bluuebunny/crossref_metadata_2025_split huggingface dataset:
Platelet Dependent Thrombogenicity, Inflammation and Five Year Mortality in Patients with Non-ST Elevation Acute Coronary Syndrome and Type 2 Diabetes Mellitus: An Observational Study
Authors: Viswanathan Girish N , Harper Andrew R. , Badimon Juan J , Marshall Sally M , Zaman Azfar G 
Published: March 2022

ABSTRACTPlatelet dependent thrombogenicity is higher in type 2 diabetes mellitus (T2DM) but there is no data on association between thrombus and mortality or vascular inflammation.We studied 80 patients who received guideline based therapy (40 T2DM) after NSTE-ACS. Platelet dependent thrombus was assessed using the validated ex vivo Badimon Chamber and all patients were followed up for five years. Bio-markers of coagulation and inflammation were measured.There were 17 (21.3%) deaths in total (12 in the T2DM, 71% of all deaths), at 5 years. Of the patients who died, thrombus burden was higher (µ2 per mm, Mean ± SD, 12,164 ± 3235 vs 9,751 ± 4333). Serum inflammatory cytokines, P selectin and soluble CD40 ligand were higher in T2DM. Univariate analysis showed thrombus area, diabetic status, age, interleukin 1 and P selectin were independent predictors of mortality. Inflammatory biomarkers were associated with thrombus burden. If these findings can be proven in large scale studies, this will lead on to novel therapeutic strategies especially in the current Covid 19 pandemic which has renewed our interest of this interplay of pathophysiology between thrombus and inflammation.
Prenatal vitamin intake in first month of pregnancy and DNA methylation in cord blood and placenta in two prospective cohorts
Authors: Dou John F. , Middleton Lauren Y.M. , Zhu Yihui , Benke Kelly S. , Feinberg Jason I. , Croen Lisa A. , Hertz-Picciotto Irva , Newschaffer Craig J. , LaSalle Janine M. , Fallin Daniele , Schmidt Rebecca J. , Bakulski Kelly M. 
Published: March 2022

AbstractBackgroundPrenatal vitamin use is recommended before and during pregnancies for normal fetal development. Prenatal vitamins do not have a standard formulation, but many contain calcium, folic acid, iodine, iron, omega-3 fatty acids, zinc, and vitamins A, B6, B12, and D, and usually they contain higher concentrations of folic acid and iron than regular multivitamins in the U.S. Nutrient levels can impact epigenetic factors such as DNA methylation, but relationships between maternal prenatal vitamin use and DNA methylation have been relatively understudied. We examined use of prenatal vitamins in the first month of pregnancy in relation to cord blood and placenta DNA methylation in two prospective pregnancy cohorts: the Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk Learning Early Signs (MARBLES) studies.ResultsIn placenta, prenatal vitamin intake was marginally associated with -0.52% (95% CI: - 1.04, 0.01) lower mean array-wide DNA methylation in EARLI, and associated with -0.60% (−1.08, -0.13) lower mean array-wide DNA methylation in MARBLES. There was little consistency in the associations between prenatal vitamin intake and single DNA methylation site effect estimates across cohorts and tissues, with only a few overlapping sites with correlated effect estimates. However, the single DNA methylation sites with p-value<0.01 (EARLI cord nCpGs=4,068, EARLI placenta nCpGs=3,647, MARBLES cord nCpGs=4,068, MARBLES placenta nCpGs=9,563) were consistently enriched in neuronal developmental pathways.ConclusionsTogether, our findings suggest that prenatal vitamin intake in the first month of pregnancy may be related to lower placental global DNA methylation and related to DNA methylation in brain-related pathways in both placenta and cord blood.
Bladder Cancer Prognosis Using Deep Neural Networks and Histopathology Images
Authors: Barrios Wayner , Abdollahi Behnaz , Goyal Manu , Song Qingyuan , Suriawinata Matthew , Richards Ryland , Ren Bing , Schned Alan , Seigne John , Karagas Margaret , Hassanpour Saeed 
Published: March 2022

AbstractRecent studies indicate bladder cancer is among the top 10 most common cancer in the world [1]. Bladder cancer frequently reoccurs, and prognostic judgments may vary among clinicians. Classification of histopathology slides is essential for accurate prognosis and effective treatment of bladder cancer patients, as a favorable prognosis might help to inform less aggressive treatment plans. Developing automated and accurate histopathology image analysis methods can help pathologists in determining the prognosis of bladder cancer. In this study, we introduced Bladder4Net, a deep learning pipeline to classify whole-slide histopathology images of bladder cancer into two classes: low-risk (combination of PUNLMP and low-grade tumors) and high-risk (combination of high-grade and invasive tumors). This pipeline consists of 4 convolutional neural network (CNN) based classifiers to address the difficulties of identifying PUNLMP and invasive classes. We evaluated our pipeline on 182 independent whole-slide images from the New Hampshire Bladder Cancer Study (NHBCS) [22] [23] [24] collected from 1994 to 2004 and 378 external digitized slides from The Cancer Genome Atlas (TCGA) database [26]. The weighted average F1-score of our approach was 0.91 (95% confidence interval (CI): 0.86–0.94) on the NHBCS dataset and 0.99 (95% CI: 0.97–1.00) on the TCGA dataset. Additionally, we computed Kaplan-Meier survival curves for patients predicted as high-risk versus those predicted as low-risk. For the NHBCS test set, patients predicted as high-risk had worse overall survival than those predicted as low-risk, with a Log-rank P-value of 0.004. If validated through prospective trials, our model could be used in clinical settings to improve patient care.
Two new Rhizobiales species isolated from root nodules of common sainfoin (Onobrychis viciifolia) show different plant colonization strategies
Authors: Ashrafi Samad , Kuzmanović Nemanja , Patz Sascha , Lohwasser Ulrike , Bunk Boyke , Spröer Cathrin , Lorenz Maria , Frühling Anja , Neumann-Schaal Meina , Verbarg Susanne , Becker Matthias , Thünen Torsten 
Published: March 2022

AbstractRoot nodules of legume plants are primarily inhabited by rhizobial nitrogen-fixing bacteria. Here we propose two new Rhizobiales species isolated from root nodules of common sainfoin (Onobrychis viciifolia), as shown by core-gene phylogeny, overall genome relatedness indices and pan-genome analysis.Mesorhizobium onobrychidis sp. nov., actively induces nodules, and achieves atmospheric nitrogen and carbon dioxide fixation. This species appears to be depleted in motility genes, and is enriched in genes for direct effects on plant growth performance. Its genome reveals functional and plant growth-promoting signatures like a large unique chromosomal genomic island with high density of symbiotic genetic traits. Onobrychidicola muellerharveyae gen. nov. sp. nov., is described as type species of the new genus Onobrychidicola in Rhizobiaceae. This species comprises unique genetic features and plant growth-promoting traits (PGPTs), which strongly indicate its function in biotic stress reduction and motility. We applied a newly developed bioinformatics approach for in silico prediction of PGPTs (PGPT-Pred), which supports the different lifestyles of the two new species and the plant growth-promoting performance of M. onobrychidis in the greenhouse trial.
Q3: An ICU Acuity Score for Exploring the Effects of Changing Acuity Throughout the Stay
Authors: Brossette Stephen E. , Zheng Ning , Wong Daisy Y. , Hymel Patrick A. 
Published: March 2022

AbstractIntroWe develop a straightforward ICU acuity score (Q3) that is calculated every 3 hours throughout the first 10 days of the ICU stay. Q3 uses components of the Oxford Acute Severity of Illness Score (OASIS) and incorporates a new component score for vasopressor use. In well-behaved models of ICU mortality, the marginal effects of Q3 are significant across the first 10 days of the ICU stay. In separate models, Q3 has significant effects on ICU remaining length of stay. The score has implications for work that seeks to explain modifiable mechanisms of changing acuity during the ICU stay.MethodsFrom the MIMIC-III database, select ICU stays from 5 adult ICUs were partitioned into consecutive 3-hour segments. For each segment, the number of vasopressors administered and all 10 OASIS component scores were computed. Models of ICU mortality were estimated. OASIS component effects were examined, and vasopressor count bins were weighted. Q3 was defined as the sum of 8 retained OASIS components and a new weighted vasopressor score. Models of ICU mortality quadratic in Q3 were estimated for each of the first 10 ICU days and were subjected to segment-level, location-specific tests of discrimination and calibration on newer ICU stays. Marginal effects of Q3 were computed at different levels of Q3 by ICU day, and average marginal effects of Q3 were computed at each location by ICU day. ICU remaining length of stay (LOS) models were also estimated and the effects of Q3 were similarly examined.ResultsDaily ICU mortality models using Q3 show no evidence of misspecification (Pearson-Windmeijer p>0.05, Stukel p>0.05), discriminate well in all ICUs over the first 10 days (AUROC ∼ 0.72 – 0.85), and are generally well calibrated (Hosemer-Lemeshow p>0.05, Spiegelhalter’s z p>0.05). A one-unit increase in Q3 from typical levels (Q3=15) affects the odds of ICU mortality by a factor of 1.14 to 1.20, depending on ICU day (p<0.001), and the ICU remaining LOS by 5.8 to 9.6% (p<0.001). On average, a one-unit increase in Q3 increases the probability of ICU mortality by 1 to 2 percentage points depending on location and ICU day, and ICU remaining LOS by 5 to 10 hours depending on location and ICU day.ConclusionQ3 significantly affects ICU mortality and ICU remaining LOS in different ICUs across the first 10 days of the ICU stay. Depending on location and ICU day, a one-unit increase in Q3 increases the probability of ICU mortality by or 1-2 percentage points and ICU remaining LOS by 5 to 10 hours. Unlike static acuity scores or those updated infrequently, Q3 could be used in explanatory models to help elucidate mechanisms of changing ICU acuity.
Genetic heritage of the BaPhuthi highlights an over ethnicised notion of ‘Bushman’ in the Maloti-Drakensberg, Southern Africa
Authors: Daniels Ryan Joseph , D’Amato Maria Eugenia , Lesaoana Mpasi , Kasu Mohaimin , Ehlers Karen , Chauke Paballo Abel , Lecheko Puseletso , Challis Sam , Rockett Kirk , Montinaro Francesco , González-Santos Miguel , Capelli Cristian 
Published: March 2022

AbstractUsing contemporary people as proxies for ancient communities is a contentious but necessary practice in anthropology. In Southern Africa, the distinction between the Cape KhoeSan and eastern KhoeSan remains unclear as ethnicity labels are continually changed through time and most communities were extirpated. The eastern KhoeSan may reflect an ‘essentialistic’ biological distinction from neighbouring Bantu-speaking communities or it may not be tied to ‘race’ and instead denote communities with a nomadic ‘life-way’ distinct from agro-pastoralism. The BaPhuthi of the 1800s in the Maloti-Drakensberg, Southern Africa had a substantial San constituency and a life-way of nomadism, cattle raiding, and horticulture. The BaPhuthi heritage could provide insights into the history of the eastern KhoeSan. We examine for the first time genetic affinities of 23 BaPhuthi to distinguish if KhoeSan ancestry reflects biologically distinct heritage or a shared life-way. Data were merged with 52 global populations. The Principle Component Analysis, ADMIXTURE clustering and F3 tests show no support for a unique eastern KhoeSan ancestry distinct from other KhoeSan or southern Bantu-speaking communities. The BaPhuthi have strong affinities with Nguni communities, as the non-Nguni show strong evidence of recent African admixture possibly related to late-iron age migrations. The BaPhuthi may have an interesting connection to the early iron-age Bantu-speaking communities as MALDER detected no signals for late-iron age admixture. We demonstrate how the ‘essentialistic’ understanding of references in historic literature creates misconstrued notions of ethnic/biological distinctions when ‘San’ and ‘Bushman’ may have reflected ambiguous references to the non-sedentary polities and practices.
Defining Factors that Influence vaccine-induced, cross-variant neutralizing antibodies for SARS-CoV-2 in Asians
Authors: Gu Yue , Shunmuganathan Bhuvaneshwari D/O , Qian Xinlei , Gupta Rashi , Tan Rebecca S.W. , Kozma Mary , Purushotorman Kiren , Murali Tanusya M. , Tan Nikki Y.J. , Preiser Peter R. , Lescar Julien , Nasir Haziq , Somani Jyoti , Tambyah Paul A. ,   SCOPE Cohort Study Group, Smith Kenneth G.C. , Renia Laurent , Ng Lisa F.P. , Lye David C. , Young Barnaby E. , MacAry Paul A. 
Published: March 2022

SummaryThe scale and duration of neutralizing antibody responses targeting SARS-CoV-2 viral variants represents a critically important serological parameter that predicts protective immunity for COVID-19. In this study, we present longitudinal data illustrating the impact of age, sex and comorbidities on the kinetics and strength of vaccine-induced neutralizing antibody responses for key variants in an Asian volunteer cohort. We demonstrate a reduction in neutralizing antibody titres across all groups six months post-vaccination and show a marked reduction in the serological binding and neutralizing response targeting Omicron compared to other viral variants. We also highlight the increase in cross-protective neutralizing antibody responses against Omicron induced by a third dose (booster) of vaccine. These data illustrate how key virological factors such as immune escape mutation combined with host factors such as age and sex of the vaccinated individuals influence the strength and duration of cross-protective serological immunity for COVID-19.
Yeast galactokinase in closed conformation can switch between catalytic and signal transducer states
Authors: Giri Nandinee , Bhat Paike Jayadeva 
Published: March 2022

AbstractS.cerevisiae galactokinase (ScGal1p), in closed conformation catalyzes the phosphorylation of galactose to galactose 1-phopshate using ATP as the phosphate donor as well as allosterically activates the GAL genetic switch in response to galactose and ATP as ligands. How both kinase and signaling activities of ScGal1p are associated with closed conformation of the protein is not understood. Conformational sampling of ScGal1p indicated that this protein samples closed kinase and closed non-kinase conformers. Closed non-kinase conformers are catalytically incompetent to phosphorylate galactose and act as a bonafide signal transducer. It was observed that toggling of side chain of highly conserved K266 of ScGal1p between S171and catalytic base D217 is responsible for transitioning of ScGal1p between signal transducer and kinase states. Interestingly in ScGal3p, the paralog of ScGal1p, which has only signal transduction activity and lacks kinase activity, a H bond between a non-conserved Y433, and a highly conserved Y57, gets broken during MD simulation. The corresponding H-bond present in ScGal1p between residues Y441 and Y63 respectively, remains intact throughout the simulations of ScGal1p.Therefore, we predicted that K266 and Y441 have a role in bifunctionality of ScGal1p. To test the above predictions, we monitored the signaling and kinase activity of ScGal1K266Rp and ScGal1Y441Ap variants. Signaling activity increased in both ScGal1Y441Ap and ScGal1K266Rp variants as compared to ScGal1wtp, whereas the kinase activity increased in ScGal1Y441Ap, but decreased in ScGal1K266Rp Based on the above, we propose that K266 and Y441 are crucial for conferring bifunctionality to ScGal1p.Author summaryGalactokinase of S.cerevisiae(ScGal1p), the first enzyme of Leloir pathway of galactose metabolism, phosphorylates galactose using ATP as the phosphate donor. ScGal1p also functions as a signal transducer of GAL regulon wherein galactose and ATP allosterically activate galactokinase. The active form of galactokinase, then sequesters the repressor ScGal80p, to activate the GAL switch. ScGal1p has a single site each for binding to galactose and ATP. How ScGal1p, a monomeric protein, performs the above two mutually exclusive activities using the same set of substrates/ligands, with the same site acting as the active site for enzymatic activity as well as allosteric site for signal transduction activity is unclear. Our findings are that this protein has a distinct conformational state for functioning as a signal transducer and a distinct conformational state for functioning as a kinase. A highly conserved lysine residue (K266) present only in fungal galactokinases, triggers the interconversion between catalysis and signal transduction states. This interconversion is subdued by H bond between Y441 and Y63. These studies suggest that the two activities of ScGal1p are fine tuned by evolution to regulate metabolism through transcriptional control.
A simple geometrical model of the electrostatic environment around the catalytic center of the ribosome
Authors: Joiret Marc , Rapino Francesca , Close Pierre , Geris Liesbet 
Published: March 2022

AbstractThe central function of the large subunit of the ribosome is to catalyze peptide bond formation. This biochemical reaction is conducted at the peptidyl transferase center (PTC). Experimental evidence shows that the catalytic activity is affected by the electrostatic environment around the peptidyl transferase center. The electrostatic field originates from the particular 3-dimensional space distribution in the phosphate moieties of the 23S (archea and bacteria) or 28S (eukarya) rRNA of the large ribosomal subunit as well as the funnel shape of the cavity at its connection with the ribosome exit tunnel. Here, we set up a minimal geometrical model fitting the available x-ray solved structure of the ribonucleoproteic cavity around the catalytic center of the large subunit of the ribosome. The purpose of this phenomenological model is to estimate quantitatively the electrostatic potential and electric field that are experienced during the peptidyl transfer reaction. At least two reasons motivate the need for developing this quantification. First, we inquire whether the electric field in this particular catalytic environment, made only of nucleic acids, is of the same order of magnitude as the one prevailing in catalytic centers of the proteic enzymes counterparts. Second, the protein synthesis rate is dependent on the nature of the amino acid sequentially incorporated in the nascent chain. The activation energy of the catalytic reaction and its detailed kinetics are expected to be dependent on the mechanical work exerted on the amino acids by the electric field, especially when one of the four charged amino acid residues (R, K, E, D) is newly incorporated in the nascent chain. Physical values of the electric field will provide quantitative knowledge of mechanical work, activation energy and kinetics of the peptide bond formation catalysed by the ribosome.
An affinity-matured DLL4 ligand for broad-spectrum activation and inhibition of Notch signaling
Authors: Gonzalez-Perez David , Das Satyajit , Medina Elliot , Antfolk Daniel , Egan Emily D. , Blacklow Stephen C. , Rodriguez Paulo C. , Luca Vincent C. 
Published: March 2022

ABSTRACTThe Notch pathway regulates cell fate decisions and is an emerging target for regenerative and cancer therapies. Recombinant Notch ligands are attractive candidates for modulating Notch signaling; however, their intrinsically low receptor-binding affinity restricts their utility in biomedical applications. To overcome this limitation, we evolved variants of the ligand Delta-like 4 (DLL4) with enhanced affinity and cross-reactivity. A consensus variant with maximized binding affinity, DeltaMAX, engages human and murine Notch receptors with 500- to 1000-fold increased affinity compared to wild-type human DLL4. DeltaMAX also potently activates human Notch in plate-bound, bead-bound, and cellular formats. When administered as a soluble decoy, DeltaMAX inhibits Notch activation in response to either Delta-like (DLL) or Jagged (Jag) ligands, highlighting its utility as both an agonist and antagonist. Finally, we demonstrate that DeltaMAX stimulates increased proliferation and expression of effector mediators in primary activated human T cells. Taken together, our data defines DeltaMAX as a versatile biotechnological tool for broad-spectrum activation or inhibition of Notch signaling.
Differential DNA methylation in Pacific oyster reproductive tissue in response to ocean acidification
Authors: Venkataraman Yaamini R. , White Samuel J. , Roberts Steven B. 
Published: March 2022

AbstractBackgroundThere is a need to investigate mechanisms of phenotypic plasticity in marine invertebrates as negative effects of climate change, like ocean acidification, are experienced by coastal ecosystems. Environmentally-induced changes to the methylome may regulate gene expression, but methylome responses can be species- and tissue-specific. Tissue-specificity has implications for gonad tissue, as gonad-specific methylation patterns may be inherited by offspring. We used the Pacific oyster (Crassostrea gigas) — a model for understanding pH impacts on bivalve molecular physiology due to its genomic resources and importance in global aquaculture— to assess how low pH could impact the gonad methylome. Oysters were exposed to either low pH (7.31 ± 0.02) or ambient pH (7.82 ± 0.02) conditions for seven weeks. Whole genome bisulfite sequencing was used to identify methylated regions in female oyster gonad samples. C->T single nucleotide polymorphisms were identified and removed to ensure accurate methylation characterization.ResultsAnalysis of gonad methylomes revealed a total of 1,284 differentially methylated loci (DML) found primarily in genes, with several genes containing multiple DML. Gene ontologies for genes containing DML were involved in development and stress response, suggesting methylation may promote gonad growth homeostasis in low pH conditions. Additionally, several of these genes were associated with cytoskeletal structure regulation, metabolism, and protein ubiquitination — commonly-observed responses to ocean acidification. Comparison of these DML with other Crassostrea spp. exposed to ocean acidification demonstrates that similar pathways, but not identical genes, are impacted by methylation.ConclusionsOur work suggests DNA methylation may have a regulatory role in gonad and larval development, which would shape adult and offspring responses to low pH stress. Combined with existing molluscan methylome research, our work further supports the need for tissue- and species-specific studies to understand the potential regulatory role of DNA methylation.