bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visual Evoked Potentials in Patients With Vitamin B12 Deficiency
Authors: Yıldız Onur , Erdem Tilki Hacer 
Published: March 2022

Purpose:
The aim of this study was to investigate the subclinical involvement of the optic nerve in asymptomatic patients with vitamin B12 deficiency using visual evoked potentials.

Methods:
This study included 40 asymptomatic patients diagnosed with vitamin B12 deficiency (considered as serum levels below 150 pg/mL) and a control group of 40 healthy individuals. All participants underwent a visual evoked potential examination. Routine screening for homocysteine was performed for patients with vitamin B12 deficiency. The levels of vitamin B12 and homocysteine and the presence of megaloblastic anemia were analyzed statistically compared with P100, N75, and N135 latencies and amplitudes.

Results:
The mean vitamin B12 level was 96 pg/mL in the patient group and 374 pg/mL in the control group. In the patient group, 24 (60%) patients had hyperhomocysteinemia and 8 (20%) patients had megaloblastic anemia. The P100 wave latency of patients with vitamin B12 deficiency was significantly prolonged compared with the control group (P < 0.01). There was no significant difference in the P100 amplitude between the patient group and the control group. P100 latencies were significantly longer in patients with hyperhomocysteinemia (P = 0.002).

Conclusions:
Our study showed that patients with vitamin B12 deficiency may have visual evoked potential abnormalities without visual symptoms or examination findings. In addition, high homocysteine levels led to a prolonged P100 latency in the patient group independent of vitamin B12 levels.
Transfer learning of an in vivo-derived senescence signature identifies conserved and tissue-specific senescence across species and diverse pathologies
Authors: Cherry Christopher , Andorko James I , Krishnan Kavita , Mejias Joscelyn C , Nguyen Helen Hieu , Stivers Katlin B , Gray-Gaillard Elise F , Ruta Anna , Hamada Naomi , Hamada Masakazu , Sturmlechner Ines , Trewartha Shawn , Michel John H , Huyer Locke Davenport , Wolf Matthew T , Tam Ada , Peña Alexis N , Le Saux Claude Jordan , Fertig Elana J , Baker Darren J , Housseau Franck , van Deursen Jan M , Pardoll Drew M , Elisseeff Jennifer H 
Published: March 2022

AbstractSenescent cells (SnCs) contribute to normal tissue development and repair but accumulate with aging where they are implicated in a number of pathologies and diseases. Despite their pathological role and therapeutic interest, SnC phenotype and function in vivo remains unclear due to the challenges in identifying and isolating these rare cells. Here, we developed an in vivo-derived senescence gene expression signature using a model of the foreign body response (FBR) fibrosis in a p16Ink4a-reporter mouse, a cell cycle inhibitor commonly used to identify SnCs. We identified stromal cells (CD45-CD31- CD29+) as the primary p16Ink4a expressing cell type in the FBR and collected the cells to produce a SnC transcriptomic signature with bulk RNA sequencing. To computationally identify SnCs in bulk and single-cell data sets across species and tissues, we used this signature with transfer learning to generate a SnC signature score (SenSig). We found senescent pericyte and cartilage-like fibroblasts in newly collected single cell RNAseq (scRNASeq) data sets of murine and human FBR suggesting populations associated with angiogenesis and secretion of fibrotic extracellular matrix, respectively. Application of the senescence signature to human scRNAseq data sets from idiopathic pulmonary fibrosis (IPF) and the basal cell carcinoma microenvironment identified both conserved and tissue-specific SnC phenotypes, including epithelial-derived basaloid and endothelial cells. In a wound healing model, ligand-receptor signaling prediction identified putative interactions between SnC SASP and myeloid cells that were validated by immunofluorescent staining and in vitro coculture of SnCs and macrophages. Collectively, we have found that our SenSig transfer learning strategy from an in vivo signature outperforms in vitro-derived signatures and identifies conserved and tissue-specific SnCs and their SASP, independent of p16Ink4a expression, and may be broadly applied to elucidate SnC identity and function in vivo.
Structure-based Evolution of G protein-biased μ-opioid Receptor Agonists
Authors: Wang Haoqing , Hetzer Florian , Huang Weijiao , Qu Qianhui , Meyerowitz Justin , Kaindl Jonas , Hübner Harald , Skiniotis Georgios , Kobilka Brian K. , Gmeiner Peter 
Published: March 2022

AbstractThe μ-opioid receptor (μOR) is the major target for opioid analgesics. Activation of μOR initiates signaling through G protein pathways as well as through β-arrestin recruitment. μOR agonists that are biased towards G protein signaling pathways demonstrate diminished side effects. PZM21, discovered by computational docking, is a G protein biased μOR agonist. Here we report the cryoEM structure of PZM21 bound μOR in complex with Gi protein. Structure-based evolution led to multiple PZM21 analogs with more pronounced Gi protein bias and increased lipophilicity to improve CNS penetration. Among them, FH210 shows extremely low potency and efficacy for arrestin recruitment. We further determined the cryoEM structure of FH210 bound to μOR in complex with Gi protein and confirmed its expected binding pose. The structural and pharmacological studies reveal a potential mechanism to reduce β-arrestin recruitment by the μOR, and hold promise for developing next-generation analgesics with fewer adverse effects.Table of Contents Graphical AbstractWe obtained cryoEM structures of the μ-opioid receptor (μOR) bound to the lead compound PZM21 and the newly developed agonist FH210 to understand the mechanism of their biased signaling and to guide the evolution of next-generation analgesics with fewer adverse effects.
Two mosquito odorant receptors with reciprocal specificity mediated by a single amino acid residue
Authors: Franco Flávia P. , Xu Pingxi , Harris Brandon J. , Yarov-Yarovoy Vladimir , Leal Walter S. 
Published: March 2022

ABSTRACTThe southern house mosquito,Culex quinquefasciatus, utilizes two odorant receptors, CquiOR10 and CquiOR2, narrowly tuned to oviposition attractants and well conserved among mosquito species. They detect skatole and indole, respectively, with reciprocal specificity. We swapped the seven transmembrane (TM) domains of CquiOR10 and CquiOR2 and identified TM2 as a specificity determinant. With additional mutations, we showed that CquiOR10A73L behaved like CquiOR2. Conversely, CquiOR2L74A recapitulated CquiOR10 specificity. Next, we generated structural models of CquiOR10 and CquiOR10A73L using RoseTTAFold and AlphaFold and docked skatole and indole using RosettaLigand. These modeling studies suggested space-filling constraints around A73. Consistent with this hypothesis, CquiOR10 mutants with a bulkier residue (Ile, Val) were insensitive to skatole and indole, whereas CquiOR10A73G retained the specificity to skatole and showed a more robust response than the wildtype receptor CquiOR10. On the other hand, Leu to Gly mutation of the indole receptor CquiOR2 reverted the specificity to skatole. Lastly, CquiOR10A73L, CquiOR2, and CquiOR2L74I were insensitive to 3-ethylindole, whereas CquiOR2L74A and CquiOR2L74G gained activity. Additionally, CquiOR10A73G gave more robust responses to 3-ethylindole than CquiOR10. Thus, we suggest the specificity of these receptors is mediated by a single amino acid substitution, leading to finely tuned volumetric space to accommodate specific oviposition attractants.
Genetic background and mistranslation frequency determine the impact of mistranslating tRNASerUGG
Authors: Berg Matthew D. , Zhu Yanrui , Loll-Krippleber Raphaël , San Luis Bryan-Joseph , Genereaux Julie , Boone Charles , Villen Judit , Brown Grant W. , Brandl Christopher J. 
Published: March 2022

ABSTRACTTransfer RNA variants increase the frequency of mistranslation, the mis-incorporation of an amino acid not specified by the “standard” genetic code, to frequencies approaching 10% in yeast and bacteria. Cells cope with these variants by having multiple copies of each tRNA isodecoder and through pathways that deal with proteotoxic stress. In this study, we define the genetic interactions of the gene encoding tRNASerUGG,G26A, which mistranslates serine at proline codons. Using a collection of yeast temperature sensitive alleles, we identify negative synthetic genetic interactions between the mistranslating tRNA and 109 alleles representing 91 genes, with nearly half of the genes having roles in RNA processing or protein folding and turnover. By regulating tRNA expression, we then compare the strength of the negative genetic interaction for a subset of identified alleles under differing amounts of mistranslation. The frequency of mistranslation correlated with impact on cell growth for all strains analyzed; however, there were notable differences in the extent of the synthetic interaction at different frequencies of mistranslation depending on the genetic background. For many of the strains the extent of the negative interaction with tRNASerUGG,G26Awas proportional to the frequency of mistranslation or only observed at intermediate or high frequencies. For others the synthetic interaction was approximately equivalent at all frequencies of mistranslation. As humans contain similar mistranslating tRNAs these results are important when analyzing the impact of tRNA variants on disease, where both the individual’s genetic background and the expression of the mistranslating tRNA variant need to be considered.
Prenatal methadone exposure leads to long-term memory impairments and disruptions of dentate granule cell function in a sex-dependent manner
Authors: Gamble Meredith E. , Marfatia Rhea , Diaz Marvin R. 
Published: March 2022

AbstractPrenatal opioid exposures lead to extensive cognitive and emotion-regulation problems in children, persisting at least through school-age. Methadone, an opioid typically used for the treatment of opioid use disorder, has been approved for use in pregnant women for several decades. Importantly, however, the impacts of prenatal methadone exposure (PME), particularly on offspring as they progress into adulthood, has not been extensively examined. In recent years, children and young animal models have shown cognitive deficits related to PME, including evidence of hippocampal dysfunction. The present work aims to examine the persistent nature of these deficits, as well as determine how they may differ by sex. Pregnant Sprague Dawley rats either received subcutaneous methadone or water injections twice daily from gestational days 3-20 or were left undisturbed. Following postnatal day 70, male and female offspring were behaviorally tested for impairments in recognition memory using the Novel Object Recognition task and working spatial memory through Spontaneous Alternation. Additionally, using whole-cell patch-clamp electrophysiology, hippocampal dentate granule cell function was examined in adult offspring. Results indicate that methadone-exposed females showed decreased excitability and increased inhibition of these dentate granule cells, while males did not. These findings were accompanied by impairments in female working spatial memory and impaired recognition memory of both sexes. Overall, this work supports the continued investigation of the long-term effects of PME on adult male and female learning and memory, as well as promotes further exploration of adult hippocampal function as a neural mechanism impacted by this exposure.
The GR2D2 Estimator for the Precision Matrices
Authors: Gan Dailin , Yin Guosheng , Zhang Yan Dora 
Published: March 2022

AbstractBiological networks are important for the analysis of human diseases, which summarize the regulatory interactions and other relationships between different molecules. Understanding and constructing networks for molecules, such as DNA, RNA and proteins, can help elucidate the mechanisms of complex biological systems. The Gaussian Graphical Models (GGMs) are popular tools for the estimation of biological networks. Nonetheless, reconstructing GGMs from high-dimensional datasets is still challenging. Current methods cannot handle the sparsity and high-dimensionality issues arising from datasets very well. Here we developed a new GGM, called the GR2D2 (Graphical R2-induced Dirichlet Decomposition) model, based on the R2D2 priors for linear models. Besides, we provided a data-augmented block Gibbs sampler algorithm. The R code is available at https://github.com/RavenGan/GR2D2. The GR2D2 estimator shows superior performance in estimating the precision matrices compared to existing techniques in various simulation settings. When the true precision matrix is sparse and of high dimension, the GR2D2 provides the estimates with smallest information divergence from the underlying truth. We also compare the GR2D2 estimator to the graphical horseshoe estimator in five cancer RNA-seq gene expression datasets grouped by three cancer types. Our results show that GR2D2 successfully identifies common cancer pathways and cancer-specific pathways for each dataset.
Multiple-timescale dynamics, mixed mode oscillations and mixed affective states in a model of Bipolar Disorder
Authors: Pavlidis Efstathios , Campillo Fabien , Goldbeter Albert , Desroches Mathieu 
Published: March 2022

AbstractMixed affective states in bipolar disorder (BD) is a common psychiatric condition that occurs when symptoms of the two opposite poles coexist during an episode of mania or depression. A four-dimensional model by A. Goldbeter [27, 28] rests upon the notion that manic and depressive symptoms are produced by two competing and auto-inhibited neural networks. Some of the rich dynamics that this model can produce, include complex rhythms formed by both small-amplitude (subthreshold) and large-amplitude (suprathreshold) oscillations and could correspond to mixed bipolar states. These rhythms are commonly referred to asmixed mode oscillations (MMOs)and they have already been studied in many different contexts [7, 50]. In order to accurately explain these dynamics one has to apply a mathematical apparatus that makes full use of the timescale separation between variables. Here we apply the framework of multiple-timescale dynamics to the model of BD in order to understand the mathematical mechanisms underpinning the observed dynamics of changing mood. We show that the observed complex oscillations can be understood as MMOs due to a so-calledfolded-node singularity. Moreover, we explore the bifurcation structure of the system and we provide possible biological interpretations of our findings. Finally, we show the robustness of the MMOs regime to stochastic noise and we propose a minimal three-dimensional model which, with the addition of noise, exhibits similar yet purely noise-driven dynamics. The broader significance of this work is to introduce mathematical tools that could be used to analyse and potentially control future, more biologically grounded models of BD.
Association of genetically-predicted lipid traits and lipid-modifying targets with the risk of heart failure
Authors: Xiao Jun , Ji Jianguang , Yang Xi , Chen Keyuan , Chen Liangwan , Huang Wuqing 
Published: March 2022

AbstractAimsTo assess the association of lipid traits and lipid-modification via licensed or investigational targets with heart failure (HF) risk using 2-sample Mendelian randomization (MR) study.Methods and resultsGenetic variants obtained from genome-wide association studies (GWASs) in UK Biobank as instrumental variables to investigate the association of lipid traits (low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), apolipoprotein B (ApoB) and apolipoprotein AI (ApoAI)) and lipid-modifying effect of eight licensed or investigational drug targets with HF risk by using the inverse-variance weighted method. In this study, we observed that genetically-predicted levels of LDL-C, TG, LDL-C and ApoB were significantly related to HF risk, which were mainly mediated by CHD. Further MR analyses identified PCSK9, CETP and LPL, but not HMGCR, as potential targets to prevent HF. The genetic proxy of LDL-C and ApoB increase modified by PCSK9 showed similar evidence in increasing risk of HF (PLDL-C=1.27*10−4; PApoB=1.94*10−4); CETP played a role in HF risk via modifying all investigational lipid traits with the strongest evidence though ApoB (P=5.87*10−6); LPL exerted effects on HF via modifying most lipid traits with the strongest evidence observed via modifying TG (P=3.73*10−12).ConclusionsThis 2-sample MR study provided genetic evidence of the associations between lipid traits and HF risk, which were mostly mediated by CHD. Besides, drug target MR studies indicated that PCSK9 inhibition, CETP inhibition and LPL activation, but not statins, were effective in reducing HF risk.
Intubation and Inhospital mortality in trauma patients with Glasgow Coma Scale Score eight or less. A multicenter cohort study
Authors: Soni Kapil Dev , Bansal Varun , Khajanchi Monty , Veetil Deepa Kizhakke , Geoffrey Anderson , Rayker Nakul , Sarang Bhakti , David Siddharth , Wärnberg Martin Gerdin , Roy Nobhojit 
Published: March 2022

AbstractBackgroundMost trauma societies recommend intubation of trauma patients with Glasgow coma scale (GCS) ≤ 8, without robust evidence supporting it.MethodsWe examined the association between intubation and inhopital 30 day mortality in trauma patients arriving with GCS ≤ 8. The data were obtained using the Towards Improved Trauma Care Outcomes (TITCO) registry in India cohort. We compared the outcomes of patients with GCS ≤ 8 who were intubated within one hour after arrival with those who were intubated later or not at all, using multiple analytical approaches to evaluate the consistency of the findings. We also examined the association in multiple subgroups to identify any variability of the effect.ResultsOf 3476 patients who arrived with a GCS ≤ 8, 1671 (48.1%) were intubated within an hour and 1805 (51.9%) were intubated later or not intubated at all. Overall, 1957 (56.3%) patients died in whole cohort. A total of 947 (56.7%) patients died in intubation group and 1010 (56%) died in non intubation group. In the main analysis, there was no significant association between intubation within an hour and mortality(OR=1.18,[CI,0.76-1.84], p value = 0.467). This result was consistent across multiple sensitivity analysis.ConclusionIn this observational study of trauma patients with GCS ≤ 8, who present to tertiary care hospitals, intubation within one hour after arrival was not associated with increased or decreased risk of inhospital mortality compared to intubation after one hour or no intubation. Further studies are needed to precisely evaluate the benefit of intubation and thus supporting the recommendations.
Effects of genetic liability to Alzheimer’s disease on circulating metabolites across the life course
Authors: Compton Hannah , Smith Madeleine L , Bull Caroline , Korologou-Linden Roxanna , Ben-Shlomo Yoav , Bell Joshua A. , Anderson Emma L 
Published: March 2022

ABSTRACTObjectiveAlzheimer’s disease (AD) has several known genetic determinants, yet the mechanisms through which they lead to disease onset remain poorly understood. This study aims to estimate the effects of genetic liability to AD on plasma metabolites measured at seven different stages across the life course.MethodsGenetic and metabolomic data from 5,648 offspring from the Avon Longitudinal Study of Parents and Children birth cohort were used. Linear regression models examined the association between higher AD liability, as measured by a genetic risk score (GRS), and plasma metabolites measured at 8, 16, 18 and 25 years of age. Two hundred twenty-nine metabolites were studied, most relating to lipid/lipoprotein traits. Two-sample Mendelian randomization was performed using summary statistics from age-stratified genome-wide association studies (GWAS) of the same metabolites for 118,466 participants from the UK Biobank, to examine the persistence of any AD liability effects into late adulthood.ResultsThe GRS including theAPOE4isoform demonstrated the strongest positive associations for cholesterol-related traits per doubling of genetic liability to AD, e.g., for low-density lipoprotein cholesterol (LDL-C) at age 25yrs (0.12 SD; 95% CI 0.09, 0.14), with similar magnitudes of association across age groups in ALSPAC. In the UK Biobank, the effect of AD liability decreased with age tertile for several lipid traits (e.g., LDL-C, youngest: 0.15 SD; 95% CI 0.07, 0.23, intermediate: 0.13 SD; 95% CI 0.07, 0.20, oldest: 0.10 SD; 95% CI 0.05, 0.16). Across both cohorts, the effect of AD liability on high-density lipoprotein cholesterol (HDL-C) attenuated as age increased. Fatty acid metabolites also demonstrated positive associations in both cohorts, though smaller in magnitude compared with lipid traits. Sensitivity analyses indicated that these effects were driven by theAPOE4isoform.ConclusionsThese results support a profound influence of theAPOE4isoform on circulating lipids and fatty acids from early life to later adulthood. Such lipid and fatty acid traits may be implicated in early AD pathogenesis and warrant further investigation as potential targets for preventing the onset of AD.
Informal Sector Employment and the Health Outcomes of Older Workers in India
Authors: Chowdhury Poulomi , Mohanty Itismita , Singh Akansha , Niyonsenga Theo 
Published: March 2022

AbstractA large proportion of the older population in India constitutes an undeniable share of workforce after the retirement age. This stresses the need to understand the implications of working at older ages on health outcomes. The main objective of this study is to examine the variations in health outcomes by formal/informal sector of employment of older workers using the Longitudinal Ageing Study in India. Using binary logistic regression models with interaction terms, the results of this study affirm that type of work does play a significant role in determining health outcomes even after controlling socio-economic, demographic, life-style behaviour, and work characteristics. The risk of Poor Cognitive Functioning (PCF) is high among informal workers, while formal workers suffer greatly from Chronic Health Conditions (CHC) and Functional Limitations (FL). The presence of CHC among informal workers is more damaging because it elevates their FL, whereas for formal workers presence of FL is unfavourable because it deteriorates their cognitive functioning. Therefore, present study underscores the relevance of policies focusing on providing health and healthcare benefits by respective economic activity and socio-economic position of older workers.