bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biochemical characterization of naturally occurring mutations in SARS-CoV-2 RNA-dependent RNA polymerase
Authors: Danda Matěj , Klimešová Anna , Kušková Klára , Dostálková Alžběta , Pagáčová Aneta , Prchal Jan , Kapisheva Marina , Ruml Tomáš , Rumlová Michaela 
Published: February 2024

AbstractSince the emergence of SARS-CoV-2, mutations in all subunits of the RNA-dependent RNA polymerase (RdRp) of the virus have been repeatedly reported. Although RdRp represents a primary target for antiviral drugs, experimental studies exploring the phenotypic effect of these mutations have been limited. This study focuses on the phenotypic effects of substitutions in the three RdRp subunits: nsp7, nsp8, and nsp12, selected based on their occurrence rate and potential impact. We employed nano-differential scanning fluorimetry and microscale thermophoresis to examine the impact of these mutations on protein stability and RdRp complex assembly. We observed diverse impacts; notably, a single mutation in nsp8 significantly increased its stability as evidenced by a 13 °C increase in melting temperature, whereas certain mutations in nsp7 and nsp8 reduced their binding affinity to nsp12 during RdRp complex formation. Using a fluorometric enzymatic assay, we assessed the overall effect on RNA polymerase activity. We found that most of the examined mutations altered the polymerase activity, often as a direct result of changes in stability or affinity to the other components of the RdRp complex. Intriguingly, a combination of nsp8 A21V and nsp12 P323L mutations resulted in a 50% increase in polymerase activity. Additionally, some of the examined substitutions in the RdRp subunits notably influenced the sensitivity of RdRp to Remdesivir®, highlighting their potential implications for therapeutic strategies. To our knowledge, this is the first biochemical study to demonstrate the impact of amino acid mutations across all components constituting the RdRp complex in emerging SARS-CoV-2 subvariants.Significance statementWhile the impact of SARS-CoV-2 spike protein mutations has been extensively explored, our understanding of mutations within the RNA-dependent RNA polymerase (RdRp), crucial for viral replication and a key target for antivirals like Remdesivir, remains limited with studies conducted solelyin silico. We focused on selected RdRp mutations identified from December 2019 to June 2022, assessing their effects on enzyme stability, complex assembly, and activity. Advanced biochemical analyses reveal how these mutations can alter RdRp functionality, providing insights into viral evolution and resistance mechanisms. This study, pioneering in assessing the biochemical implications of RdRp mutations, provides invaluable insights into their roles in viral replication and antiviral resistance, hereby opening new pathways for developing therapies against the continuously evolving SARS-CoV-2 variants.
ADELLE: A global testing method for Trans-eQTL mapping
Authors: Akinbiyi Takintayo , McPeek Mary Sara , Abney Mark 
Published: February 2024

AbstractUnderstanding the genetic regulatory mechanisms of gene expression is a challenging and ongoing problem. Genetic variants that are associated with expression levels are readily identified when they are proximal to the gene (i.e., cis-eQTLs), but SNPs distant from the gene whose expression levels they are associated with (i.e., trans-eQTLs) have been much more difficult to discover, even though they account for a majority of the heritability in gene expression levels. A major impediment to the identification of more trans-eQTLs is the lack of statistical methods that are powerful enough to overcome the obstacles of small effect sizes and large multiple testing burden of trans-eQTL mapping. Here, we propose ADELLE, a powerful statistical testing framework that requires only summary statistics and is designed to be most sensitive to SNPs that are associated with multiple gene expression levels, a characteristic of many trans-eQTLs. In simulations, we show that for detecting SNPs that are associated with 0.1%–2% of 10,000 traits, among the 7 methods we consider ADELLE is clearly the most powerful overall, with either the highest power or power not significantly different from the highest for all settings in that range. We apply ADELLE to a mouse advanced intercross line data set and show its ability to find trans-eQTLs that were not significant under a standard analysis. This demonstrates that ADELLE is a powerful tool at uncovering trans regulators of genetic expression.
β-amino acids reduce ternary complex stability and alter the translation elongation mechanism
Authors: Cruz-Navarrete F. Aaron , Griffin Wezley C. , Chan Yuk-Cheung , Martin Maxwell I. , Alejo Jose L. , Natchiar S. Kundhavai , Knudson Isaac J. , Altman Roger B. , Schepartz Alanna , Miller Scott J. , Blanchard Scott C. 
Published: February 2024

ABSTRACTTemplated synthesis of proteins containing non-natural amino acids (nnAAs) promises to vastly expand the chemical space available to biological therapeutics and materials. Existing technologies limit the identity and number of nnAAs than can be incorporated into a given protein. Addressing these bottlenecks requires deeper understanding of the mechanism of messenger RNA (mRNA) templated protein synthesis and how this mechanism is perturbed by nnAAs. Here we examine the impact of both monomer backbone and side chain on formation and ribosome-utilization of the central protein synthesis substate: the ternary complex of native, aminoacylated transfer RNA (aa-tRNA), thermally unstable elongation factor (EF-Tu), and GTP. By performing ensemble and single-molecule fluorescence resonance energy transfer (FRET) measurements, we reveal the dramatic effect of monomer backbone on ternary complex formation and protein synthesis. Both the (R) and (S)-β2isomers of Phe disrupt ternary complex formation to levels belowin vitrodetection limits, while (R)- and (S)-β3-Phe reduce ternary complex stability by approximately one order of magnitude. Consistent with these findings, (R)- and (S)-β2-Phe-charged tRNAs were not utilized by the ribosome, while (R)- and (S)-β3-Phe stereoisomers were utilized inefficiently. The reduced affinities of both species for EF-Tu ostensibly bypassed the proofreading stage of mRNA decoding. (R)-β3-Phe but not (S)-β3-Phe also exhibited order of magnitude defects in the rate of substrate translocation after mRNA decoding, in line with defects in peptide bond formation that have been observed for D-α-Phe. We conclude from these findings that non-natural amino acids can negatively impact the translation mechanism on multiple fronts and that the bottlenecks for improvement must include consideration of the efficiency and stability of ternary complex formation.
Global variation in the ratio of sapwood to leaf area explained by optimality principles
Authors: Xu Huiying , Wang Han , Prentice I. Colin , Harrison Sandy P. , Rowland Lucy , Mencuccini Maurizio , Sanchez-Martinez Pablo , He Pengcheng , Wright Ian J. , Sitch Stephen , Ye Qing 
Published: February 2024

AbstractThe sapwood area supporting a given leaf area (vH) reflects a coordinated coupling between carbon uptake, water transport and loss at a whole plant level. Worldwide variation invHreflects diverse plants strategies adapt to prevailing environments, and impact the evolution of global carbon and water cycles. Why such a variation has not been convincingly explained yet, thus hinder its representation in Earth System Models. Here we hypothesize that optimalvHtends to mediate between plant hydraulics and leaf photosynthesis so that leaf water loss matches water supply. By compiling and testing against two extensive datasets, we show that our hypothesis explains nearly 60% ofvHvariation responding to light, vapour pressure deficit, temperature, and sapwood conductance in a quantitively predictable manner. Sapwood conductance or warming-enhanced hydraulic efficiency reduces the demand on sapwood area for a given total leaf area and, whereas brightening and air dryness enhance photosynthetic capacities consequently increasing the demand. This knowledge can enrich Earth System Models where carbon allocation and water hydraulics play key roles in predicting future climate-carbon feedback.
Multi-omics clustering analysis carries out the molecular specific subtypes of thyroid carcinoma: implicating for the precise treatment strategies
Authors: Wang Zhenglin , Han Qijun , Hu Xianyu , Wang Xu , Sun Rui , Huang Siwei , Chen Wei 
Published: February 2024

AbstractBackgroundThyroid cancer is the most prevalent endocrine malignancy, Recent classifications highlight the importance of molecular characteristics in TC, including BRAF, TERT, and RET fusion gene mutations, which are crucial for diagnosis, prognosis, and targeted therapy. This study aims to explore molecular subtypes of TC to identify new biomarkers and improve patient selection for targeted therapies.MethodsThis study utilized multi-omics data from the TCGA-THCA dataset and additional cohorts (GSE29265, GSE33630, GSE54958, GSE65074) involving a total of 539 patients. Various data types, including DNA methylation, gene mutations, mRNA, LncRNA, and miRNA expression, were analyzed. The study employed consensus clustering algorithms to identify molecular subtypes and used various bioinformatics tools to analyze genetic alterations, signaling pathways, immune infiltration, and responses to chemotherapy and immunotherapy. The statistical significance was established at P < 0.05.ResultsTwo prognostically relevant thyroid cancer subtypes, termed CS1 and CS2, were identified. CS2 was associated with a poorer prognosis of shorter progression-free survival times (P < 0.001). CS1 exhibited higher copy number alterations but lower tumor mutation burden (TMB) than CS2. Notably, CS2 showed higher TMB and cytolytic activity scores, suggesting a potential for higher immunogenicity. Different pathway activations were observed between subtypes, with CS2 showing activation in cell proliferation and immune-related pathways. Drug sensitivity analysis indicated CS2’s higher sensitivity to cisplatin, doxorubicin, paclitaxel, and sunitinib, whereas CS1 was more sensitive to bicalutamide and FH535. The different activated pathways and sensitive to drugs for subtypes were further validated in external cohort. After dimensionality reduction, five genes of CXCL17, LCN2, MUC1, SERPINA1, and SLC34A2 were validated that can distinguish subtypes across pan-cohorts. 24 paired tumor and adjacent normal tissues by immunohistochemical staining further show the prognostic value of CXCL17 for advanced thyroid cancer.ConclusionThe study revealed two distinct molecular subtypes of thyroid cancer with significant implications for prognosis, genetic alterations, pathway activation, and treatment response. These findings underscore the potential of multi-omics approaches in enhancing personalized medicine in thyroid cancer.
Correlates of non-dipping blood pressure in persons with and without hypertension
Authors: Liweleya Situmbeko , Hamooya Benson M. , Mungalu Obrain M. L. , Zimba Sharon D. , Masenga Sepiso K. 
Published: February 2024

AbstractBackgroundBlood pressure (BP) is known to follow a circadian rhythm with 10% to 15% lower values during the night than daytime. Non-dipping BP refers to the absence of BP dipping and has been associated with the development of target organ damage. The general goal of this study was to determine the correlates of non-dipping BP in persons with and without hypertension.MethodsThis was a cross-sectional study that recruited 98 participants at Chikankata Mission General Hospital. The outcome variable of the study was non-dipping BP, with sociodemographic and clinical explanatory variables. We used SPSS version 22 to describe and make inferences.ResultsThe median (interquartile range (IQR)) age of participants was 42 years (34.7-52) and 54.1% (53/98) had hypertension while 45.9% (45/98) were normotensive. The proportion of females was slightly higher (59.2%, n=58) than that of males (40.2%, n=40), this being similar in hypertensives but equal in normotensives. The median (IQR) age of hypertensives was higher compared to the normotensives, 46 (40-56) vs. 35 (25-41) years.The prevalence of non-dipping BP was 38.8% overall and higher among those with hypertension (54.7%) compared to the normotensive group (20%). The factors associated with non-dipping BP in the multivariate analysis were age (adjusted odds ratios (AOR) of 1.15; 95% CI: 1.05 - 1.25), spot urine sodium (AOR of 1.16; 95% CI: 0.99 - 1.36), daytime systolic blood pressure (SBP) load (AOR of 1.28; 95% CI: 1.06 - 1.55), daytime diastolic blood pressure (DBP) load (AOR of 0.77; 95% CI: 0.65 - 0.92), and nighttime DBP load (AOR of 1.10; 95% CI: 1.02, 1.18). However, this was abrogated by hypertension status albeit among normotensives only age remained significantly associated with non-dipping BP, none of the factors remained significantly associated with non-dipping BP among persons with hypertension.ConclusionThe prevalence of non-dipping BP was high, among hypertensives. This provides insights into the intricate links between BP patterns, sociodemographic and clinical characteristics but further underscores the need for mechanistic researches to further advance the understanding of mechanisms of associated characteristics.
Fluorosurfactants in groundwater increase the incidence of chronic health conditions among California Medicare beneficiaries
Authors: Neas Lucas M. , Steinhardt William , Hill K. Lloyd , Short Riley , Hubal Elaine , Reich Brian J , Yang Shu , Sheng Alvin , Rappold Ana G. 
Published: February 2024

AbstractBackgroundPer- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants with emerging environmental and regulatory concerns.ObjectivesThis study aimed to estimate the burden of PFAS exposures through ground water on the incidence of chronic health conditions among Medicare beneficiaries aged 65 years and older.MethodsWe estimated PFAS groundwater concentrations for every ZIP code tabulated area (ZCTA) in California counties where 25 percent or more of the population’s drinking water was derived from groundwater. We calculated the annual incidence of non-cancer chronic health conditions among 1,696,247 Medicare beneficiaries aged 65 and older by residential ZCTA over the seven-year study period (2011-2017). A Poisson regression model was used to estimate associations between PFAS groundwater concentration and chronic condition incidence with an offset for the number of beneficiary-years at risk and adjusting for bias due to non-random sampling of wells, use of groundwater for drinking water, demographic characteristics, and lung cancer incidence as a control for smoking.ResultsResults suggest an association between a 10 ng/L increment in PFAS contaminated groundwater and chronic health conditions including hypertension (+1.15%, 95% confidence interval (CI) 1.01, 1.30), chronic kidney disease (+0.83%, 95% CI 0.68, 0.99) and cataracts (+1.50%, 95% CI 1.35, 1.66).DiscussionThis small increment in the incidence rate would produce an additional 1,700 new cases of hypertension each year in the study population.
Deep Learning Model Using Continuous Skin Temperature Data Predicts Labor Onset
Authors: Basavaraj Chinmai , Grant Azure D. , Aras Shravan G. , Erickson Elise N. 
Published: February 2024

AbstractBackgroundChanges in body temperature anticipate labor onset in numerous mammals, yet this concept has not been explored in humans.MethodsWe evaluated patterns in continuous skin temperature data in 91 pregnant women using a wearable smart ring. Additionally, we collected daily steroid hormone samples leading up to labor in a subset of 28 pregnancies and analyzed relationships among hormones and body temperature trajectory. Finally, we developed a novel autoencoder long-short-term-memory (AE-LSTM) deep learning model to provide a daily estimation of days until labor onset.ResultsFeatures of temperature change leading up to labor were associated with urinary hormones and labor type. Spontaneous labors exhibited greater estriol to α-pregnanediol ratio, as well as lower body temperature and more stable circadian rhythms compared to pregnancies that did not undergo spontaneous labor. Skin temperature data from 54 pregnancies that underwent spontaneous labor between 34 and 42 weeks of gestation were included in training the AE-LSTM model, and an additional 40 pregnancies that underwent artificial induction of labor or Cesarean without labor were used for further testing. The model was trained only on aggregate 5-minute skin temperature data starting at a gestational age of 240 until labor onset. During cross-validation AE-LSTM average error (true – predicted) dropped below 2 days at 8 days before labor, independent of gestational age. Labor onset windows were calculated from the AE-LSTM output using a probabilistic distribution of model error. For these windows AE-LSTM correctly predicted labor start for 79% of the spontaneous labors within a 4.6-day window at 7 days before true labor, and 7.4-day window at 10 days before true labor.ConclusionContinuous skin temperature reflects progression toward labor and hormonal status during pregnancy. Deep learning using continuous temperature may provide clinically valuable tools for pregnancy care.
Resilliance Among Turkish Adolescents: A Multi-Level Approach
Authors: Çakir Gökhan , Işik Utku , Ustun Umit Dogan , Su Nihan , Gumusgul Osman 
Published: February 2024

AbstractIntroductionThe objective of this study is to determine the components that contribute to psychological resilience in adolescents and to determine if physical exercise, emotion control, or self-efficacy are more effective predictors of resilience.MethodsData from participants was collected through a personal information form, the International Physical Activity Questionnaire—Short Form, the Self-Efficacy Scale for Children, the Emotion Regulation Scale for Children and Adolescents, and the Psychological Resilience Scale for Children and Adolescents. The data were gathered online from 16 out of the 81 provinces in Turkey, representing 7 different regions, using convenience sampling. The study sample comprised 505 adolescents, with 309 females and 196 males. The average age of the participants was 15.66 years, with a standard deviation of 1.34. The data obtained from the students was analyzed using SPSS 27.0 statistical software. The Chi-Square test was employed to establish the correlation between the demographic features of adolescents and their levels of physical activity. The relationship between the independent variables and the dependent variable was determined using correlation analysis and hierarchical regression analysis.ResultsThe results suggest that physical exercise, the ability to regulate emotions through reappraisal, and self-efficacy are significant indicators of adolescents’ resilience.ConclusionsThe research conclusions point out that self-efficacy has a greater impact on psychological resilience compared to physical activity and emotion regulation.
Clinical Pattern and Outcome of Patients with Acute Kidney Injury in the Emergency Department of Saint Paul’s Hospital Millennium Medical College
Authors: Assefa Berihu , Gebremedhin Yemane , Bahta Benyam , Worku Frehiwot , Mamo Dirijit , Sultan Menbeu , Kalifa Mohammed 
Published: February 2024

AbstractBackgroundWorldwide, 13.3 million people experience Acute Kidney Injury (AKI) each year. 85% of individuals impacted are thought to reside in underdeveloped nations. AKI continues to be one of the most widespread diseases in the world, although little is known about its clinical profile or outcome. The ability to pinpoint particular causes enables the implementation of targeted therapy and the development of preventative measures.The main goal of this study was to identify the patterns and outcomes of patients with AKI in the emergency department of Saint Paul’s Hospital Millennium Medical College (SPHMMC).Method and materialsA cross-sectional study was conducted at the emergency department of SPHMMC in Addis Ababa, Ethiopia, from June 1-2021 to June 1-2022. Google Forms was used to collect the data, which was then cleaned up in Microsoft Excel before being sent to SPSS version 25 for analysis. To evaluate demographic, clinical profile, and outcome determinants, descriptive statistics, and binary logistic regression analysis were utilized. A paired samples T-test was used to compare the patient’s laboratory findings at admission and discharge.ResultsAmong the 222 AKI patients included in the study 110 (49.5%) were males and 112 (50.5%) were females. The mean age of presentation was 48+18 years old. The majority of patients were from Addis Ababa (41.4%) and the Oromia region (40.5%). The most common causes of AKI were infections (26.2%), acute glomerulonephritis (20.4%), volume depletion (18.5%), and obstructive uropathy (16.6%). Uremic encephalopathy, infection, malignancy, potassium at discharge from emergency, and low initial Glasgow coma scale (GCS) significantly contributed to the death. The presence of nephrotoxic antibiotics, infection, and hyponatremia significantly contributed to the admission rate to the wards and intensive care unit (ICU).ConclusionIn conclusion, infection is the dominant cause and mortality predictor of AKI at SPHMMC. The majority of patients with infections were sepsis (78.1%), pyelonephritis (11.4%), and pneumonia (10.3%). Early initiation of antibiotics in the emergency is better for a good outcome.
Structural analysis and conformational dynamics of a holo-adhesion GPCR reveal interplay between extracellular and transmembrane domains
Authors: Kordon Szymon P. , Cechova Kristina , Bandekar Sumit J. , Leon Katherine , Dutka Przemysław , Siffer Gracie , Kossiakoff Anthony A. , Vafabakhsh Reza , Araç Demet 
Published: February 2024

ABSTRACTAdhesion G Protein-Coupled Receptors (aGPCRs) are key cell-adhesion molecules involved in numerous physiological functions. aGPCRs have large multi-domain extracellular regions (ECR) containing a conserved GAIN domain that precedes their seven-pass transmembrane domain (7TM). Ligand binding and mechanical force applied on the ECR regulate receptor function. However, how the ECR communicates with the 7TM remains elusive, because the relative orientation and dynamics of the ECR and 7TM within a holoreceptor is unclear. Here, we describe the cryo-EM reconstruction of an aGPCR, Latrophilin3/ADGRL3, and reveal that the GAIN domain adopts a parallel orientation to the membrane and has constrained movement. Single-molecule FRET experiments unveil three slow-exchanging FRET states of the ECR relative to the 7TM within the holoreceptor. GAIN-targeted antibodies, and cancer-associated mutations at the GAIN-7TM interface, alter FRET states, cryo-EM conformations, and receptor signaling. Altogether, this data demonstrates conformational and functional coupling between the ECR and 7TM, suggesting an ECR-mediated mechanism of aGPCR activation.