bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of multiple cardiovascular disease risk factors
Authors: DeForest Natalie , Kavitha Babu , Hu Siqi , Isaac Roi , Wang Minxian , Du Xiaomi , De Arruda Saldanha Camila , Gylys Jenny , Abagyan Ruben , Najmi Laeya , Mohan Viswanathan ,   Alnylam Human Genetics,   AMP-T2D Consortium, Flannick Jason , Peloso Gina M. , Gordts Philip , Heinz Sven , Deaton Aimee M. , Khera Amit V. , Olefsky Jerrold , Radha Venkatesan , Majithia Amit R. 
Published: March 2022

AbstractLoss-of-function mutations in Hepatocyte Nuclear Factor 1A (HNF1A) are known to cause rare forms of diabetes and alter hepatic physiology through unclear mechanisms. In the general population, 1:100 individuals carry a rare protein-coding variant in HNF1A, most of unknown functional consequence. To characterize the full allelic series, we performed deep mutational scanning of 11,970 protein-coding HNF1A variants in human hepatocytes and clinical correlation with 553,246 exome-sequenced individuals. Surprisingly, we found ∼1:5 rare protein-coding HNF1A variants found in the general population cause molecular gain-of-function (GOF), increasing the transcriptional activity of HNF1A by up to 50%. GOF in HNF1A conferred protection from type 2 diabetes (T2D) (OR=0.60, p=8.4 x 10-7), but not against coronary artery disease. Independently of T2D, increased hepatic expression of HNF1A promoted a pro-inflammatory and pro-atherogenic serum profile mediated in part by enhanced transcription of risk genes including PCSK9. In summary, ∼1:300 individuals carry a GOF variant in HNF1A that protects carriers from diabetes but enhances hepatic secretion of metabolic disease risk factors.
High-throughput imaging and quantitative analysis uncovers the nature of plasmid positioning by ParABS
Authors: Köhler Robin , Murray Seán M. 
Published: March 2022

AbstractThe faithful segregation and inheritance of bacterial chromosomes and low-copy number plasmids requires dedicated partitioning systems. The most common of these, ParABS, consists of ParA, a DNA-binding ATPase and ParB a protein that binds to centromeric-like parS sequences on the DNA cargo. The resulting nucleoprotein complexes are believed to move up a self-generated gradient of nucleoid-associated ParA. However, it remains unclear how this leads to the observed cargo positioning and dynamics. In particular, the evaluation of models of plasmid positioning has been hindered by the lack of quantitative measurements. Here, we use high-throughput imaging, analysis and modelling to determine the dynamical nature of these systems. We find that F plasmid is actively brought to specific subcellular home positions within the cell with dynamics akin to an over-damped spring. We identify ParA hopping on the nucleoid as the primary determinant of this geometry-sensing and develop a unified computational model that quantitatively explains the observed behaviour. Furthermore, we confirm our model prediction that cells with the lowest plasmid concentration transition to oscillatory dynamics and find similar behaviour in a distantly-related ParABS system. Our results indicate that ParABS regularly positions plasmids across the nucleoid but operates just below the threshold of an oscillatory instability, minimising ATP consumption. Overall, this work uncovers the dynamical nature of plasmid positioning by ParABS and provides insights relevant for chromosome-based systems.
Ptbp1 knockdown in mouse striatum did not induce astrocyte-to-neuron conversion using HA-tagged labeling system
Authors: Yang Guixiang , Yan Zixiang , Wu Xiaoqing , Zhang Meng , Xu Chunlong , Shi Linyu , Yang Hui , Fang Kailun 
Published: March 2022

AbstractConversion of astrocytes to neurons (AtN) is a promising potential strategy for the treatment of neurodegenerative diseases. Recent studies have reported that shRNA-, CasRx-, or ASO-mediated Ptbp1 suppression could reprogram resident astrocytes to neurons1–3. However, some groups have disputed the data interpretation of the reported AtN conversion events4–7. These controversies surrounding AtN conversion may due to differences in the astrocyte fate-mapping systems they applied from that in the original study, i.e., recombinant mouse strains with astrocyte specific reporter constructs versus AAV-based labeling systems. Here, we applied AAV-based tracing systems to label astrocytes with GFAP-driven HA-tagged Cas13X (AAV-GFAP::Cas13X-NLS-HA-sgPtbp1). Compared to GFAP-driven tdTomato reporter (AAV-GFAP::tdTomato) system in previous studies, we found no AtN conversion in mouse striatum. Furthermore, no intermediate neurons and no neuron density increase suggested no AtN conversion. Our findings indicated that inconsistent AtN outcomes may arise from different fate-mapping systems between AAV and transgenic mice, as well as through use of different reporter proteins. Thus, the complexity of astrocyte labeling systems warrants careful attention when drawing conclusions about whether AtN conversion occurs.
Effect of seizures on developmental trajectories in children with autism
Authors: Forman Phillip , Khokhlovich Edward , Vyshedskiy Andrey 
Published: March 2022

AbstractThe effect of seizures in 2 to 5-year-old children with ASD was investigated in the largest and the longest observational study to-date. Parents assessed the development of 8461 children quarterly for three years on five orthogonal subscales: combinatorial receptive language, expressive language, sociability, sensory awareness, and health. Seizures were reported in 11% of children. Children with no seizures developed faster compared to matched children with seizures in all subscales. On an annualized basis, participants with no seizures improved their receptive language 1.5-times faster than those with seizures; expressive language: 1.3-times faster; sociability: 2.3-times faster; sensory awareness: 6.2-times faster; and health: 20.0-times faster. This study confirms a high prevalence of seizures in ASD children and points to the need for more systematic approach to the development of treatment strategies.
Jumping out of trouble: Evidence for a cognitive map in guppies (Poecilia reticulata)
Authors: de Waele Hannah , Pouca Catarina Vila , van Boerdonk Dimphy , Luiten Ewoud , Leenheer Lisanne M. , Mitchell David , Vega-Trejo Regina , Kotrschal Alexander 
Published: March 2022

AbstractSpatial cognitive abilities allow individuals to remember the location of food patches, predator hide-outs, or shelters. Animals typically incorporate learnt spatial information or use external environmental cues to navigate their surroundings. A spectacular example of how some fishes move is through aerial jumping. For instance, fish that are trapped within isolated pools, cut off from the main body of water during dry periods, may jump over obstacles and direct their jumps to return to safe locations. However, what information such re-orientation behaviour during jumping is based on remains enigmatic. Here we combine a lab and field experiment to test if guppies (Poecilia reticulata) incorporate learnt spatial information and external environmental cues (visual and auditory) to determine where to jump. In a spatial memory assay we found that guppies were more likely to jump towards deeper areas, hence incorporating past spatial information to jump to safety. In a matched vs. mismatched spatial cue experiment in the field, we found that animals only showed directed jumping when visual and auditory cues matched. We show that in unfamiliar entrapments guppies direct their jumps by combining visual and auditory cues, while in familiar entrapments they use a cognitive map. We hence conclude that jumping behaviour is a goal-directed behaviour, guided by different sources of information and involving important spatial cognitive skills.
Obligate sexual reproduction of a homothallic fungus closely related to the Cryptococcus pathogenic species complex
Authors: Passer Andrew Ryan , Clancey Shelly Applen , Shea Terrance , David-Palma Márcia , Averette Anna Floyd , Boekhout Teun , Porcel Betina M. , Nowrousian Minou , Cuomo Christina A. , Sun Sheng , Heitman Joseph , Coelho Marco A. 
Published: March 2022

AbstractSexual reproduction is a ubiquitous and ancient trait of eukaryotic life. While sexual organisms are usually faced with the challenge of finding a compatible mating partner, species as diverse as animals, plants, and fungi have repeatedly evolved the ability to reproduce sexually without an obligate requirement for another individual. Here, we uncovered the underlying mechanism of self-compatibility (homothallism) in Cryptococcus depauperatus, a fungal species sister to the clinically relevant human fungal pathogens Cryptococcus neoformans and Cryptococcus gattii species complexes. In contrast to C. neoformans or C. gattii, which grow as a yeast in the asexual stage, and produce hyphae, basidia, and infectious spores during the sexual stage, C. depauperatus grows exclusively as hyphae decorated with basidia and abundant spores and appears to be continuously engaged in sexual reproduction. By combining the insights from comparative genomics and genetic analyses of mutants defective in key mating and meiosis genes, we demonstrate the sexual cycle of C. depauperatus involves meiosis, and reveal that self-compatibility is orchestrated by the expression, in the same cell, of an unlinked mating receptor (Ste3a) and pheromone ligand (MFα) pair seemingly derived from opposite mating types of a heterothallic (self-sterile) ancestor. We identified a putative mating-type (MAT) determining region containing genes phylogenetically aligned with MATa alleles of other species, and a few MATα gene alleles scattered and unlinked throughout the genome, but no homologs of the mating-type homeodomain genes SXI1 (HD1) and SXI2 (HD2). Comparative genomic analyses suggested a dramatic remodeling of the MAT locus possibly owing to reduced selective constraints to maintain mating-type genes in tight linkage, associated with a transition to self-fertility. Our findings support C. depauperatus as an obligately sexual, homothallic fungal species and provide additional insight into the repeated transitions between modes of sexual reproduction that have occurred throughout the fungal kingdom.
Nitrite lowers the oxygen cost of ATP supply in skeletal muscle cells by stimulating the rate of glycolytic ATP synthesis
Authors: Wynne Anthony G. , Affourtit Charles 
Published: March 2022

AbstractDietary nitrate lowers the oxygen cost of human exercise. This effect has been suggested to result from stimulation of coupling efficiency of skeletal muscle oxidative phosphorylation by reduced nitrate derivatives. In this paper, we report the acute effects of sodium nitrite on the bioenergetic behaviour of L6 myocytes. At odds with improved efficiency of mitochondrial ATP synthesis, extracellular flux analysis reveals that a ½-hour exposure to NaNO2 (0.1 – 5 µM) significantly decreases mitochondrial coupling efficiency in static myoblasts and tends to lower it in spontaneously contracting myotubes. Unexpectedly, NaNO2 stimulates the rate of glycolytic ATP production in both myoblasts and myotubes. Increased ATP supply through glycolysis does not emerge at the expense of oxidative phosphorylation, which means that NaNO2 acutely increases the rate of overall myocellular ATP synthesis, highly significantly so in myoblasts and tending towards significance in contractile myotubes. Notably, NaNO2 exposure shifts myocytes to a more glycolytic phenotype. Mitochondrial oxygen consumption does not decrease after NaNO2 exposure, and non-mitochondrial respiration tends to drop. When total ATP synthesis rates are normalised to total cellular oxygen consumption rates, it thus transpires that NaNO2 lowers the oxygen cost of ATP supply in L6 myocytes.
3D Organic Bioelectronics for Monitoring In Vitro Stem Cell Cultures
Authors: Savva Achilleas , Saez Janire , Barberio Chiara , Lu Zixuan , Moysidou Chrysanthi-Maria , Kallitsis Konstantinos , Withers Aimee , Pitsalidis Charalampos , Owens Róisín M. 
Published: March 2022

AbstractThree-dimensional in vitro stem cell models has enabled a fundamental understanding of cues that direct stem cell fate and be used to develop novel stem cell treatments. While sophisticated 3D tissues can be generated, technology that can accurately monitor these complex models in a high-throughput and non-invasive manner is not well adapted. Here we show the development of 3D bioelectronic devices based on the electroactive polymer poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) - PEDOT:PSS and their use for non-invasive, electrical monitoring of stem cell growth. We show that the electrical, mechanical and wetting properties as well as the pore size/architecture of 3D PEDOT:PSS scaffolds can be fine-tuned simply by changing the processing crosslinker additive. We present a comprehensive characterization of both 2D PEDOT:PSS thin films of controlled thicknesses, and 3D porous PEDOT:PSS structures made by the freeze-drying technique. By slicing the bulky scaffolds we show that homogeneous, porous 250 um thick PEDOT:PSS slices are produced, generating biocompatible 3D constructs able to support stem cell cultures. These multifunctional membranes are attached on Indium-Tin oxide substrates (ITO) with the help of an adhesion layer that is used to minimize the interface charge resistance. The optimum electrical contact result in 3D devices with a characteristic and reproducible, frequency dependent impedance response. This response changes drastically when human adipose derived stem cells grow within the porous PEDOT:PSS network as revealed by fluorescence microscopy. The increase of these stem cell population within the PEDOT:PSS porous network impedes the charge flow at the interface between PEDOT:PSS and ITO, enabling the interface resistance to be extracted by equivalent circuit modelling, used here as a figure of merit to monitor the proliferation of stem cells. The strategy of controlling important properties of 3D PEDOT:PSS structures simply by altering processing parameters can be applied for development of a number of stem cell in vitro models. We believe the results presented here will advance 3D bioelectronic technology for both fundamental understanding of in vitro stem cell cultures as well as the development of personalized therapies.
Telehealth versus Self-Directed Lifestyle Intervention to Promote Healthy Blood Pressure: a Randomized Controlled Trial
Authors: Chang Alex R , Gummo Lauren , Yule Christina , Bonaparte Heather , Collins Charlotte , Naylor Allison , Appel Lawrence , Juraschek Stephen P , Bailey-Davis Lisa 
Published: April 2022

AbstractIntroductionLifestyle behavior modification interventions, delivered using telehealth, have been shown to be effective in reducing weight. However, limited data exists on the benefits of lifestyle behavior change delivered using telehealth and web-based applications on blood pressure (BP).MethodsWe conducted a 2-site randomized controlled trial in the Geisinger Health System (January 2019 to March 2021) to compare the efficacy of a self-guided vs. a dietitian telehealth approach using web-based applications in 187 participants with 24-hour systolic BP 120-160 mmHg and body mass index ≥ 25 kg/m2. Both arms received recommendations to improve diet based on a web-based food frequency questionnaire, and access to an online weight management program. The telehealth arm received weekly telephone calls with a dietitian who used motivational interviewing. The primary outcome was 12-week change in 24-hour systolic BP. Secondary outcomes included changes in sleep/awake systolic BP and diastolic BP, self-reported physical activity, healthy eating index (HEI)-2015 score, and weight.ResultsA total of 187 participants (mean age 54.6 [SD 13.2] years, 52% female, 23% on BP medications, mean body mass index 34.5 [6.5] kg/m2, mean HEI-2015 score 60.8 [11.1] units) were randomized with 156 (83.4%) completing the trial. Mean 24-hour systolic BP improved from baseline to 12 weeks similarly in the dietitian (−6.73 mmHg, 95% CI: −8.64, −4.82) and the self-directed arm (−4.92, 95% CI: −7.01, −2.77; p comparing groups=0.2). The dietitian telehealth arm had greater 12-week improvements in sleep systolic BP (mean −6.92 vs. −1.45; p=0.004), sleep diastolic BP (−3.31 vs. 0.73; p=0.001), and self-reported physical activity (866 vs. −243 metabolic equivalent of task minutes/week; p=0.01). The dietitian telehealth arm also tended to have greater 12-week improvements in weight loss (−5.11 vs. −3.89 kg; p=0.1) and HEI-2015 score (9.23 vs. 6.43 units; p=0.09), though these differences were not statistically significant.ConclusionsDietitian-led telehealth supported by web-based applications resulted in a similar reduction in 24-hour systolic BP as a self-directed approach, with secondary improvements in sleep BP and physical activity.Trial registration numberClinicalTrials.gov Identifier NCT03700710
WWP2 osteoarthritis risk allele rs1052429-A confers risk by affecting cartilage matrix deposition via hypoxia associated genes
Authors: Tuerlings Margo , Janssen George M.C. , Boone Ilja , van Hoolwerff Marcella , Rodriguez Ruiz Alejandro , Houtman Evelyn , Suchiman Eka H.E.D. , van der Wal Robert J.P. , Nelissen Rob G.H.H. , Coutinho de Almeida Rodrigo , van Veelen Peter A. , Ramos Yolande F.M. , Meulenbelt Ingrid 
Published: March 2022

ABSTRACTObjectiveTo explore the co-expression network of the osteoarthritis (OA) risk gene WWP2 in articular cartilage and study cartilage characteristics when mimicking the effect of OA risk allele rs1052429-A on WWP2 expression in a human 3D in vitro model of cartilage.MethodsCo-expression behavior of WWP2 with genes expressed in lesioned OA articular cartilage (N=35 samples) was explored. By applying lentiviral particle mediated WWP2 upregulation in 3D in vitro pellet cultures of human primary chondrocytes (N=8 donors) the effects of upregulation on cartilage matrix deposition was evaluated. Finally, we transfected primary chondrocytes with miR-140 mimics to evaluate whether miR-140 and WWP2 are involved in similar pathways.ResultsUpon performing Spearman correlations in lesioned OA cartilage, 98 highly correlating genes (|ρ|>0.7) were identified. Among these genes, we identified GJA1, GDF10, STC2, WDR1, and WNK4. Subsequent upregulation of WWP2 on 3D chondrocyte pellet cultures resulted in a decreased expression of COL2A1 and ACAN and an increase in EPAS1 expression. Additionally, we observed a decreased expression of GDF10, STC2, and GJA1. Proteomics analysis identified 42 proteins being differentially expressed with WWP2 upregulation, which were enriched for ubiquitin conjugating enzyme activity. Finally, upregulation of miR-140 in 2D chondrocytes resulted in significant upregulation of WWP2 and WDR1.ConclusionsMimicking the effect of OA risk allele rs1052429-A on WWP2 expression initiates detrimental processes in the cartilage shown by a response in hypoxia associated genes EPAS1,GDF10, and GJA1 and a decrease in anabolic markers, COL2A1 and ACAN.
Decoding mitochondrial genes in pediatric AML and development of a novel prognostic mitochondrial gene signature
Authors: Chaudhary Shilpi , Ganguly Shuvadeep , Palanichamy Jayanth Kumar , Singh Archna , Pradhan Dibyabhaba , Bakhshi Radhika , Chopra Anita , Bakhshi Sameer 
Published: April 2022

AbstractBackgroundGene expression profile of mitochondrial-related genes is not well deciphered in pediatric acute myeloid leukaemia (AML). We aimed to identify mitochondria-related differentially expressed genes (DEGs) in pediatric AML with their prognostic significance.MethodsChildren with de novo AML were included prospectively between July 2016-December 2019. Transcriptomic profiling was done for a subset of samples, stratified by mtDNA copy number. Top mitochondria-related DEGs were identified and validated by real-time PCR. A prognostic gene signature risk score was formulated using DEGs independently predictive of overall survival (OS) in multivariable analysis. Predictive ability of the risk score was estimated along with external validation in The Tumor Genome Atlas (TCGA) AML dataset.ResultsIn 143 children with AML, twenty mitochondria-related DEGs were selected for validation, of which 16 were found to be significantly dysregulated. Upregulation of SDHC (p<0.001), CLIC1 (p=0.013) and downregulation of SLC25A29 (p<0.001) were independently predictive of inferior OS, and included for developing prognostic risk score. The risk score model was independently predictive of survival over and above ELN risk categorization (Harrell’s c-index: 0.675). High-risk patients (risk score above median) had significantly inferior OS (p<0.001) and event free survival (p<0.001); they were associated with poor-risk cytogenetics (p=0.021), ELN intermediate/poor risk group (p=0.016), absence of RUNX1-RUNX1T1 (p=0.027), and not attaining remission (p=0.016). On external validation, the risk score also predicted OS (p=0.019) in TCGA dataset.ConclusionWe identified and validated mitochondria-related DEGs with prognostic impact in pediatric AML and also developed a novel 3-gene based externally validated gene signature predictive of survival.
Associations of current and childhood socioeconomic status and health outcomes amongst patients with knee or hip osteoarthritis in a Mexico City family-practice setting
Authors: Pisanty-Alatorre Julio , Bello-Chavolla Omar Yaxmehen , Vilchis-Chaparro Eduardo , Goycochea-Robles María Victoria 
Published: April 2022

AbstractObjectivesTo examine the association of current and childhood socioeconomic status (SES) with patient-reported functional status, quality of life and disability in patients with knee osteoarthritis (OA)MethodsWe conducted a cross-sectional study amongst individuals seeking care for any medical reason in a primary care family-practice clinic in Mexico City. We included individuals with self-reported doctor-diagnosed arthritis and administered a survey using validated Spanish language versions of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Osteoarthritis of Lower Limbs and Quality of Life (AMICAL), and the Stanford Health Assessment Questionnaire-Disability Index (HAQ-DI). To estimate current and childhood SES, we and used a validated tool to estimate income quintile, as well as education level and occupation type, for both the patient and their parents.ResultsWe recruited 154 patients and excluded 8 patients. Estimated income and education levels were correlated with WOMAC, AMICAL and HAQ-DI scores, and significant differences were found in all scores by occupation type. The association for estimated income and all scores remained significant independently of age, sex, BMI, and presence of diabetes or hypertension. Maternal education was best correlated with AMICAL scores, though its effect seemed largely mediated by its association with current SES measures.ConclusionsCurrent and – to a lesser extent – childhood Socioeconomic Status impacts functional status, quality of life and disability amongst OA patients in Mexico City. Awareness of life-course SES can help identify patients at risk for worse outcomes.