynamics of models with inhibitory or excitatory synapses. We show that NMM1 fails to reproduce important dynamical features of the exact model, such as the self-sustained oscillations of an inhibitory interneuron QIF network. Furthermore, in the exact model but not in the limit one, stimulation of a pyramidal cell population induces resonant oscillatory activity whose peak frequency and amplitude increase with the self-coupling gain and the external excitatory input. This may play a role in the enhanced response of densely connected networks to weak uniform inputs, such as the electric fields produced by non-invasive brain stimulation.
Valproic Acid Affects Neuronal Specification and Differentiation During Early Optic Tectum Development of Zebrafish
Authors: Dixon Sierra C. , Calder Bailey J. , Lilya Shane M. , Davies Brandon M. , Martin Annalie , Peterson Maggie , Hansen Jason M. , Suli Arminda 
Published: June 2022

ABSTRACTThe mammalian superior colliculus and its non-mammalian homolog, the optic tectum (OT), are midbrain structures that integrate multimodal sensory inputs and guide non-voluntary movements in response to prevalent stimuli. Recent studies have implicated this structure as a possible site affected in Autism Spectrum Disorder (ASD). Interestingly, fetal exposure to valproic acid (VPA) has also been associated with an increased risk of ASD in humans and animal models. Therefore, we took the approach of determining the effects of VPA treatment on zebrafish OT development as a first step in identifying the mechanisms that allow its formation. We describe the normal OT development during the first 5 days of development and show that in VPA treated embryos, while proliferation of the OT neuroepithelium continued, neuronal specification stalled. This was followed by impairment of neurite extension and complexity, suggesting that in addition to neurogenesis, VPA treatment affects axonogenesis and dendritogenesis. VPA treatment was most detrimental during the first three days of development and did not appear to be linked to oxidative stress. In conclusion, our work provides a foundation for research into mechanisms driving OT development, as well as the relationship between the OT, VPA, and ASD.
Relating pupil diameter and blinking to cortical activity and hemodynamics across arousal states
Authors: Turner Kevin L. , Gheres Kyle W. , Drew Patrick J. 
Published: June 2022

AbstractArousal state affects neural activity and vascular dynamics in the cortex, with sleep associated with large changes in the local field potential (LFP) and increases in cortical blood flow. We investigated the relationship between pupil diameter and blink rate with neural activity and blood volume in the somatosensory cortex in male and female unanesthetized, head-fixed mice. We monitored these variables while the mice were awake, during periods of rapid eye movement (REM), and non-rapid eye movement (NREM) sleep. Pupil diameter was smaller during sleep than in the awake state. Changes in pupil diameter were coherent with both gamma-band power and blood volume in the somatosensory cortex, but the strength and sign of this relationship varied with arousal state. We observed a strong negative correlation between pupil diameter and both gamma-band power and blood volume during periods of awake rest and NREM sleep, though the correlations between pupil diameter and these signals became positive during periods of alertness, active whisking, and REM. Blinking was associated with increases in arousal and decreases in blood volume when the mouse was asleep. Bilateral coherence in gamma-band power and in blood volume dropped following awake blinking, indicating a ‘reset’ of neural and vascular activity. Using only eye metrics (pupil diameter and eye motion), we could determine the mouse’s arousal state (‘Awake’, ‘NREM’, ‘REM’) with greater than 90% accuracy with a 5 second resolution. There is a strong relationship between pupil diameter and hemodynamics signals in mice, reflecting the pronounced effects of arousal on cerebrovascular dynamics.Significance StatementDetermining arousal state is a critical component of any neuroscience experiment. Pupil diameter and blinking are influenced by arousal state, as are hemodynamics signals in the cortex. We investigated the relationship between cortical hemodynamics and pupil diameter and found that pupil diameter was strongly related to the blood volume in the cortex. Mice were more likely to be awake after blinking than before, and blinking ‘resets’ neural activity. Pupil diameter and eye motion can be used as a reliable, non-invasive indicator of arousal state. As mice transition from wake to sleep and back again over a timescale of seconds, monitoring pupil diameter and eye motion permits the non-invasive detection of sleep events during behavioral or resting-state experiments.
Relationship between national changes in mobility due to non-pharmaceutical interventions and emergency department visits due to pediatric acute respiratory infections during the COVID-19 pandemic
Authors: Díaz Franco , Carvajal Cristóbal , Gatica Sebastian , Vásquez-Hoyos Pablo , Jabornisky Roberto , Moltke Richard Von , Jaramillo-Bustamante Juan Camilo , Pizarro Federico , Cruces Pablo 
Published: June 2022

AbstractBackgroundStrong social distancing measures were quickly implemented in Chile during the SARS-CoV-2 outbreak. One of the aims of non-pharmaceutical interventions (NPI) mandates was to decrease overcrowding, thus is usually measured as mobility changes.Methodswe gather data from national health statistics for pediatric emergency (PED) visits for acute respiratory infection (ARI) in children younger than 15. We defined a historical cohort, including data from 2016 to 2019, and compared them with 2020 and 2021 pandemic years. Also, Chile’s national mobility reports from the online google database were downloaded. We tested the correlation between changes in mobility and relative reduction in PED-ARI by Spearman’s Rank Test.ResultsHistorical data showed a mean of 46863 ± 3071 PED-ARI weekly visits with a high seasonal variation, with two peaks in weeks 20 and 28 and weeks 32 to 36. This transient drop was temporally associated with the mid-winter 2-week holiday of schools. The usual PED visits peaks did not occur in 2020 and 2021. Mobility declined from week 9, reaching lower than historical data from week 12 and a minimum of 43% in week 15 of 2020 (Figure 1).The correlation between mobility and PED-ARI visits showed a strong monotonic relationship (quadratic) with a Spearman’s rho of 0.80 (95% CI 0.75 to 0.86) (Figure 2).ConclusionNPI resulting in a decrease in mobility should be considered a robust public health measure to relieve the winter’s collapse of the national health system, decreasing morbimortality in children due to PED-ARI.WHAT’S KNOWN ON THIS SUBJECTA remarkable decrease in pediatric respiratory infections has been described during the pandemic, although the causes are still poorly understood.WHAT THIS STUDY ADDSIn a historical cohort before the pandemic, we observed a temporal association between mid-winter holidays and the gap between the two peaks of acute pediatric respiratory infections. We found a strong correlation between national mobility changes due to non-pharmaceutical interventions and acute pediatric respiratory infections during the pandemic. Therefore, timely implementation of non-pharmaceutical interventions might be considered as a robust public health measure to attenuate the seasonal epidemic of non-COVID viral acute respiratory infections. With these data, we wonder if the time has come to implement non-pharmaceutical interventions to mitigate the stress, and frequently collapse, of national health systems due to the increase in pediatric acute respiratory infection, placing children as a priority, and provide the best care to this vulnerable population.