bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oncogenic mutations of PIK3CA lead to increased membrane recruitment driven by reorientation of the ABD, p85 and C-terminus
Authors: Jenkins Meredith L. , Ranga-Prasad Harish , Parson Matthew A. H. , Harris Noah J. , Rathinaswamy Manoj K. , Burke John E. 
Published: January 2023

AbstractPIK3CA encoding the phosphoinositide 3-kinase (PI3K) p110α catalytic subunit is frequently mutated in cancer, with mutations occurring widely throughout the primary sequence. The full set of mechanisms underlying how PI3Ks are activated by all oncogenic mutations on membranes are unclear. Using a synergy of biochemical assays and hydrogen deuterium exchange mass spectrometry (HDX-MS), we reveal unique regulatory mechanisms underlying PI3K activation. Engagement of p110α on membranes leads to disengagement of the ABD of p110α from the catalytic core, and the C2 domain from the iSH2 domain of the p85 regulatory subunit. PI3K activation also requires reorientation of the p110α C-terminus, with mutations that alter the inhibited conformation of the C-terminus increasing membrane binding. Mutations at the C-terminus (M1043I/L, H1047R, G1049R, and N1068KLKR) activate p110α through distinct mechanisms, with this having important implications for mutant selective inhibitor development. This work reveals unique mechanisms underlying how PI3K is activated by oncogenic mutations, and explains how double mutants can synergistically increase PI3K activity.
Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes
Authors: Huang Yingbo , Shan Yuting , Zhang Weijie , Lee Adam M. , Li Feng , Stranger Barbara E. , Huang R. Stephanie 
Published: January 2023

AbstractSex differences have been widely observed in human health. However, little is known about the underlying mechanism behind these observed sex differences. We hypothesize that sex-differentiated genetic effects are contributors of these phenotypic differences. Focusing on a collection of drug metabolism enzymes and transporters (DMET) genes, we discover sex-differentiated genetic regulatory mechanisms between these genes and human complex traits. Here, we show that sex-differentiated genetic effects were present at genome-level and at DMET gene regions for many human complex traits. These sex-differentiated regulatory mechanisms are reflected in the levels of gene expression and endogenous serum biomarkers. Through Mendelian Randomization analysis, we identify putative sex-differentiated causal effects in each sex separately. Furthermore, we identify and validate sex differential gene expression of a subset of DMET genes in human liver samples. We observe higher protein abundance and enzyme activity of CYP1A2 in male-derived liver microsomes, which leads to higher level of an active metabolite formation of clozapine, a commonly prescribed antipsychotic drug. Taken together, our results demonstrate the presence of sex-differentiated genetic effects on DMET gene regulation, which manifest in various phenotypic traits including disease risks and drug responses.
Distributed context-dependent choice information in mouse posterior cortex
Authors: Orlandi Javier G. , Abdolrahmani Mohammad , Aoki Ryo , Lyamzin Dmitry R. , Benucci Andrea 
Published: January 2023

AbstractChoice information appears in multi-area brain networks mixed with sensory, motor, and cognitive variables. In the posterior cortex—traditionally implicated in decision computations—the presence, strength, and area specificity of choice signals are highly variable, limiting a cohesive understanding of their computational significance. Examining the mesoscale activity in the mouse posterior cortex during a visual task, we found that choice signals defined a decision variable in a low-dimensional embedding space with a prominent contribution along the ventral visual stream. Their subspace was near-orthogonal to concurrently represented sensory and motor-related activations, with modulations by task difficulty and by the animals’ attention state. A recurrent neural network trained with animals’ choices revealed an equivalent decision variable whose context-dependent dynamics agreed with that of the neural data. Our results demonstrated an independent, multi-area decision variable in the posterior cortex, controlled by task features and cognitive demands, possibly linked to contextual inference computations in dynamic animal–environment interactions.
Changes in PRC1 activity during interphase modulate lineage transition in pluripotent cells
Authors: Asenjo Helena G. , Alcazar-Fabra María , Espinosa-Martínez Mencía , Lopez-Onieva Lourdes , Gallardo Amador , Dimitrova Emilia , Feldmann Angelika , Pachano Tomas , Martorell-Marugán Jordi , Carmona-Sáez Pedro , Sanchez-Pozo Antonio , Rada-Iglesias Álvaro , Klose Robert J. , Landeira David 
Published: January 2023

AbstractThe potential of pluripotent cells to respond to developmental cues and trigger cell differentiation is enhanced during the G1 phase of the cell cycle, but the molecular mechanisms involved are poorly understood. Variations in polycomb activity during interphase progression have been hypothesized to regulate the cell-cycle-phase-dependent transcriptional activation of differentiation genes during lineage transition in pluripotent cells. Here, we show that recruitment of Polycomb Repressive Complex 1 (PRC1) and associated molecular functions, ubiquitination of H2AK119 and three-dimensional chromatin interactions, are enhanced during S and G2 phases compared to the G1 phase. In agreement with the accumulation of PRC1 at target promoters upon G1 phase exit, cells in S and G2 phases show firmer transcriptional repression of developmental regulator genes that is drastically perturbed upon genetic ablation of the PRC1 catalytic subunit RING1B. Importantly, depletion of RING1B during retinoic acid stimulation interferes with the preference of mouse embryonic stem cells (mESCs) to induce the transcriptional activation of differentiation genes in G1 phase. We propose that incremental enrolment of polycomb repressive activity during interphase progression reduces the tendency of cells to respond to developmental cues during S and G2 phases, facilitating activation of cell differentiation in the G1 phase of the pluripotent cell cycle.
Agricultural drought over water-scarce Central Asia aggravated by internal climate variability
Authors: Jiang Jie , Zhou Tianjun 
Published: January 2023

AbstractA severe agricultural drought swept Central Asia in 2021, causing mass die-offs of crops and livestock. The anthropogenic contribution to declines in soil moisture in this region over recent decades has remained unclear. Here we show from analysis of large ensemble simulations that the aggravation of agricultural droughts over southern Central Asia since 1992 can be attributed to both anthropogenic forcing and internal variability associated with the Interdecadal Pacific Oscillation (IPO). Although the negative-to-positive phase transition of IPO before 1992 offset human-induced soil moisture decline, we find that the positive-to-negative phase transition thereafter has doubled the externally forced rate of drying in the early growing season. Human-induced soil moisture loss will probably be further aggravated in the following century due to warming, albeit with increasing precipitation, and our simulations project that this trend will not be counterbalanced by the IPO phase change. Instead, this internal variability could modulate drying rates in the near term with an amplitude of −2 (+2) standard deviation of the IPO trend projected to amplify (weaken) the externally forced decrease in surface soil moisture by nearly 75% (60%). The findings highlight the need for the interplay between anthropogenic forcing and the natural variability of the IPO to be considered by policymakers in this climate-sensitive region.
Preterm birth is associated with xenobiotics and predicted by the vaginal metabolome
Authors: Kindschuh William F. , Baldini Federico , Liu Martin C. , Liao Jingqiu , Meydan Yoli , Lee Harry H. , Heinken Almut , Thiele Ines , Thaiss Christoph A. , Levy Maayan , Korem Tal 
Published: January 2023

AbstractSpontaneous preterm birth (sPTB) is a leading cause of maternal and neonatal morbidity and mortality, yet its prevention and early risk stratification are limited. Previous investigations have suggested that vaginal microbes and metabolites may be implicated in sPTB. Here we performed untargeted metabolomics on 232 second-trimester vaginal samples, 80 from pregnancies ending preterm. We find multiple associations between vaginal metabolites and subsequent preterm birth, and propose that several of these metabolites, including diethanolamine and ethyl glucoside, are exogenous. We observe associations between the metabolome and microbiome profiles previously obtained using 16S ribosomal RNA amplicon sequencing, including correlations between bacteria considered suboptimal, such as Gardnerella vaginalis, and metabolites enriched in term pregnancies, such as tyramine. We investigate these associations using metabolic models. We use machine learning models to predict sPTB risk from metabolite levels, weeks to months before birth, with good accuracy (area under receiver operating characteristic curve of 0.78). These models, which we validate using two external cohorts, are more accurate than microbiome-based and maternal covariates-based models (area under receiver operating characteristic curve of 0.55–0.59). Our results demonstrate the potential of vaginal metabolites as early biomarkers of sPTB and highlight exogenous exposures as potential risk factors for prematurity.
Accuracy of tropical peat and non-peat fire forecasts enhanced by simulating hydrology
Authors: Mezbahuddin Symon , Nikonovas Tadas , Spessa Allan , Grant Robert F. , Imron Muhammad Ali , Doerr Stefan H. , Clay Gareth D. 
Published: January 2023

AbstractSoil moisture deficits and water table dynamics are major biophysical controls on peat and non-peat fires in Indonesia. Development of modern fire forecasting models in Indonesia is hampered by the lack of scalable hydrologic datasets or scalable hydrology models that can inform the fire forecasting models on soil hydrologic behaviour. Existing fire forecasting models in Indonesia use weather data-derived fire probability indices, which often do not adequately proxy the sub-surface hydrologic dynamics. Here we demonstrate that soil moisture and water table dynamics can be simulated successfully across tropical peatlands and non-peatland areas by using a process-based eco-hydrology model (ecosys) and publicly available data for weather, soil, and management. Inclusion of these modelled water table depth and soil moisture contents significantly improves the accuracy of a neural network model in predicting active fires at two-weekly time scale. This constitutes an important step towards devising an operational fire early warning system for Indonesia.
A multiplexed microflow LC–MS/MS-PRM assay for serologic quantification of IgG N- and HPX O- glycoforms in liver fibrosis
Authors: Panigrahi Aswini , Zhang Lihua , Benicky Julius , Sanda Miloslav , Ahn Jaeil , Goldman Radoslav 
Published: January 2023

AbstractTargeted quantification of glycoproteins has not reached its full potential because of limitations of the existing analytical workflows. In this study, we introduce a targeted microflow LC–MS/MS-PRM method for the quantification of multiple glycopeptides in unfractionated serum samples. The entire preparation of 16 samples in a batch is completed within 3 h, and the LC–MS quantification of all the glycoforms in a sample is completed in 15 min in triplicate, including online capture and desalting. We demonstrate applicability of the workflow on a multiplexed quantification of eight N-glycoforms of immunoglobulin G (IgG) together with two O-glycoforms of hemopexin (HPX). We applied the assay to a serologic study of fibrotic liver disease in patients of HCV etiology. The results document that specific IgG- and HPX-glycoforms detect efficiently fibrotic disease of different degree, and suggest that the LC–MS/MS-PRM assays may provide rapid and reproducible biomarker assay targeting simultaneously the N- and O-glycoforms of the peptides. We propose that such high throughput multiplexed methods may advance the clinical use of the LC–MS/MS assays.
Individual identification of inbred medaka based on characteristic melanophore spot patterns on the head
Authors: Morizumi Hajime , Sugimoto Naozo , Ueno Tomohiro 
Published: January 2023

AbstractWith disease progression, individual differences appear, even in an animal disease model with genetic homogeneity. Therefore, non-invasive long term observation and individual identification is desirable for late-onset diseases. To this end, the natural markings used in ecological studies are preferable to the external invasive markings used in animal husbandry and fisheries management. Here, we propose using the distribution pattern of melanophore spots on the head of an inbred strain of medaka, a small fish model organism with monotonous pigmentation, as biometric identifier. Long term and variation analyses show different patterns whose characteristics can be attributed to individual animals. These findings were also valid in a non-inbred medaka strain and will help individual follow-up of late-onset disease medaka models for the elucidation of the pathogenesis and drug discovery.
Mechanisms shaping the gypsum stromatolite-like structures in the Salar de Llamara (Atacama Desert, Chile)
Authors: Criado-Reyes Joaquín , Otálora Fermín , Canals Àngels , Verdugo-Escamilla Cristóbal , García-Ruiz Juan-Manuel 
Published: January 2023

AbstractThe explanation of the origin of microbialites and specifically stromatolitic structures is a problem of high relevance for decoding past sedimentary environments and deciphering the biogenicity of the oldest plausible remnants of life. We have investigated the morphogenesis of gypsum stromatolite-like structures currently growing in shallow ponds (puquíos) in theSalar de Llamara(Atacama Desert, Northern Chile). The crystal size, aspect ratio, and orientation distributions of gypsum crystals within the structures have been quantified and show indications for episodic nucleation and competitive growth of millimetric to centimetric selenite crystals into a radial, branched, and loosely cemented aggregate. The morphogenetical process is explained by the existence of a stable vertical salinity gradient in the ponds. Due to the non-linear dependency of gypsum solubility as a function of sodium chloride concentration, the salinity gradient produces undersaturated solutions, which dissolve gypsum crystals. This dissolution happens at a certain depth, narrowing the lower part of the structures, and producing their stromatolite-like morphology. We have tested this novel mechanism experimentally, simulating the effective dissolution of gypsum crystals in stratified ponds, thus providing a purely abiotic mechanism for these stromatolite-like structures.
Antisocial and impulsive personality traits are linked to individual differences in somatosensory maps of emotion
Authors: Wainio-Theberge Soren , Armony Jorge L. 
Published: January 2023

AbstractSomatosensory experience is an important component of emotion, playing a prominent role in many traditional emotion theories. Nonetheless, and despite the extensive literature on the influence of individual differences in emotional processing, the relation between personality traits and emotion-related somatosensation has received little attention. Here, we addressed this question in a large sample of healthy individuals through the “bodily maps of emotion” behavioural paradigm, in which participants indicated the location and extent of their body sensations for the 6 basic and 4 additional social emotions (contempt, envy, pride, shame). We found that emotional somatosensation in specific body areas, including the heart, the stomach, and the head, was related to specific personality factors, particularly antisocial attitudes and impulsivity. Moreover, the similarity of individual participants’ maps to the group-average was likewise negatively correlated with antisocial tendencies. Overall, our results suggest that differences in individuals’ sensitivity to somatosensation from different body areas, as well as the typicality of their topographical patterns, may partly underlie variation in higher-order social and affective traits.
Rapid stool antigenic test for typhoid fever among suspected cases, Northeast, Ethiopia
Authors: Geteneh Alene , Tadesse Selamyhun , Biset Sirak , Girma Lencho , Fissiha Paulos 
Published: January 2023

AbstractTyphoid fever continued to be the key cause of morbidity and mortality in developing countries with poor hygienic practices and limited access to safe drinking water. The Widal card agglutination test is the main diagnostic tool in Ethiopia, which is limited in differentiating the overlapping symptoms with other acute febrile illnesses such as malaria and viral enteritis. This eventually leds to unnecessary antibiotic use and eventual drug resistance. Therefore this study wants to assess the burden and associated potential risk factors of typhoid fever among suspected cases using the typhoid rapid stool antigen test in Northeast Ethiopia. A hospital-based cross-sectional study was conducted at Gaint and Meket Shediho primary hospitals from May to July 2021. A total of 255 patients clinically suspected of typhoid fever, and willing to grant informed consent were included systematically. The demographic and hygiene-related variables were collected using a pre-tested structured questionnaire. The rapid stool antigenic test and xylose-lysine-deoxycholate agar (XLD) stool culture were evaluated for the level of agreement. The present study indicated that the prevalence of typhoid fever was 15.3%. This displayed that the human-restricted infectious disease, typhoid fever remained a challenge to Ethiopians. Washing hands with soap, history of typhoid fever, having previous history of hospitalization, and chronic underlying disease was the significant potential factor for typhoid fever. The higher agreement of the rapid stool antigenic test with the stool culture can indicate the factual burden of typhoid fever in the suspected population. This could minimize empiric treatment and the possible emergence of drug resistance. Thus, resource-poor settings may need to look for a rapid and reliable stool antigenic test.
Identification and validation of oxidative stress and immune-related hub genes in Alzheimer’s disease through bioinformatics analysis
Authors: Li Shengjie , Xiao Jinting , Huang Chuanjiang , Sun Jikui 
Published: January 2023

AbstractAlzheimer’s disease (AD) is the leading cause of dementia in aged population. Oxidative stress and neuroinflammation play important roles in the pathogenesis of AD. Investigation of hub genes for the development of potential therapeutic targets and candidate biomarkers is warranted. The differentially expressed genes (DEGs) in AD were screened in GSE48350 dataset. The differentially expressed oxidative stress genes (DEOSGs) were analyzed by intersection of DEGs and oxidative stress-related genes. The immune-related DEOSGs and hub genes were identified by weighted gene co-expression network analysis (WGCNA) and protein–protein interaction (PPI) analysis, respectively. Enrichment analysis was performed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The diagnostic value of hub genes was assessed by receiver operating characteristic analysis and validated in GSE1297. The mRNA expression of diagnostic genes was determined by qRT-PCR analysis. Finally, we constructed the drug, transcription factors (TFs), and microRNA network of the diagnostic genes. A total of 1160 DEGs (259 up-regulated and 901 down-regulated) were screened in GSE48350. Among them 111 DEOSGs were identified in AD. Thereafter, we identified significant difference of infiltrated immune cells (effector memory CD8 T cell, activated B cell, memory B cell, natural killer cell, CD56 bright natural killer cell, natural killer T cell, plasmacytoid dendritic cell, and neutrophil) between AD and control samples. 27 gene modules were obtained through WGCNA and turquoise module was the most relevant module. We obtained 66 immune-related DEOSGs by intersecting turquoise module with the DEOSGs and identified 15 hub genes through PPI analysis. Among them, 9 hub genes (CCK, CNR1, GAD1, GAP43, NEFL, NPY, PENK, SST, and TAC1) were identified with good diagnostic values and verified in GSE1297. qRT-PCR analysis revealed the downregulation of SST, NPY, GAP43, CCK, and PENK and upregulation of NEFL in AD. Finally, we identified 76 therapeutic agents, 152 miRNAs targets, and 91 TFs regulatory networks. Our study identified 9 key genes associated with oxidative stress and immune reaction in AD pathogenesis. The findings may help to provide promising candidate biomarkers and therapeutic targets for AD.
Characterization of Ethyl Butyrate–Induced Cough Before and After Breath Control Techniques in Healthy Adults
Authors: Novaleski Carolyn K. , Hegland Karen Wheeler , Aleksandruk Mikala M. , Dalton Pamela H. , Mainland Joel D. 
Published: January 2023

Purpose:
Methods for cough elicitation frequently involve aerosolized tussive agents. Here, we sought to determine whether healthy individuals demonstrate a quantifiable cough response after inhaling a volatile ester and if breath control techniques modify this chemically induced cough response.

Method:
Sixty adult male and female participants inhaled prepared liquid dilutions of ethyl butyrate dissolved in paraffin oil at 20%, 40%, and 60% v/v concentrations in triplicate, with presentation order randomized. We delivered stimuli through a face mask connected to an olfactometer and respiratory pneumotachograph. Participants rated sensations of their urge to cough and pleasantness of the odor while cough airflow was measured. Following baseline testing, participants were randomized to implement pursed-lip breathing or slow-paced breathing after inhaling ethyl butyrate to determine the effects of breath control on cough measures.

Results:

Inhaled ethyl butyrate elicited cough in 70% of participants. Higher concentrations of ethyl butyrate resulted in significantly greater sensation of the urge to cough,
F
(2, 80) = 10.72,
p
< .001, and significantly more generated coughs,
F
(2, 63) = 13.14,
p
< .001. Compared to baseline, participants rated significantly decreased urge to cough during breath control techniques,
F
(1, 40) = 11.01,
p
= .0019. No significant changes were observed in the number of generated coughs between baseline and breath control techniques,
F
(1, 31) = 7.23,
p
= .01.

Conclusions:
Airborne ethyl butyrate is a tussigenic agent in humans. Our findings provide opportunities for future research directions in normal and disordered cough responses to volatile compounds.