bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determinants of Developmental Milestones in Infants and Young Children in Bihar, India
Authors: Larson Leila , Mehta Rukshan , Kekre Priya , Verma Pankaj , Young Melissa , Girard Amy Webb , Ramakrishnan Usha , Chaudhuri Indrajit , Srikantiah Sridhar , Martorell Reynaldo 
Published: November 2023

Approximately 200 million children globally fail to fulfill their developmental potential. Children in Bihar, India may be at particularly high risk as the extensive malnutrition in the region could have important implications for brain development. The objectives of this study are to use baseline data from an ongoing cluster randomized effectiveness trial of home fortification with micronutrient powders in Bihar to 1) validate a modified version of the Developmental Milestones Checklist II (DMC‐II) and 2) determine nutritional and socioeconomic risk factors for mental and motor development of infants and young children.Cross‐sectional data from 4360 children 6–18 months of age living in West Champaran district of Bihar, India, were used to determine the predictive validity of the modified DMC‐II by comparing scores by age, nutritional status, and maternal education. Multivariate regression was used to examine determinants of child development score.The mean score on the modified DMC‐II was 40.9 (95%CI 40.6, 41.3) out of 82.0. The overall score and scores for each subscale (motor, language, personal‐social, and cognitive) were significantly associated with child age and maternal education. After adjustment for age, overall and all subscale scores were each significantly associated with height‐for‐age, weight‐for‐age, and weight‐for‐height z‐scores. A multivariate linear model for the child's overall modified DMC‐II scores (R2=0.60) revealed significant associations (P<0.05) with age (coefficient (SE): 2.49 (0.05)), gender (−0.84 (0.28)), height‐for‐age z‐score (0.57 (0.15)) weight‐for‐age z‐score (1.10 (0.17)), dietary diversity score (1.00 (0.14)), timely initiation of complementary foods (1.00 (0.29)), no use of prelacteal feeds (0.67 (0.29)), Family Care Indicators or home stimulation (0.56 (0.04)), and maternal education (0.97 (0.30)). Recent morbidity (fever, cough, or diarrhea) was not significantly associated with DMC‐II scores in the multivariate model.Predictive validity of the DMC‐II was established in this population. Comparison of standardised regression coefficients identified weight‐for‐age z‐score, Family Care Indicators, and dietary diversity as the strongest determinants of the child's overall score on the developmental milestones; length‐for‐age z‐score, weight‐for‐age z‐score, and weight‐for‐length z‐score were the strongest predictors of score on the motor development subscale. Strategies to improve child development should simultaneously address these issues.Support or Funding InformationFunding support provided by a BMGF grant through a subcontract with CARE‐India
Maternal Vitamin D Status and Adverse Pregnancy and Neonatal Outcomes in India
Authors: Finkelstein Julia L. , Duggan Christopher , Mehta Saurabh , Thomas Tinku , Srinivasan Krishnamachari , Kurpad Anura V. 
Published: November 2023

ObjectiveTo examine the prevalence of vitamin D deficiency and its association with risk of adverse pregnancy and neonatal outcomes in Southern India.MethodsA total of 366 women participating in a vitamin B12 supplementation trial in India were monitored to assess plasma 25‐hydroxyvitamin D (25OHD) concentrations in each trimester during pregnancy. All women received daily iron and folic acid supplementation during pregnancy. Binomial and linear regression models were used to evaluate the associations of maternal vitamin D status and pregnancy and neonatal outcomes.ResultsVitamin D insufficiency was common in pregnancy: 85% of mothers were vitamin D deficient (25OHD <20.0 ng/mL), and 40% had vitamin D concentrations less than 10.0 ng/mL at their first prenatal visit. Maternal vitamin D concentrations increased significantly during pregnancy (p<0.05). However, 75% of mothers were vitamin D deficient (25OHD <20.0 ng/mL) and 31% had vitamin D concentrations less than 10.0 ng/mL in the third trimester. Maternal vitamin D status was not significantly associated with risk of adverse pregnancy outcomes, including infant birth weight, low birth weight (<2,500 g), intrauterine growth restriction, gestational age at delivery, or preterm delivery (<37 weeks). However, maternal vitamin D concentrations at baseline were associated with increased neonatal head circumference (p=0.02) in multivariate analyses, after adjusting for gestational age at sample collection, vitamin B12 intervention, maternal body mass index (BMI), socioeconomic status, and C‐reactive protein concentrations. Maternal vitamin D deficiency at enrollment was associated with significantly lower neonatal mid‐upper arm circumference (p=0.02) and biceps skinfold thickness (p=0.04) in multivariate analyses, after adjusting for gestational age at sample collection, vitamin B12 intervention, maternal BMI, socioeconomic status, and C‐reactive protein concentrations.ConclusionsVitamin D deficiency is common in pregnant Indian women, and is associated with lower neonatal arm anthropometric and fat measures.Support or Funding InformationNational Institutes of Health, Indian Council of Medical Research, Harvard University
Maternal Obesity, 25(OH)D Concentration and Bone Mineral Density in Breastfeeding Dyads
Authors: Sen Sarbattama , Penfield‐Cyr Annie , Lu Zhigang , Ebeling Myla , Hollis Bruce , Howard Cindy , Wagner Carol 
Published: November 2023

BackgroundPrevious studies have shown inverse relationships between Body Mass Index (BMI) and serum levels of vitamin D. Among other sequelae, vitamin D deficiency is related to bone health risks including rickets in children and osteomalacia in adults. The impact of maternal BMI on vitamin D levels and bone mineral density (BMD) in breastfeeding mother‐infant dyads has not been studied.ObjectiveTo examine the association between maternal BMI and vitamin 25(OH)D concentration and BMD in exclusively breastfeeding mother‐infant pairs.MethodsWe conducted a secondary analysis of a cohort of 278 breastfeeding mother‐infant dyads who were recruited in the first month post‐partum. Using ANOVA and linear regression, we examined associations between maternal BMI continuously and categorically (Lean (L), BMI 18.5–25kg/m2; overweight (Ow), BMI 25–30kg/m2; and Obese (Ob), BMI≥30kg/m2) with four outcomes: Maternal and infant 25(OH)D concentration, maternal and infant BMD using DXA.ResultsMean maternal BMI was 28.5 kg/m2. Maternal BMI negatively associated with maternal serum concentration of 25(OH)D (β=−0.29 nmol/L decreased in 25(OH)D concentration for each increase in BMI point, p<0.0001), with Ob mothers having significantly lower mean levels than L or Ow (mean±SD nmol/L: L: 38.4±14.6, Ow: 34.2±14.3, Ob: 29.4±9.9; p<0.05 for Ob vs. L and Ob vs. Ow). Despite lower serum 25(OH)D concentrations, Ob women had higher BMD than either L or Ow women (L: 0.97±0.14g/cm3, Ow 1.01±0.11g/cm3, Ob 1.05±0.11g/cm3; p<0.05 for Ob vs. L and Ob vs. Ow). There was no association between maternal BMI and infant serum 25(OH)D concentration or infant BMD (p=0.5 and 0.98 respectively).ConclusionsMaternal obesity was associated with lower serum 25(OH)D concentration in breastfeeding women, but not infant serum 25(OH)D concentration or infant BMD. There seems to be a protective effect of obesity on maternal bone mineralization at this early time point in lactation. The effect of prolonged 25(OH)D deficit throughout lactation on maternal and infant bone mineralization is currently being analyzed.Support or Funding InformationFunded in part by National Institutes of Health (NIH) 5R01HD043921, NIH RR01070, Medical University of South Carolina Department of Pediatrics, and by the South Carolina Clinical & Translational Research (SCTR) Institute, with an academic home at the Medical University of South Carolina, NIH/National Center for Advancing Translational Sciences grant UL1 TR000062, and a K23 grant from the NIH (ref. no. K23HD074648).
TMPRSS4: a novel serine protease involved in IPF development?
Authors: Valero Ana Mayela , Cisneros José , Ramírez Remedios , Gaxiola Miguel , Becerril Carina , Pardo Annie , Selman Moisés 
Published: November 2023

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive and lethal lung disease characterized by the expansion of the fibroblast population and excessive extracellular matrix accumulation with the subsequent destruction of the lung architecture. Its pathogenesis is incompletely understood but evidence suggests an epithelial pathway in which IPF may result from epithelial microinjuries and activation and abnormal wound healing. TMPRSS4 is a novel type II transmembrane serine protease found at the cell surface. Although their biological functions are unknown it has been suggested that TMPRSS4 promotes migration and facilitates the epithelial to mesenchymal transition (EMT), two critical processes in the pathogenesis of IPF. Thus, we hypothesized that overexpression of TMPRSS4 in the lung could promote the initiation and/or progression of IPF.AimTo determine the role of TMPRSS4 in IPF.MethodsWe first examined the lung expression and localization of TMPRSS4 in IPF and normal lungs by qPCR and immunohistochemistry. Additionally, we measured the expression of TMPRSS4 in human lung fibroblasts and one alveolar and one bronchial epithelial cell lines. Then we explored the role of this protease in an experimental model of lung fibrosis. TMPRSS4 haplodeficient and wild type mice received an intratracheal instillation of bleomycin and were studied at 28 days post‐instillation.ResultsWe found that this protease is not expressed in normal human lungs while variable amounts of the mRNA were found in IPF lungs (2−DCT 1.1×10−2 ± 9.4×10−5). TMPRSS4 was primarily expressed by epithelial and mast cells. The protease was not found in lung fibroblasts but different levels of mRNA were revealed in alveolar (2−DCT 7.5×10−7 ± 2×10−7) and bronchial (2−DCT 4.2×10−5 ± 3.6×10−6) epithelial cells. The lung fibrotic response, measured by hydroxyproline ( 178.9 ± 12.4 versus 110.7 ± 13.8 mg/lung; p<0.05) and morphology (40% versus 15% extent of the lesions) was significantly attenuated in the haplodeficient mice.ConclusionsOur findings indicate that TMPRSS4 may have a profibrotic role in IPF and other fibrotic lung disorders.Support or Funding InformationPosgrado en Ciencias Biológicas, UNAM; CONACYT SALUD‐2014‐01‐234088
Digital Determination of Chemotherapeutic Drug‐Induced Damage Sites in Single DNA Molecules using Nanofluidic Channels
Authors: Kaufman David Gordon , Chastain Paul David , Soper Steven Allan 
Published: November 2023

We have shown that DNA can be extended on glass slides permitting the observation of fluorescently labeled DNA fibers and facilitating the quantitation of their length. When the stretched DNA fibers are also immunostained for the presence of apurinic/apyrimidinic (AP) sites, it was possible to quantitate the number of AP sites per unit length of DNA. Measurements of AP site frequency that are determined in this manner are comparable in accuracy to the “gold standard” method of AP site quantitation, but have a lower variance and the ability to analyze even single DNA molecules. Using this method, it has been possible to detect the increased frequency of AP site formation in DNA of cells exposed to hydrogen peroxide in cell culture. Furthermore, it was possible to show that DNA located at replication sites were more intensely damaged than the remainder of the DNA. Similar increases in the quantity of DNA damage sites have also been found in the DNA of cells treated with the cancer chemotherapeutic drug doxycycline. While this technique appears to be a powerful method to detect DNA damage in cells exposed to damaging agents in culture and in vivo, it has the liability of being extremely labor intensive and requires an extended time (weeks to days) for completion. To remedy these shortcomings and to allow clinical translation of this technology, we have developed an alternate approach, which involves the extraction of DNA from circulating tumor cells isolated from whole blood using a unique microfluidic device, immunostaining the DNA and the associated DNA AP sites in micro‐scale reaction chambers and the alignment and deposition of individual DNA fibers in nanochannels (<100 nm in width and depth). This enables single DNA molecules to be stretched reproducibly in nanochannels to near their full contour length which facilitates quantification of labeled AP sites. The DNA fibers positioned within the nanochannels are fluorescently imaged and the images subjected to a unique image analysis technique to provide highly quantitative information on AP site frequency. When using this image analysis approach, it is possible to obtain statistically significant results from even single cells. The combination of these microfluidic and nanofluidic devices into a single analysis platform for quantitating rates of DNA damage reduces the time required for this measurement to an hour or less, reduces technical time to that needed to load samples and reagents, and should permit these analyses to be made in the clinical setting by clinical laboratory personnel.Support or Funding InformationSupported by NIH Grants R21‐125337 and P41‐EB020594.
Role of Sumoylation in Aldehyde Dehydrogenase 2 (ALDH) function during Alcoholic Liver Disease
Authors: Cossu Carla , Ramani Komal , Spissu Ylenia , Floris Andrea , Tomasi Maria Lauda 
Published: November 2023

BackgroundChronic alcohol abuse causes liver disease that progress from steatosis through stages of steatohepatitis, fibrosis, cirrhosis and eventually hepatic failure. Acetaldehyde, a major toxic ethanol metabolite, is mutagenic and carcinogenic, playing an important role in the pathogenesis of alcoholic liver disease (ALD) inducing production of reactive oxygen species (ROS) and apoptosis. ALDH2 is the major enzyme that metabolizes acetaldehyde produced from alcohol metabolism. Sumoylation is a posttranslational modification able to modify the activity, localization, and expression of the target protein by a covalent bind where small ubiquitin modifier (SUMO) is a tag. Increased ROS production enhances the global protein SUMO conjugation profile. We previously demonstrated that the level of Ubiquitin‐conjugation enzyme 9 (Ubc9), a sole E2‐conjugating enzyme essential for sumoylation, is induced in the livers of intragastric ethanol‐infusion (EI) treated mice. Our aim was to examine whether the dysregulated sumoylation could regulate the ethanol‐induced ALDH2 function in ALD and elucidate the molecular mechanism(s).MethodsStudies were done using in vivo binge ethanol‐fed mice and primary mouse hepatocytes. Sumoylation protein profiling and expression were measured by Mass Spectrometry and Western blot analyses, respectively. ALDH2 activity was analyzed using commercial kit.ResultsWe found that ALDH2 is sumoylated in binge mice livers analyzing the peptide‐sequencing data from sample purified by SUMO immunoaffinity columns. In addition, we found that both Ubc9 and ALDH2 mRNA and protein levels are increased in the livers of binge mice and ethanol‐treated hepatocytes. Interestingly, Ubc9 silencing prevented ethanol‐mediated induction in ALDH2 protein level. ALDH2 activity assay showed that Ubc9 is required for ALDH2 to be enzymatically active in primary mouse hepatocytes. Finally, we confirmed the peptide‐sequencing data of sumoylated ALDH2 using in vivo binge mice livers finding increased level of SUMO1/2/3‐ALDH2 complex formation following ethanol treatment.ConclusionsWe report for the first time that ethanol‐mediated sumoylation increased ALDH2 protein level and enzymatic activity in livers of binge mice and primary hepatocytes. This novel finding thereby opens a new area of investigation examining the importance of ALDH2 sumoylation in alcoholic liver disease.Support or Funding InformationNIAAA Grant: 5 K01 AA022372‐04
Role of TLR7 in development of alcoholic fatty liver disease: a new target for prevention of alcoholic fatty liver disease
Authors: Matsumoto Hiroshi , Yang Chipin , Sugimoto Kana 
Published: November 2023

TLRs play an important role in development of alcoholic fatty liver disease. Especially, TLR4 contributes to promote alcoholic fatty liver disease via priming via LPS. Recently, it has been reported that the treatment of a TLR7 ligands induces fatty liver disease. It has been recognized circulating microRNAs in experimental alcoholic fatty liver disease. TLR7 recognizes RNA to lead activation of innate immune system. Then we hypothesized that TLR7 contributes to develop alcoholic fatty liver disease. Lieber‐DiCarli alcohol‐diet pair feeding for 4 weeks performed in TLR7 knockout and wild mice. CpG, a ligand of TLR7, was treated in both mice. TLR7 deletion improved fatty liver injuries in histopathological findings, while CpG treatment promoted fatty liver injuries in TLR knockout mice. Therefore, these findings show that TLR7 contributes to develop fatty liver disease, indicating that regulation of TLR7 activation may prevent development of alcoholic fatty liver disease.Support or Funding InformationA part of Grands‐in‐Aid for Scientific Reserch (B) (Grant #24390175) by Japan Society for the Promotion of Science (JSPS)
Caveolin‐1 regulation of DISC1 as a potential therapeutic target for schizophrenia
Authors: Kassan Adam , Egawa Junji , Zhang Zheng , Lajevardi Yasaman , Kim Kaitlyn , Nguyen Quynh My , Posadas Edmund S. , Sawada Atsushi , Jeste Dilip V. , Roth David M. , Patel Piyush M. , Patel Hemal H. , Head Brian P. 
Published: November 2023

BackgroundSchizophrenia (SZ) is a debilitating neuropsychiatric disorder manifested in early adulthood. Disrupted‐In‐Schizophrenia‐1 (DISC1) is a promising candidate gene for SZ, but the molecular mechanisms underlying its role in the pathogenesis of the disease is still poorly understood. Caveolin‐1 (Cav‐1) is a cholesterol‐binding and plasma membrane scaffolding protein implicated in neuronal signal transduction and plasticity. Here we examined the role of CAV1 in mediating DISC1 expression in neurons in vitro and the hippocampus in vivo.Methods and resultsOverexpressing Cav‐1 in primary neonatal rodent neurons using a neuron specific synapsin promoter (SynCav1) isolated from hippocampi resulted in increased DISC1 and synaptic plasticity markers (PSD95, synaptobrevin, synaptophysin, and syntaxin‐1A). Similarly, SynCav1‐transfected differentiated human neurons derived from induced pluripotent stem cells (iPSCs) exhibited increased expression of DISC1 and markers of synaptic plasticity. Furthermore, these markers and DISC1 were significantly reduced in the hippocampi from Cav‐1 knockout (KO) mice. Finally, SynCav1 delivery to the hippocampus of Cav‐1 KO mice and neurons lacking Cav‐1 restored DISC1 protein expression as well as markers of synaptic plasticity.ConclusionThese findings show an important role for neuronal Cav‐1 as a mediator of DISC1; therefore, SynCav1 might be a potential therapeutic target for SZ.Support or Funding Information5 T32 MH 19934‐20
Effect of Stabilizing Alpha Synuclein‐Membrane Interactions on the Protein's Aggregation and Neurotoxicity
Authors: Ysselstein Daniel , Mishra Vartika , McCabe George , Rochet Jean‐Christophe 
Published: November 2023

Oligomerization of the protein alpha‐synuclein (aSyn) is a critical factor in the onset of both familial and sporadic Parkinson's disease (PD). In healthy individuals aSyn exists in a number of conformations, including a membrane‐bound state that displays resistance to aggregation. How this aggregation‐resistant state is altered is a significant problem in PD research, as a better understanding of the events that initiate aSyn aggregation is critical for designing neuroprotective strategies. We hypothesize that disruption of interactions between aSyn and phospholipid membranes leads to a shift to a conformation that is more susceptible to the formation of neurotoxic aSyn oligomers due to exposure of the protein's central hydrophobic region. Therefore, stabilization of membrane‐bound aSyn should prevent membrane‐induced aggregation and alleviate aSyn neurotoxicity.We generated aSyn variants predicted to disrupt aSyn‐membrane interactions, including the familial mutants A30P and G51D. We characterized the variants in terms of their aggregation on synthetic phospholipid vesicles and their ability to permeate the membrane by measuring release of encapsulated fluorescent dye. Dopaminergic neurotoxicity was examined using adenoviral‐mediated expression in a primary midbrain culture model. To examine the protective effects of stabilizing aSyn‐membrane interactions, we first investigated the impact of endosulfine alpha (ENSA), a protein found to interact with membrane‐bound aSyn. Additionally, we performed a phage display screen to identify small peptides that interact with membrane‐bound aSyn. These potential “stabilizers” of membrane‐bound aSyn were examined for their effects on membrane‐induced aSyn aggregation, membrane permeabilization, and dopaminergic neurotoxicity.We found that aSyn variants that displayed enhanced accumulation of SDS‐resistant aggregates at the membrane, including A30P and G51D, also displayed increased neurotoxicity. Upon co‐incubating A30P and G51D aSyn with ENSA in the presence of vesicles, we observed a reduction in membrane‐induced aSyn aggregation. This reduction was partially abrogated when the experiment was repeated with the S109E mutant of ENSA, indicating that residue S109 (previously shown to be important for the interaction of ENSA with membrane‐bound aSyn) is involved in the protective effect of ENSA. Co‐expression of ENSA with A30P and G51D in primary midbrain cultures alleviated dopaminergic cell death, suggesting that “stabilizers” of membrane‐bound aSyn may protect against aSyn neurotoxicity. Lastly, we identified several peptides that bind membrane‐associated aSyn and inhibit membrane‐induced aggregation and membrane permeabilization. These peptide stabilizers could be a powerful tool to examine how membrane‐induced aggregation plays a role in aSyn neurotoxicity.Support or Funding InformationNational Institutes of Health (NINDS), Branfman Foundation, Floss Endowment Graduate Research Award