bluuebunny/crossref_metadata_2025_split huggingface dataset:
E2EGraph: An End-to-end Graph Learning Model for Interpretable Prediction of Pathlogical Stages in Prostate Cancer
Authors: Zhan Wenkang , Song Chen , Das Supratim , Rebbeck Timothy R. , Shi Xinghua 
Published: March 2023

AbstractProstate cancer is one of the deadliest cancers worldwide. An accurate prediction of pathological stages using the expressions and interactions of genes is effective for clinical assessment and treatment. However, identification of interactions using biological procedure is time consuming and prohibitively expensive. A graph is a powerful representation for the complex interactome of genes, their transcripts, and proteins. Recently, Graph Neural Networks (GNNs) have gained great attention in machine learning due to their capability to capture the graphical interactions among data entities. To leverage GNNs for predicting pathological stage stages, we developed an end-to-end graph representation and learning model, namely E2EGraph, which can automatically generate a graph representation using gene expression data and a multi-head graph attention network to learn the strength of interactions among genes and make the prediction. To ensure the reliability of model prediction, we identify critical components of graph representation and GNN model to interpret prediction results from multiple perspectives at gene and patient levels. We evaluated E2EGraph to predict pathological stages of prostate cancer using The Cancer Genome Atlas (TCGA) data. Our experimental results demonstrate that E2EGraph reaches the state-of-art prediction performance while being effective in identifying marker genes indicated by interpretability. Our results point to a direction where adaptive graph construction and attention based GNNs can be leveraged for various prediction tasks and interpretation of model prediction in a variety of data domains including disease prediction.
Optical coherence tomography of human fetal membrane sub-layers during dynamic loading
Authors: Samimi Kayvan , Contreras Guzman Emmanuel , Wu May , Carlson Lindsey , Feltovich Helen , Hall Timothy J. , Myers Kristin M. , Oyen Michelle L. , Skala Melissa C. 
Published: March 2023

AbstractFetal membranes have important mechanical and antimicrobial roles in maintaining pregnancy. However, the small thickness (<800 μm) of fetal membranes places them outside the resolution limits of most ultrasound and magnetic resonance systems. Optical imaging methods like optical coherence tomography (OCT) have the potential to fill this resolution gap. Here, OCT and machine learning methods were developed to characterize theex vivoproperties of human fetal membranes under dynamic loading. A saline inflation test was incorporated into an OCT system, and tests were performed on n=33 and n=32 human samples obtained from labored and C-section donors, respectively. Fetal membranes were collected in near-cervical and near-placental locations. Histology, endogenous two photon fluorescence microscopy, and second harmonic generation microscopy were used to identify sources of contrast in OCT images of fetal membranes. A convolutional neural network was trained to automatically segment fetal membrane sub-layers with high accuracy (Dice coefficients >0.8). Intact amniochorion bilayer and separated amnion and chorion were individually loaded, and the amnion layer was identified as the load-bearing layer within intact fetal membranes for both labored and C-section samples, consistent with prior work. Additionally, the rupture pressure and thickness of the amniochorion bilayer from the near-placental region were greater than those of the near-cervical region for labored samples. This location-dependent change in fetal membrane thickness was not attributable to the load-bearing amnion layer. Finally, the initial phase of the loading curve indicates that amniochorion bilayer from the near-cervical region is strain-hardened compared to the near-placental region in labored samples. Overall, these studies fill a gap in our understanding of the structural and mechanical properties of human fetal membranes at high resolution under dynamic loading events.
Novel hydroxamic acid derivative induces apoptosis and constrains autophagy in leukemic cells
Authors: Fischer Marten A. , Mustafa Al-Hassan M. , Hausmann Kristin , Ashry Ramy , Kansy Anita G. , Liebl Magdalena C. , Brachetti Christina , Piée-Staffa Andrea , Zessin Matthes , Ibrahim Hany S. , Hofmann Thomas G. , Schutkowski Mike , Sippl Wolfgang , Krämer Oliver H. 
Published: March 2023

AbstractIntroductionPosttranslational modification of proteins by reversible acetylation regulates key biological processes. Histone deacetylases (HDACs) catalyze protein deacetylation and are frequently dysregulated in tumors. This has spurred the development of HDAC inhibitors (HDACi). Such epigenetic drugs modulate protein acetylation, eliminate tumor cells, and are approved for the treatment of blood cancers.ObjectivesWe aimed to identify novel, nanomolar HDACi with increased potency over existing agents and selectivity for the cancer-relevant class I HDACs (HDAC1/-2/-3/-8). Moreover, we wanted to define how such drugs control the apoptosis-autophagy interplay. As test systems, we used human leukemic cells and embryonic kidney-derived cells.MethodsWe synthesized novel pyrimidine-hydroxamic acid HDACi (KH9/KH16/KH29) and performed in vitro activity assays and molecular modeling of their direct binding to HDACs. We analyzed how these HDACi affect leukemic cell fate, acetylation, and protein expression with flow cytometry and immunoblot. The publicly available DepMap database of CRISPR-Cas9 screenings was used to determine sensitivity factors across human leukemic cells.ResultsNovel HDACi show nanomolar activity against class I HDACs. These agents are superior to the clinically used hydroxamic acid HDACi vorinostat. Within the KH-series of compounds, KH16 (yanostat) is the most effective inhibitor of HDAC3 (IC50= 6 nM) and the most potent inducer of apoptosis (IC50= 110 nM; p<0.0001) in leukemic cells. KH16 though spares embryonic kidney-derived cells. Global data analyses of knockout screenings verify that HDAC3 is a dependency factor in human blood cancer cells of different lineages, independent of mutations in the tumor suppressor p53. KH16 alters pro- and anti-apoptotic protein expression, stalls cell cycle progression, and induces a caspase-dependent processing of the autophagy proteins ULK1 and p62.ConclusionThese data reveal that HDACs are required to stabilize autophagy proteins through a suppression of apoptosis in leukemic cells. HDAC3 appears as a valid anti-cancer target for pharmacological intervention.HighlightsNovel HDACi with nanomolar activity against leukemic cells were synthesized.HDACi of the KH-series are superior to a clinical grade HDACi.HDACi of the KH-series modulate acetylation and phosphorylation of proteins.The new HDACi KH16 regulates cell cycle arrest, apoptosis, and autophagy.Apoptosis acts upstream of autophagy in KH16-treated cells.
Characterization of a mouse model of ICF syndrome reveals enhanced CD19 activation in inducing hypogammaglobulinemia
Authors: Ying Zhengzhou , Hardikar Swanand , Plummer Joshua B. , Hamidi Tewfik , Liu Bin , Chen Yueping , Shen Jianjun , Mu Yunxiang , McBride Kevin M. , Chen Taiping 
Published: March 2023

ABSTRACTImmunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency. It is caused by mutations inDNMT3B, ZBTB24, CDCA7orHELLS. While progress has been made in elucidating the roles of these genes in regulating DNA methylation, little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype. Here we show that mice deficient forZbtb24in the hematopoietic lineage recapitulate major clinical features of patients with ICF syndrome. Specifically, Vav-Cre-mediated ablation ofZbtb24does not affect lymphocyte development but results in reduced plasma cells and low levels of IgM, IgG1 and IgA.Zbtb24-deficient mice are hyper- and hypo-responsive to T-dependent and Tindependent type 2 antigens, respectively, and marginal zone B cell activation is impaired. B cells fromZbtb24-deficient mice display elevated CD19 phosphorylation. Heterozygous disruption ofCd19can revert the hypogammaglobulinemia phenotype in these mice. Mechanistically,Il5ra(interleukin-5 receptor subunit alpha) is derepressed inZbtb24-deficient B cells, and elevated IL-5 signaling enhances CD19 phosphorylation. Our results reveal a novel link between IL-5 signaling and CD19 activation and suggest that abnormal CD19 activity contributes to immunodeficiency in ICF syndrome.SIGNIFICANCE STATEMENTICF syndrome is a rare immunodeficiency disorder first reported in the 1970s. The lack of appropriate animal models has hindered the investigation of the pathogenesis of antibody deficiency, the major cause of death in ICF syndrome. Here we show that, in mice, disruption ofZbtb24, one of the ICF-related genes, in the hematopoietic lineage results in low levels of immunoglobulins. Characterization of these mice reveals abnormal B cell activation due to elevated CD19 phosphorylation. Mechanistically,Il5ra(interleukin-5 receptor subunit alpha) is derepressed inZbtb24-deficient B cells, and increased IL-5 signaling enhances CD19 phosphorylation.
What can we learn when fitting a simple telegraph model to a complex gene expression model?
Authors: Jiao Feng , Li Jing , Liu Ting , Zhu Yifeng , Che Wenhao , Bleris Leonidas , Jia Chen 
Published: March 2023

AbstractIn experiments, the distributions of mRNA or protein numbers in single cells are often fitted to the random telegraph model which includes synthesis and decay of mRNA or protein, and switching of the gene between active and inactive states. While commonly used, this model does not describe how fluctuations are influenced by crucial biological mechanisms such as feedback regulation, non-exponential gene inactivation durations, and multiple gene activation pathways. Here we investigate the dynamical properties of four relatively complex gene expression models by fitting their steady-state mRNA or protein number distributions to the simple telegraph model. We show that despite the underlying complex biological mechanisms, the telegraph model with three effective parameters can accurately capture the steady-state gene product distributions, as well as the conditional distributions in the active gene state, of the complex models. Some effective parameters are reliable and can reflect realistic dynamic behaviors of the complex models, while others may deviate significantly from their real values in the complex models. The effective parameters can also be applied to characterize the capability for a complex model to exhibit multimodality. Using additional information such as single-cell data at multiple time points, we provide an effective method of distinguishing the complex models from the telegraph model. Furthermore, using measurements under varying experimental conditions, we show that fitting the mRNA or protein number distributions to the telegraph model may even reveal the underlying gene regulation mechanisms of the complex models. The effectiveness of these methods is confirmed by analysis of single-cell data forE. coliand mammalian cells. All these results are robust with respect to cooperative transcriptional regulation and extrinsic noise. In particular, we find that faster relaxation speed to the steady state results in more precise parameter inference under large extrinsic noise.
Iohexol-measured glomerular filtration rate and urinary biomarker changes between vancomycin and vancomycin plus piperacillin-tazobactam in a translational rat model
Authors: Chang Jack , Pais Gwendolyn M. , Marianski Sylwia , Valdez Kimberly , Lesnicki Emily , Barreto Erin F. , Rhodes Nathaniel J. , Yarnold Paul R. , Scheetz Marc H. 
Published: March 2023

AbstractRecent clinical studies have reported additive nephrotoxicity with the combination of vancomycin and piperacillin-tazobactam. However, preclinical models have failed to replicate this finding. This study assessed differences in iohexol-measured glomerular filtration rate (GFR) and urinary injury biomarkers among rats receiving this antibiotic combination.Male Sprague-Dawley rats received either intravenous vancomycin, intraperitoneal piperacillin-tazobactam, or both for 96 hours. Iohexol-measured GFR was used to quantify real-time kidney function changes. Kidney injury was evaluated via the urinary biomarkers: kidney injury molecule-1 (KIM-1), clusterin, and osteopontin.Compared to the control, rats that received vancomycin had numerically lower GFR after drug dosing on day 3. Rats in this group also had elevations in urinary KIM-1 on experimental days 2 and 4. Increasing urinary KIM-1 was found to correlate with decreasing GFR on experimental days 1 and 3. Rats that received vancomycin+piperacillin-tazobactam did not exhibit worse kidney function or injury biomarkers compared to vancomycin alone.The combination of vancomycin+piperacillin-tazobactam does not cause additive nephrotoxicity in a translational rat model. Future clinical studies investigating this antibiotic combination should employ more sensitive biomarkers of kidney function and injury, similar to those utilized in this study.
Diversity ofCFTRvariants across ancestries characterized using 454,727 UK biobank whole exome sequences
Authors: Ideozu Justin E. , Liu Mengzhen , Riley-Gillis Bridget M. , Paladugu Sri R. , Rahimov Fedik , Krishnan Preethi , Tripathi Rakesh , Dorr Patrick , Levy Hara , Singh Ashvani , Waring Jeffery F. , Vasanthakumar Aparna 
Published: March 2023

AbstractLimited understanding of the diversity ofCFTRvariants across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Characterizing the distribution ofCFTRvariants across ancestries is, therefore, critical for revolutionizing molecular diagnoses of CF. By interrogating 454,727 UK biobank whole exome Sequences, we detected over 4,000CFTRvariants, including novel ancestry-specific variants, across six ancestries. F508del was the most prevalent CF-causing variant found across the ancestries, except in East Asia, where V520F was the most prevalent. Sixteen participants had two CF-causing variants, with two diagnosed as CF. We found 154 participants with a CF-causing and varying clinical consequences (VCC) variant. Overall, participants with multiple clinically relevant variants reported indications significantly associated with CF and its pulmonary phenotypes [Bonferroni adjusted p<0.05]. Potentially, participants with classical CF phenotypes may benefit from current CF therapies.
Analyzing the amplification of touch sense in visually impaired individuals and comparison with normal individuals
Authors: Desai Dev Himanshubhai 
Published: March 2023

AbstractBackgroundIt has been said for ages that if a person loses one of the basic senses like sight or hearing, other senses are amplified to make up for it. This has been substantially proved without a doubt that amplification helps the specially-abled individual in their day-to-day life to an extent. These increases are present but have not been quantified and measured on how much the increases are present.Aim1)To estimate and compare sensitivity of touch between visually impaired and normal people and analyze the amplification if present.MethodologyA Cross-Sectional Case-control Study was carried out. Individuals with 6/6 vision and normal in other senses were first examined with the Static Two-point discrimination test to have a baseline value and then different categories of visually impaired individuals were subjected to this test. The test was carried out on the forehead and fingertips of all subjects. Their results were compared using different statistical tools.ResultsTotal 45 visually impaired individuals with various severity of blindness with 20 Normal individuals taken for the study. Two-point discrimination values for normal individuals (Fingertip=3.43±1.519,Forehead=13.531±2.364), whereas for all and any type of visually impaired individual (fingertip=2.83±0.27,Forehead=13.08±0.26)is statistically(Fingertip, p=0.0101)(Forehead, p=0.4461).R-value for time spent since the disability and degree of amplification is -0.356.ConclusionA significant difference is present between the values of test between visually impaired and normal individuals. Appreciable that with various degrees of blindness, the average values of two-point-discrimination value are different. Totally blind shows the highest sensitivity.
Social Networks and Cardiovascular Disease Events in the Jackson Heart Study
Authors: Glover LáShauntá , Sutton Janiyah , O’Brien Emily , Sims Mario 
Published: March 2023

AbstractBackgroundCardiovascular disease (CVD) disproportionately affects African American adults. Greater social networks (SN), or social connectedness, may lower the risk of CVD events.ObjectiveDetermine the association of SN and incident CVD and test mediation by depressive symptoms, hypertension control and diabetes control.MethodsWe used the Social Network Index (SNI) at exam 1 (2000-2004) to develop a continuous standardized SN score and binary categories (high vs. low) among participants in the Jackson Heart Study (n=5252, mean age=54.8 years). Surveillance of coronary heart disease (CHD), stroke, and heart failure (HF) events occurred after exam 1 (2005 for HF) until 2016. Using Cox proportional hazards regression, we estimated the association of SN and CVD events by sex and tested the mediation of depressive symptoms, hypertension control and diabetes control. Models adjusted for age, education, health behaviors, and CVD co-morbidities.ResultsAmong women, the SN score was associated with a lower risk of CHD and HF after full adjustment (HR 0.78, 95% CI 0.68, 0.89 and HR 0.78, 95% CI 0.63, 0.95, respectively), but the association with stroke attenuated after adjustment for co-morbidities (HR 95% CI 0.88 95% CI 0.67, 1.14). SN scores were also associated with CHD in men (HR 0.84, 95% CI 0.70, 0.99) after full adjustment. High vs. low SN was associated with CHD in men and women, but not after adjustment for co-morbidities. There was no evidence of mediation by depressive symptoms, diabetes control, and hypertension control.ConclusionHigher SN may lower the risk of CVD events, especially in women.
Genetic tracing of the white-bellied pangolin’s trade in western central Africa
Authors: Dipita Alain Din , Missoup Alain Didier , Aguillon Samantha , Lecompte Emilie , Momboua Brice Roxan , Chaber Anne-Lise , Abernethy Katharine , Njiokou Flobert , Tindo Maurice , Ntie Stephan , Gaubert Philippe 
Published: March 2023

AbstractAfrican pangolins are intensively harvested to feed illegal trade networks. We focused on the conservation genetics of the most trafficked African species, the white-bellied pangolin (WBP;Phataginus tricuspis), through the genotyping of 562 individuals from reference populations and urban bushmeat markets in a vibrant trade hub from western Central Africa. Across Cameroon, Equatorial Guinea and northern Gabon, we observed a lack of genetic differentiation and a signature of isolation-by-distance possibly due to unsuspected dispersal capacities involving a Wahlund effect. Despite a higher level of genetic diversity compared to western Africa, we detected a 74-83% decline in the effective population size of WBP during the Middle Holocene. Private allele frequency tracing approach indicated up to 600 km sourcing distance by large urban markets from Cameroon, involving transnational trade activities. The 20 microsatellites markers used in this study provided the necessary power to distinguish among all WBP individuals and should be considered a valuable resource for future forensic applications. Because lineage admixture was detected in the study area, we recommend a multi- locus approach for tracing the WBP trade. The Yaoundé market was a major recruiter of genetic diversity in the region, and should receive urgent conservation action to mitigate the pangolin trade.
Impact of Phosphorylation on the Physiological Form of Human alpha-Synuclein in Aqueous Solution
Authors: de Bruyn Emile , Dorn Anton Emil , Rossetti Giulia , Fernandez Claudio , Outeiro Tiago F. , Schulz Jörg B. , Carloni Paolo 
Published: March 2023

AbstractSerine 129 can be phosphorylated in pathological inclusions formed by the intrinsically disordered protein humanα-synuclein (AS), a key player in Parkinson’s disease and other synucleinopathies. Here, molecular simulations provide insight into the structural ensemble of phosphorylated AS. The simulations suggest that phosphorylation does not impact the structural content of the physiological AS conformational ensemble in aqueous solution, as the phosphate group is mostly solvated. The hydrophobic region of AS containsβ-hairpin structures, which may increase the propensity of the protein to undergo amyloid formation, as seen in the non-physiological (non-acetylated) form of the protein in a recent molecular simulation study. Our findings are consistent with existing experimental data, with the caveat of the observed limitations of the force field for the phosphorylated moiety.Abstract Figure
Optimization of extraction, Structural characterization of immunomodulatory acidic polysaccharide fromEuphorbia caducifolia
Authors: Venumadhav Kusuma , Seshagirirao Kottapalli 
Published: March 2023

AbstractHeating confluence method in combination with response surface methodology (RSM) was performed to optimize polysaccharides extraction fromEuphorbia caducifoliaHaines. The Box-Behnken Design was used to optimize the extraction conditions with three parameters such as temperature (A), Solid to liquid ratio (B), and time (C). The percentage yields obtained were fitted to a 2ndorder polynomial equation using multiple regression analysis. From the regression equation, the optimal polysaccharides extraction parameters for 2.3% of yield are Temperature-120°C, Solid to liquid ratio-75 g/L, and Time-2 h. Further, crude polysaccharide was purified and disclosed GlaUA, Rha, Glc, Gal, Xyl and Ara (1:2.5:4:3.6:3.7:3.3) ratio of poysaccharide. Thermogram of the EC polysaccharide showed typical natural polysaccharide behavior, and hydrophilic nature of polysaccharide attributed to endothermic water loss. Furthermore, purified polysaccharides exhibited strongin vitrofree radical scavenging activities, reducing ability, and immunomodulatory activity by the effective production of pro-inflammatory cytokines with RAW 264.7 cells.
Unusual starch grains from theEuphorbia caducifoliaHaines
Authors: Venumadhav Kusuma , Seshagirirao Kottapalli 
Published: March 2023

AbstractNature has chosen the starch as a universal form for storing carbohydrate. In granule form, it is semi-crystalline, water-insoluble, dense and a ubiquitous constituent. Structure of the starch granules depends on their biological source and varies from part to part of the sources. In sequence to that, starch granules from the latex ofEuphorbia caducifoliawas isolated and characterized under different conditions to reveal its uniqueness in the structure. A flat dumbbell-shaped starch was notified with distinctive “maltese cross” under various microscopes. These starches are found to be high amylose contents, which resist water solubility, swelling index, and turbidity of the starches. X-Ray Diffraction studies states the presence C type pattern of crystallinity whereas typical polysaccharide spectrum was observed with ATR studies. Gelatinization of the starches remarked them as highly thermal stable and retrogradation studies failed to detect realignment of the heat disrupted amylose and amylopectin. Lintnerization of starch granules reveals the high complexity of the structure. Thus, latex starch granules from theE caducifoliaare considered to be unusual because of their highly complex structure, shape and properties.