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The daily nutrient intake of 90 pregnant women from farming and non-farming communities in six rural villages of Haryana State, Northern India have been determined. As a result of questionnaires and interviews, nutrient intake for 3 consecutive days were calculated. Mean daily intakes of farming and non-farming pregnant women examined in this study were lower for energy, calcium and iron than the recently prescribed Indian recommended dietary allowances (RDAs). Protein intake of non-farming women was significantly lower and that of farming women was almost similar to RDA. Intake of fat by pregnant women was double the RDA. The mean daily intakes of thiamine, riboflavin and niacin by women of both the communities were found to be adequate. The diets of pregnant women could meet half the requirement of folic acid and even less than half for ascorbic acid. Income of pregnant women did not show any influence on nutrient intakes but educational level of women certainly reflected differences in vitamin intakes. [ABSTRACT FROM AUTHOR]

Average daily food intakes of 90 rural pregnant women of farming and non-farming communities of Northern India were determined. As a result of questionnaires and interviews, food intakes for three consecutive days were collected. Intakes of cereals, pulses, roots and tubers, and sugar and jaggery, by both farming and non-farming females were significantly lower than the prescribed Indian recommended dietary intakes (RDI). The consumption of milk and milk products and fats and oils was adequate whereas green leafy vegetables and fruits were the most limited food items. No significant overall differences were observed between females from farming and non-farming backgrounds. Level of education did not show significant influence on intakes of different food items. The consumption of fruits and green leafy vegetables increased with the increase in family monthly income. There is a pressing need to educate rural pregnant women regarding their increased nutritional requirements. [ABSTRACT FROM AUTHOR]

The nonlinear analysis of the metal–insulator semiconductor shows that the ac currents charging the interface traps lead to large dc operating voltage and an inefficient operation of the monolithic convolvers. These interface traps are annihilated during a low temperature anneal, which utilizes hydrogen atoms implanted underneath the SiO[sub 2]–Si interface. The overlay piezoelectric ZnO film in the metal–ZnO–Si[sub 3]N[sub 4]–SiO[sub 2]–Sistructure is protected from the influx of hydrogen atoms by an interposed silicon nitride layer. Hydrogen implantation and rapid thermal annealing steps are integrated in the process sequence of realizing an efficient metal–ZnO–Si[sub 3]N[sub 4]–SiO[sub 2]–Si monolithic surface acoustic wave convolver. © 2002 American Institute of Physics. [ABSTRACT FROM AUTHOR]

A post-implant rapid thermal annealing technique is proposed to achieve very low interface trap density (<1010/eV cm2) at the SiO2-Si interface in a metal-Si3N4-SiO2-Si structure. The constitution of a donor layer induced by implanted hydrogen is explained with the aid of a model that predicts the formation of SiH groups. The proposed model is substantiated by comparing the IR data for furnace and rapid thermal annealed samples. [ABSTRACT FROM AUTHOR]

Abstract Background The vitamins are important cofactors in various enzymatic-reactions. In past, many inhibitors have been designed against vitamin binding pockets in order to inhibit vitamin-protein interactions. Thus, it is important to identify vitamin interacting residues in a protein. It is possible to detect vitamin-binding pockets on a protein, if its tertiary structure is known. Unfortunately tertiary structures of limited proteins are available. Therefore, it is important to develop in-silico models for predicting vitamin interacting residues in protein from its primary structure. Results In this study, first we compared protein-interacting residues of vitamins with other ligands using Two Sample Logo (TSL). It was observed that ATP, GTP, NAD, FAD and mannose preferred {G,R,K,S,H}, {G,K,T,S,D,N}, {T,G,Y}, {G,Y,W} and {Y,D,W,N,E} residues respectively, whereas vitamins preferred {Y,F,S,W,T,G,H} residues for the interaction with proteins. Furthermore, compositional information of preferred and non-preferred residues along with patterns-specificity was also observed within different vitamin-classes. Vitamins A, B and B6 preferred {F,I,W,Y,L,V}, {S,Y,G,T,H,W,N,E} and {S,T,G,H,Y,N} interacting residues respectively. It suggested that protein-binding patterns of vitamins are different from other ligands, and motivated us to develop separate predictor for vitamins and their sub-classes. The four different prediction modules, (i) vitamin interacting residues (VIRs), (ii) vitamin-A interacting residues (VAIRs), (iii) vitamin-B interacting residues (VBIRs) and (iv) pyridoxal-5-phosphate (vitamin B6) interacting residues (PLPIRs) have been developed. We applied various classifiers of SVM, BayesNet, NaiveBayes, ComplementNaiveBayes, NaiveBayesMultinomial, RandomForest and IBk etc., as machine learning techniques, using binary and Position-Specific Scoring Matrix (PSSM) features of protein sequences. Finally, we selected best performing SVM modules and obtained highest MCC of 0.53, 0.48, 0.61, 0.81 for VIRs, VAIRs, VBIRs, PLPIRs respectively, using PSSM-based evolutionary information. All the modules developed in this study have been trained and tested on non-redundant datasets and evaluated using five-fold cross-validation technique. The performances were also evaluated on the balanced and different independent datasets. Conclusions This study demonstrates that it is possible to predict VIRs, VAIRs, VBIRs and PLPIRs from evolutionary information of protein sequence. In order to provide service to the scientific community, we have developed web-server and standalone software VitaPred (http://crdd.osdd.net/raghava/vitapred/).

Abstract Background Predicting the function of a protein is one of the major challenges in the post-genomic era where a large number of protein sequences of unknown function are accumulating rapidly. Lectins are the proteins that specifically recognize and bind to carbohydrate moieties present on either proteins or lipids. Cancerlectins are those lectins that play various important roles in tumor cell differentiation and metastasis. Although the two types of proteins are linked, still there is no computational method available that can distinguish cancerlectins from the large pool of non-cancerlectins. Hence, it is imperative to develop a method that can distinguish between cancer and non-cancerlectins. Results All the models developed in this study are based on a non-redundant dataset containing 178 cancerlectins and 226 non-cancerlectins in which no two sequences have more than 50% sequence similarity. We have applied the similarity search based technique, i.e. BLAST, and achieved a maximum accuracy of 43.25%. The amino acids compositional analysis have shown that certain residues (e.g. Leucine, Proline) were preferred in cancerlectins whereas some other (e.g. Asparatic acid, Asparagine) were preferred in non-cancerlectins. It has been found that the PROSITE domain "Crystalline beta gamma" was abundant in cancerlectins whereas domains like "SUEL-type lectin domain" were found mainly in non-cancerlectins. An SVM-based model has been developed to differentiate between the cancer and non-cancerlectins which achieved a maximum Matthew's correlation coefficient (MCC) value of 0.32 with an accuracy of 64.84%, using amino acid compositions. We have developed a model based on dipeptide compositions which achieved an MCC value of 0.30 with an accuracy of 64.84%. Thereafter, we have developed models based on split compositions (2 and 4 parts) and achieved an MCC value of 0.31, 0.32 with accuracies of 65.10% and 66.09%, respectively. An SVM model based on Position Specific Scoring Matrix (PSSM), generated by PSI-BLAST, was developed and achieved an MCC value of 0.36 with an accuracy of 68.34%. Finally, we have integrated the PROSITE domain information with PSSM and developed an SVM model that has achieved an MCC value of 0.38 with 69.09% accuracy. Conclusion BLAST has been found inefficient to distinguish between cancer and non-cancerlectins. We analyzed the protein sequences of cancer and non-cancerlectins and identified interesting patterns. We have been able to identify PROSITE domains that are preferred in cancer and non-cancerlectins and thus provided interesting insights into the two types of proteins. The method developed in this study will be useful for researchers studying cancerlectins, lectins and cancer biology. The web-server based on the above study, is available at http://www.imtech.res.in/raghava/cancer_pred/

Abstract Background Aminoacyl tRNA synthetases (aaRSs) catalyse the first step of protein synthesis in all organisms. They are responsible for the precise attachment of amino acids to their cognate transfer RNAs. There are twenty different types of aaRSs, unique for each amino acid. These aaRSs have been divided into two classes, each comprising ten enzymes. It is important to predict and classify aaRSs in order to understand protein synthesis. Results In this study, all models were developed on a non-redundant dataset containing 117 aaRSs and an equal number of non-aaRSs, in which no two sequences have more than 30% similarity. First, we applied the similarity search technique, BLAST, and achieved a maximum accuracy of 67.52%. We observed that 62% of tRNA synthetases contain one or more domains from amongst the following four PROSITE domains: PS50862, PS00178, PS50860 and PS50861. An SVM-based model was developed to discriminate between aaRSs, and non-aaRSs, and achieved a maximum MCC of 0.68 with accuracy of 83.73%, using selective dipeptide composition. We developed a hybrid approach and achieved a maximum MCC of 0.72 with accuracy of 85.49%, where SVM model developed using selected dipeptide composition and information of four PROSITE domains. We further developed an SVM-based model for classifying the aaRSs into class-1 and class-2, using selective dipeptide composition and achieved an MCC of 0.79. We also observed that two domains (PS00178, PS50889) in class-1 and three domains (PS50862, PS50860, PS50861) in class-2 were preferred. A hybrid method was developed using these domains as descriptor, along with selected dipeptide composition, and achieved an MCC of 0.87 with a sensitivity of 94.55% and an accuracy of 93.19%. All models were evaluated using a five-fold cross-validation technique. Conclusions We have analyzed protein sequences of aaRSs (class-1 and class-2) and non-aaRSs and identified interesting patterns. The high accuracy achieved by our SVM models using selected dipeptide composition demonstrates that certain types of dipeptide are preferred in aaRSs. We were able to identify PROSITE domains that are preferred in aaRSs and their classes, providing interesting insights into tRNA synthetases. The method developed in this study will be useful for researchers studying aaRS enzymes and tRNA biology. The web-server based on the above study, is available at http://www.imtech.res.in/raghava/icaars/.

A green house experiment was conducted to determine the interactive effects of cadmium (0, 2.5, 5, 10, and 20 mg Cd kg-1 soil)and phosphorus (0, 20 and 40 mg P kg-1 soil) on dry matter yield of cowpea and mungbean, and tissue concentration and uptake of cadmium (Cd) and Phosphorus (P). Application of Cd to soil decreased the dry matter yield of both the crops significantly at each level of applied P. Phosphorus application, on the other hand, increased the dry matter yield of both crops significantly at each level of Cd additions to the soil. Cadmium concentration in plant tissue and uptakeof Cd by plants increased markedly with the increasing rates of Cd in the soil. The magnitude of increase in tissue Cd concentration, however, was higher in the absence than in the presence of added P. Consequently, the concentration of Cd in plants decreased with increasinglevels of P application to the soil. This decrease in tissue Cd concentration with increasing P supply in the soil was mainly attributed to increased dry matter yield of crops. The concentration of P in cowpea and mungbean tissue increased while the uptake of P by these crops decreased markedly with increasing levels of Cd in the soil, irrespective of the rates of P applied. [ABSTRACT FROM AUTHOR]

AMG 330, a bispecific T-cell engager (BiTE®) that binds CD33 and CD3 on T cells facilitates T-cell-mediated cytotoxicity against CD33+ cells. This first-in-human, open-label, dose-escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of AMG 330 in adults with relapsed/refractory acute myeloid leukemia (R/R AML). Amongst 77 patients treated with AMG 330 (0.5 µg/day-1.6 mg/day) on 14-day or 28-day cycles, maximum tolerated dose was not reached; median duration of treatment was 29 days. The most frequent treatment-related adverse events were cytokine release syndrome (CRS; 78%) and rash (30%); 10% of patients experienced grade 3/4 CRS. CRS was mitigated with stepwise dosing of AMG 330, prophylactic dexamethasone, and early treatment with tocilizumab. Among 60 evaluable patients, eight achieved complete remission or morphologic leukemia-free state; of the 52 non-responders, 37% had ≥50% reduction in AML bone marrow blasts. AMG 330 is a promising CD33-targeted therapeutic strategy for R/R AML.

Blinatumomab is a BiTE® (bispecific T-cell engager) molecule that redirects CD3 + T-cells to engage and lyse CD19 + target cells. Here we demonstrate that subcutaneous (SC) blinatumomab can provide high efficacy and greater convenience of administration. In the expansion phase of a multi-institutional phase 1b trial (ClinicalTrials.gov, NCT04521231), heavily pretreated adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) received SC blinatumomab at two doses: (1) 250 μg once daily (QD) for week 1 and 500 μg three times weekly (TIW) thereafter (250 μg/500 μg) or (2) 500 μg QD for week 1 and 1000 μg TIW thereafter (500 μg/1000 μg). The primary endpoint was complete remission/complete remission with partial hematologic recovery (CR/CRh) within two cycles. At the data cutoff of September 15, 2023, 29 patients were treated: 14 at the 250 μg/500 μg dose and 13 at 500 μg/1000 μg dose. Data from two ineligible patients were excluded. At the end of two cycles, 12 of 14 patients (85.7%) from the 250 μg/500 μg dose achieved CR/CRh of which nine patients (75.0%) were negative for measurable residual disease (MRD; <10 -4 leukemic blasts). At the 500 μg/1000 μg dose, 12 of 13 patients (92.3%) achieved CR/CRh; all 12 patients (100.0%) were MRD-negative. No treatment-related grade 4 cytokine release syndrome (CRS) or neurologic events (NEs) were reported. SC injections were well tolerated and all treatment-related grade 3 CRS and NEs responded to standard-of-care management, interruption, or discontinuation. Treatment with SC blinatumomab resulted in high efficacy, with high MRD-negativity rates and acceptable safety profile in heavily pretreated adults with R/R B-ALL., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Immune-checkpoint blockade (ICB) has shown remarkable clinical success in boosting antitumor immunity. However, the breadth of its cellular targets and specific mode of action remain elusive. We find that tumor-infiltrating follicular regulatory T (T FR ) cells are prevalent in tumor tissues of several cancer types. They are primarily located within tertiary lymphoid structures and exhibit superior suppressive capacity and in vivo persistence as compared with regulatory T cells, with which they share a clonal and developmental relationship. In syngeneic tumor models, anti-PD-1 treatment increases the number of tumor-infiltrating T FR cells. Both T FR cell deficiency and the depletion of T FR cells with anti-CTLA-4 before anti-PD-1 treatment improve tumor control in mice. Notably, in a cohort of 271 patients with melanoma, treatment with anti-CTLA-4 followed by anti-PD-1 at progression was associated with better a survival outcome than monotherapy with anti-PD-1 or anti-CTLA-4, anti-PD-1 followed by anti-CTLA-4 at progression or concomitant combination therapy., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Systemic lupus erythematosus (SLE) is an incurable autoimmune disease disproportionately affecting women. A major obstacle in finding targeted therapies for SLE is its remarkable heterogeneity in clinical manifestations as well as in the involvement of distinct cell types. To identify cell-specific targets as well as cross-correlation relationships among expression programs of different cell types, we here analyze six major circulating immune cell types from SLE patient blood. Our results show that presence of an interferon response signature stratifies patients into two distinct groups (IFNneg vs. IFNpos). Comparing these two groups using differential gene expression and differential gene coexpression analysis, we prioritize a relatively small list of genes from classical monocytes including two known immune modulators: TNFSF13B/BAFF (target of belimumab , an approved therapeutic for SLE) and IL1RN (the basis of anakinra, a therapeutic for rheumatoid arthritis). We then develop a multi-cell type extension of the weighted gene coexpression network analysis (WGCNA) framework, termed mWGCNA. Applying mWGCNA to RNA-seq data from six sorted immune cell populations (15 SLE, 10 healthy donors), we identify a coexpression module with interferon-stimulated genes (ISGs) among all cell types and a cross-cell type correlation linking expression of specific T helper cell markers to B cell response as well as to TNFSF13B expression from myeloid cells, all of which in turn correlates with disease severity of IFNpos patients. Our results demonstrate the power of a hypothesis-free and data-driven approach to discover drug targets and to reveal novel cross-correlation across cell types in SLE with implications for other autoimmune diseases., (© 2021 Panwar et al.; Published by Cold Spring Harbor Laboratory Press.)

Background and Objectives: Ferric citrate is an oral medication approved for treatment of iron deficiency anemia in patients with CKD not requiring dialysis. The relative efficacy of ferric citrate versus ferrous sulfate in treating iron deficiency in patients with CKD is unclear., Design, Setting, Participants, & Measurements: We randomized 60 adults with moderate to severe CKD (eGFR 15-45 ml/min per 1.73 m 2 ) and iron deficiency (transferrin saturation [TSAT] ≤30% and ferritin ≤300 ng/ml) to ferric citrate (2 g three times a day with meals, n =30) or ferrous sulfate (325 mg three times a day, n =30) for 12 weeks. Primary outcomes were change in TSAT and ferritin from baseline to 12 weeks. Secondary outcomes were change in hemoglobin, fibroblast growth factor 23 (FGF23), and hepcidin., Results: Baseline characteristics were well balanced between study arms. There was a greater increase in TSAT (between-group difference in mean change, 8%; 95% confidence interval [95% CI], 1 to 15; P =0.02) and ferritin (between-group difference in mean change, 37 ng/ml; 95% CI, 10 to 64; P =0.009) from baseline to 12 weeks in participants randomized to ferric citrate as compared with ferrous sulfate. Similarly, as compared with ferrous sulfate, treatment with ferric citrate resulted in a greater increase in hepcidin from baseline to 12 weeks (between-group difference, 69 pg/ml; 95% CI, 8 to 130). There were no between-group differences in mean change for hemoglobin (0.3 g/dl; 95% CI, -0.2 to 0.8), intact FGF23 (-29 pg/ml; 95% CI, -59 to 0.1), or C-terminal FGF23 (61 RU/ml; 95% CI, -181 to 58). The incidence of adverse events did not differ between treatment arms., Conclusions: As compared with ferrous sulfate, treatment with ferric citrate for 12 weeks resulted in a greater mean increase in TSAT and ferritin concentrations in individuals with moderate to severe CKD and iron deficiency., Clinical Trial Registry Name and Registration Number: Impact of Ferric Citrate vs Ferrous Sulfate on Iron Parameters and Hemoglobin in Individuals With Moderate to Severe Chronic Kidney Disease (CKD) With Iron Deficiency, NCT02888171., (Copyright © 2020 by the American Society of Nephrology.)

High numbers of tissue-resident memory T (T RM ) cells are associated with better clinical outcomes in cancer patients. However, the molecular characteristics that drive their efficient immune response to tumors are poorly understood. Here, single-cell and bulk transcriptomic analysis of T RM and non-T RM cells present in tumor and normal lung tissue from patients with lung cancer revealed that PD-1-expressing T RM cells in tumors were clonally expanded and enriched for transcripts linked to cell proliferation and cytotoxicity when compared with PD-1-expressing non-T RM cells. This feature was more prominent in the T RM cell subset coexpressing PD-1 and TIM-3, and it was validated by functional assays ex vivo and also reflected in their chromatin accessibility profile. This PD-1 + TIM-3 + T RM cell subset was enriched in responders to PD-1 inhibitors and in tumors with a greater magnitude of CTL responses. These data highlight that not all CTLs expressing PD-1 are dysfunctional; on the contrary, T RM cells with PD-1 expression were enriched for features suggestive of superior functionality., (© 2019 Clarke et al.)

Despite recent advances in asthma management with anti-IL-5 therapies, many patients have eosinophilic asthma that remains poorly controlled. IL-3 shares a common β subunit receptor with both IL-5 and GM-CSF but, through α-subunit-specific properties, uniquely influences eosinophil biology and may serve as a potential therapeutic target. We aimed to globally characterize the transcriptomic profiles of GM-CSF, IL-3, and IL-5 stimulation on human circulating eosinophils and identify differences in gene expression using advanced statistical modeling. Human eosinophils were isolated from the peripheral blood of healthy volunteers and stimulated with either GM-CSF, IL-3, or IL-5 for 48 h. RNA was then extracted and bulk sequencing performed. DESeq analysis identified differentially expressed genes and weighted gene coexpression network analysis independently defined modules of genes that are highly coexpressed. GM-CSF, IL-3, and IL-5 commonly upregulated 252 genes and downregulated 553 genes, producing a proinflammatory and survival phenotype that was predominantly mediated through TWEAK signaling. IL-3 stimulation yielded the most numbers of differentially expressed genes that were also highly coexpressed ( n = 119). These genes were enriched in pathways involving JAK/STAT signaling. GM-CSF and IL-5 stimulation demonstrated redundancy in eosinophil gene expression. In conclusion, IL-3 produces a distinct eosinophil gene expression program among the β-chain receptor cytokines. IL-3-upregulated genes may provide a foundation for research into therapeutics for patients with eosinophilic asthma who do not respond to anti-IL-5 therapies., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Background: Low baseline plasma 25-hydroxyvitamin D (25(OH)D) is associated with increased risk of acute respiratory infections, but its association with long-term risk of sepsis remains unclear., Methods: We performed a case-cohort analysis of participants selected from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a US cohort of 30239 adults aged ≥45 years. We measured baseline plasma 25(OH)D in 711 sepsis cases and in 992 participants randomly selected from the REGARDS cohort. We captured sepsis events by screening records with International Classification of Disease methods and then adjudicating clinical charts for significant, suspected infection and severe inflammatory response syndrome criteria on presentation., Results: In the study sample, the median age of participants was 65.0 years, 41% self-identified as black, and 45% were male. Mean plasma 25(OH)D concentration was 25.8 ng/mL; for 31% of participants, it was <20 ng/mL. The adjusted risk of community-acquired sepsis was higher for each lower category of baseline 25(OH)D. Specifically, in a Cox proportional hazards model adjusting for multiple potential confounders, when compared to a baseline 25(OH)D >33.6 ng/mL, lower 25(OH)D groups were associated with higher hazards of sepsis (16.5-22.4 ng/mL; hazard ratio [HR]; 3.21; 95% confidence interval [CI], 1.98 to 5.21 and <16.5 ng/mL; HR, 6.81, 95% CI, 3.95 to 11.73). Results did not materially differ in analyses stratified by race or age., Conclusions: In the REGARDS cohort of community-dwelling US adults, low plasma 25(OH)D measured at a time of relative health was independently associated with increased risk of sepsis., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Genetic variants at the PTPN2 locus, which encodes the tyrosine phosphatase PTPN2, cause reduced gene expression and are linked to rheumatoid arthritis (RA) and other autoimmune diseases. PTPN2 inhibits signaling through the T cell and cytokine receptors, and loss of PTPN2 promotes T cell expansion and CD4- and CD8-driven autoimmunity. However, it remains unknown whether loss of PTPN2 in FoxP3+ regulatory T cells (Tregs) plays a role in autoimmunity. Here we aimed to model human autoimmune-predisposing PTPN2 variants, the presence of which results in a partial loss of PTPN2 expression, in mouse models of RA. We identified that reduced expression of Ptpn2 enhanced the severity of autoimmune arthritis in the T cell-dependent SKG mouse model and demonstrated that this phenotype was mediated through a Treg-intrinsic mechanism. Mechanistically, we found that through dephosphorylation of STAT3, PTPN2 inhibits IL-6-driven pathogenic loss of FoxP3 after Tregs have acquired RORγt expression, at a stage when chromatin accessibility for STAT3-targeted IL-17-associated transcription factors is maximized. We conclude that PTPN2 promotes FoxP3 stability in mouse RORγt+ Tregs and that loss of function of PTPN2 in Tregs contributes to the association between PTPN2 and autoimmunity.

Importance: Higher circulating fibroblast growth factor 23 (FGF23) concentrations are associated with cardiovascular disease events linked to heart failure, but associations of FGF23 with coronary heart disease (CHD) have been less consistent., Objective: To determine the association of plasma FGF23 concentrations with incident CHD and whether this association differs by race, sex, or chronic kidney disease status., Design, Setting, and Participants: We examined the association of FGF23 concentrations with incident CHD risk within the Reasons for Geographic and Racial Differences in Stroke study, a prospective cohort of black and white adults 45 years and older enrolled between January 2003 and October 2007 with follow-up through December 31, 2011. Using a case-cohort design, we measured FGF23 concentrations in 829 participants who developed incident CHD and in 812 participants randomly selected from the Reasons for Geographic and Racial Differences in Stroke study cohort (cohort random sample). To account for the stratified sampling design, the cohort random sample was weighted back to the original cohort overall (n = 22 127). Cox proportional hazards models were used to examine the association of FGF23 concentration with incident CHD, adjusting for CHD risk factors and kidney function. In prespecified analyses, we examined whether race, sex, or chronic kidney disease modified the association of FGF23 concentration with incident CHD., Exposures: Plasma C-terminal FGF23 concentrations., Main Outcomes and Measures: Investigator-adjudicated incident CHD events., Results: Of the 22 127 participants in the weighted cohort random sample, 13 059 (58.9%) were female and 9435 (42.6%) were black, and the mean age was 64.3 (95% CI, 63.7-64.9) years. Greater age, lower estimated glomerular filtration rate, higher urine albumin to creatinine ratio, and female sex were associated with higher FGF23 concentration at baseline. In multivariable models adjusted for established CHD risk factors and kidney function, higher FGF23 concentrations were associated with greater risk of CHD (hazard ratio [HR] comparing fourth with first quartile, 2.15; 95% CI, 1.35-3.42). The magnitude and strength of these associations differed by sex. However, these differences were no longer observed when adjusting for hormone therapy in women (men: HR comparing fourth with first quartile, 2.40; 95% CI, 1.30-4.42; women: HR comparing fourth with first quartile, 2.34; 95% CI, 1.04-5.27) or when using sex-specific FGF23 quartiles (men: HR comparing fourth with first quartile, 2.65; 95% CI, 1.43-4.90; women: HR comparing fourth with first quartile, 2.26; 95% CI, 1.02-5.03)., Conclusions and Relevance: Higher FGF23 concentrations were associated with greater risk of CHD. Heterogeneity in the association by sex may be caused by differences in the distribution of plasma FGF23 concentrations or the use of hormone therapy in men vs women.

Background: Anemia is highly prevalent in chronic kidney disease (CKD). Elevated hepcidin concentrations are an important mediator of disordered iron metabolism, a key mechanism underlying anemia of CKD. Vitamin D was recently shown to reduce serum hepcidin concentrations in healthy individuals. We examined whether treatment with calcitriol reduces serum hepcidin in individuals with CKD., Methods: A total of 40 participants with stage 3 or 4 CKD (eGFR 15-60 ml/min/1.73m 2 ) were randomized to receive either oral calcitriol 0.5 mcg daily or identically-matched placebo for 6 weeks. The primary outcome variable was change in serum hepcidin concentrations. Secondary outcomes variables included the change in iron parameters, calcium, phosphorus, intact parathyroid hormone and hemoglobin concentrations. Study samples were drawn at baseline, 3 days, 1 week, 4 weeks and 6 weeks after randomization. Repeated measures analysis was used to examine differences in outcome variables over time in the two groups., Results: There were no significant differences in the baseline characteristics between the placebo and calcitriol arms. Over 6 weeks of follow-up there were no significant differences in the change in serum hepcidin, iron parameters, or hemoglobin between the two groups. Serum calcium and phosphorus significantly increased and PTH significantly decreased after 6 weeks in calcitriol group whereas these analytes did not change in the placebo group., Conclusion: Calcitriol did not reduce serum hepcidin concentrations among individuals with mild to moderate CKD. Future studies are needed to assess if nutritional forms of vitamin D affect hepcidin concentrations in CKD., Trial Registration: ClinicalTrials.gov Identifier: NCT01988116 . Registered: November 4, 2013.

Background: The olfactory stimulus-percept problem has been studied for more than a century, yet it is still hard to precisely predict the odor given the large-scale chemoinformatic features of an odorant molecule. A major challenge is that the perceived qualities vary greatly among individuals due to different genetic and cultural backgrounds. Moreover, the combinatorial interactions between multiple odorant receptors and diverse molecules significantly complicate the olfaction prediction. Many attempts have been made to establish structure-odor relationships for intensity and pleasantness, but no models are available to predict the personalized multi-odor attributes of molecules. In this study, we describe our winning algorithm for predicting individual and population perceptual responses to various odorants in the DREAM Olfaction Prediction Challenge., Results: We find that random forest model consisting of multiple decision trees is well suited to this prediction problem, given the large feature spaces and high variability of perceptual ratings among individuals. Integrating both population and individual perceptions into our model effectively reduces the influence of noise and outliers. By analyzing the importance of each chemical feature, we find that a small set of low- and nondegenerative features is sufficient for accurate prediction., Conclusions: Our random forest model successfully predicts personalized odor attributes of structurally diverse molecules. This model together with the top discriminative features has the potential to extend our understanding of olfactory perception mechanisms and provide an alternative for rational odorant design.

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a polyglutamine-encoding CAG repeat expansion in the ATXN3 gene. This expansion leads to misfolding and aggregation of mutant ataxin-3 (ATXN3) and degeneration of select brain regions. A key unanswered question in SCA3 and other polyglutamine diseases is the extent to which neurodegeneration is mediated through gain-of-function versus loss-of-function. To address this question in SCA3, we performed transcriptional profiling on the brainstem, a highly vulnerable brain region in SCA3, in a series of mouse models with varying degrees of ATXN3 expression and aggregation. We include two SCA3 knock-in mouse models: our previously published model that erroneously harbors a tandem duplicate of the CAG repeat-containing exon, and a corrected model, introduced here. Both models exhibit dose-dependent neuronal accumulation and aggregation of mutant ATXN3, but do not exhibit a behavioral phenotype. We identified a molecular signature that correlates with ATXN3 neuronal aggregation yet is primarily linked to oligodendrocytes, highlighting early white matter dysfunction in SCA3. Two robustly elevated oligodendrocyte transcripts, Acy3 and Tnfrsf13c, were confirmed as elevated at the protein level in SCA3 human disease brainstem. To determine if mutant ATXN3 acts on oligodendrocytes cell-autonomously, we manipulated the repeat expansion in the variant SCA3 knock-in mouse by cell-type specific Cre/LoxP recombination. Changes in oligodendrocyte transcripts are driven cell-autonomously and occur independent of neuronal ATXN3 aggregation. Our findings support a primary toxic gain of function mechanism and highlight a previously unrecognized role for oligodendrocyte dysfunction in SCA3 disease pathogenesis., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Allelic exclusion describes the essential immunological process by which feedback repression of sequential DNA rearrangements ensures that only one autosome expresses a functional T or B cell receptor. In wild-type mammals, approximately 60% of cells have recombined the DNA of one T cell receptor β (TCRβ) V-to-DJ-joined allele in a functional configuration, while the second allele has recombined only the DJ sequences; the other 40% of cells have recombined the V to the DJ segments on both alleles, with only one of the two alleles predicting a functional TCRβ protein. Here we report that the transgenic overexpression of GATA3 leads predominantly to biallelic TCRβ gene ( Tcrb ) recombination. We also found that wild-type immature thymocytes can be separated into distinct populations based on intracellular GATA3 expression and that GATA3 LO cells had almost exclusively recombined only one Tcrb locus (that predicted a functional receptor sequence), while GATA3 HI cells had uniformly recombined both Tcrb alleles (one predicting a functional and the other predicting a nonfunctional rearrangement). These data show that GATA3 abundance regulates the recombination propensity at the Tcrb locus and provide new mechanistic insight into the historic immunological conundrum for how Tcrb allelic exclusion is mediated., (Copyright © 2017 American Society for Microbiology.)

Motivation: MicroRNAs (miRNAs) are small non-coding RNAs that are involved in post-transcriptional regulation of gene expression. In this high-throughput sequencing era, a tremendous amount of RNA-seq data is accumulating, and full utilization of publicly available miRNA data is an important challenge. These data are useful to determine expression values for each miRNA, but quantification pipelines are in a primitive stage and still evolving; there are many factors that affect expression values significantly., Results: We used 304 high-quality microRNA sequencing (miRNA-seq) datasets from NCBI-SRA and calculated expression profiles for different tissues and cell-lines. In each miRNA-seq dataset, we found an average of more than 500 miRNAs with higher than 5x coverage, and we explored the top five highly expressed miRNAs in each tissue and cell-line. This user-friendly miRmine database has options to retrieve expression profiles of single or multiple miRNAs for a specific tissue or cell-line, either normal or with disease information. Results can be displayed in multiple interactive, graphical and downloadable formats., Availability and Implementation: http://guanlab.ccmb.med.umich.edu/mirmine., Contact: bharatpa@umich.edu., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Vitamin D protects against cognitive decline in animals but evidence in humans has been inconsistent. Fibroblast growth factor 23 (FGF23) is a hormone that inhibits vitamin D activation yet few studies examined whether FGF23 is associated with cognitive impairment. The objective of this study was to examine associations of 25(OH)D and FGF23 with incident cognitive impairment in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults ≥45 years old. FGF23 and 25(OH)D were measured in 474 incident impairment cases and 561 controls. In multivariable-adjusted models, there were no significant associations of FGF23 with incident cognitive impairment. In analyses using clinically-relevant categories of 25(OH)D (< 20 ng/ml, 20-29.9 ng/ml, ≥30 ng/ml), there was no statistically significant association of lower 25(OH)D concentrations with odds of incident cognitive impairment in models adjusted for demographic, clinical, and laboratory variables and season of blood draw (tertile 1 [≥30 ng/ml] reference; tertile 2 [20-29.9 ng/ml], odds ratio [OR] 0.96, 95%CI 0.67, 1.38; tertile 3 [<20 ng/ml] OR 1.26, 95%CI 0.83, 1.91). When 25(OH)D was modeled as race-specific tertiles, there were no significant associations of 25(OH)D with incident cognitive impairment in whites, whereas lower 25(OH)D was associated with higher odds in blacks (tertile 1 [>23 ng/ml] reference; tertile 2 [15-23 ng/ml], OR 2.96, 95%CI 1.48,5.94; tertile 3 [<15 ng/ml] OR 2.40, 95%CI 1.07,5.40) in the fully adjusted model. In this cohort of older adults, lower race-specific tertiles of 25(OH)D were associated with higher incidence of cognitive impairment in black individuals but not white individuals. These data suggest that treating low 25(OH)D may be a novel strategy for addressing racial disparities in neurocognitive outcomes., Competing Interests: The authors have declared that no competing interests exist.

We present COMPASS, a COmputational Model to Predict the development of Alzheimer's diSease Spectrum, to model Alzheimer's disease (AD) progression. This was the best-performing method in recent crowdsourcing benchmark study, DREAM Alzheimer's Disease Big Data challenge to predict changes in Mini-Mental State Examination (MMSE) scores over 24-months using standardized data. In the present study, we conducted three additional analyses beyond the DREAM challenge question to improve the clinical contribution of our approach, including: (1) adding pre-validated baseline cognitive composite scores of ADNI-MEM and ADNI-EF, (2) identifying subjects with significant declines in MMSE scores, and (3) incorporating SNPs of top 10 genes connected to APOE identified from functional-relationship network. For (1) above, we significantly improved predictive accuracy, especially for the Mild Cognitive Impairment (MCI) group. For (2), we achieved an area under ROC of 0.814 in predicting significant MMSE decline: our model has 100% precision at 5% recall, and 91% accuracy at 10% recall. For (3), "genetic only" model has Pearson's correlation of 0.15 to predict progression in the MCI group. Even though addition of this limited genetic model to COMPASS did not improve prediction of progression of MCI group, the predictive ability of SNP information extended beyond well-known APOE allele.

Aims: Vitamin D is a fat-soluble vitamin classically known for its role in calcium absorption and bone health. Growing evidence indicates that vitamin D deficiency may be associated with inflammation, insulin resistance, and obesity. However, prior studies examining the association of vitamin D with metabolic risk factors had relatively low representation of individuals of black race, limiting their ability to characterize associations of vitamin D and parameters of metabolic health in black vs. white individuals., Methods: We examined associations of 25-hydroxyvitamin D (25(OH)D) concentrations with markers of inflammation (interleukin [IL]-6, IL-10, high sensitivity C-reactive protein [hsCRP]), insulin sensitivity (adiponectin, resistin, HOMA-IR), and obesity (body mass index [BMI], waist circumference) in 1,042 participants from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a large national cohort of black and white adults 45 years or older., Results: In unadjusted analyses, lower 25(OH)D concentrations were associated with higher IL-6 and hsCRP concentrations; lower adiponectin concentrations; higher HOMA-IR; and higher BMI and waist circumference ( P <0.05 for all). After adjustment for sociodemographic, clinical, lifestyle, and laboratory variables, lower 25(OH) D concentrations remained associated with lower adiponectin concentrations, higher IL-6 concentrations, higher HOMA-IR, and higher BMI and waist circumference ( P <0.05 for all). The magnitude of these associations did not differ by race ( P interaction >0.1)., Conclusions: Lower 25(OH)D concentrations are associated with disturbances in metabolic health in both blacks and whites. Whether correcting vitamin D deficiency could offer a beneficial therapy for additional disease prevention requires further study.

Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA&#95;Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h(2)=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data.

Background and Purpose: In previous observational studies, hemoglobin concentrations have been associated with an increased risk of stroke. However, these studies were limited by a relatively low number of stroke events, making it difficult to determine whether the association of hemoglobin and stroke differed by demographic or clinical factors., Methods: Using Cox proportional hazards analysis and Kaplan-Meier plots, we examined the association of baseline hemoglobin concentrations with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults aged ≥45 years., Results: A total of 518 participants developed stroke over a mean 7±2 years of follow-up. There was a statistically significant interaction between hemoglobin and sex (P=0.05) on the risk of incident stroke. In Cox regression models adjusted for demographic and clinical variables, there was no association of baseline hemoglobin concentration with incident stroke in men, whereas in women, the lowest (<12.4 g/dL) and highest (>14.0 g/dL) quartiles of hemoglobin were associated with higher risk of stroke when compared with the second quartile (12.4-13.2 g/dL; quartile 1: hazard ratio, 1.59; 95% confidence interval, 1.09-2.31; quartile 2: referent; quartile 3: hazard ratio, 0.91; 95% confidence interval, 0.59-1.38; quartile 4: hazard ratio, 1.59; 95% confidence interval, 1.08-2.35). Similar results were observed in models stratified by hemoglobin and sex and when hemoglobin was modeled as a continuous variable using restricted quadratic spline regression., Conclusions: Lower and higher hemoglobin concentrations were associated with a higher risk of incident stroke in women. No such associations were found in men., (© 2016 American Heart Association, Inc.)

Dysregulated iron homeostasis plays a central role in the development of anemia of chronic kidney disease (CKD) and is a major contributor toward resistance to treatment with erythropoiesis-stimulating agents. Understanding the underlying pathophysiology requires an in-depth understanding of normal iron physiology and regulation. Recent discoveries in the field of iron biology have greatly improved our understanding of the hormonal regulation of iron trafficking in human beings and how its alterations lead to the development of anemia of CKD. In addition, emerging evidence has suggested that iron homeostasis interacts with bone and mineral metabolism on multiple levels, opening up new avenues of investigation into the genesis of disordered iron metabolism in CKD. Building on recent advances in our understanding of normal iron physiology and abnormalities in iron homeostasis in CKD, this review characterizes how anemia related to disordered iron metabolism develops in the setting of CKD. In addition, this review explores our emerging recognition of the connections between iron homeostasis and mineral metabolism and their implications for the management of altered iron status and anemia of CKD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Functional genomics has enormous potential to facilitate our understanding of normal and disease-specific physiology. In the past decade, intensive research efforts have been focused on modeling functional relationship networks, which summarize the probability of gene co-functionality relationships. Such modeling can be based on either expression data only or heterogeneous data integration. Numerous methods have been deployed to infer the functional relationship networks, while most of them target the global (non-context-specific) functional relationship networks. However, it is expected that functional relationships consistently reprogram under different tissues or biological processes. Thus, advanced methods have been developed targeting tissue-specific or developmental stage-specific networks. This article brings together the state-of-the-art functional relationship network modeling methods, emphasizes the need for heterogeneous genomic data integration and context-specific network modeling and outlines future directions for functional relationship networks., (© The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

The vast majority of human multiexon genes undergo alternative splicing and produce a variety of splice variant transcripts and proteins, which can perform different functions. These protein-coding splice variants (PCSVs) greatly increase the functional diversity of proteins. Most functional annotation algorithms have been developed at the gene level; the lack of isoform-level gold standards is an important intellectual limitation for currently available machine learning algorithms. The accumulation of a large amount of RNA-seq data in the public domain greatly increases our ability to examine the functional annotation of genes at isoform level. In the present study, we used a multiple instance learning (MIL)-based approach for predicting the function of PCSVs. We used transcript-level expression values and gene-level functional associations from the Gene Ontology database. A support vector machine (SVM)-based 5-fold cross-validation technique was applied. Comparatively, genes with multiple PCSVs performed better than single PCSV genes, and performance also improved when more examples were available to train the models. We demonstrated our predictions using literature evidence of ADAM15, LMNA/C, and DMXL2 genes. All predictions have been implemented in a web resource called "IsoFunc", which is freely available for the global scientific community through http://guanlab.ccmb.med.umich.edu/isofunc .

Background: Black individuals are at greater risk of stroke and vitamin D deficiency than white individuals. Epidemiologic studies have shown that low 25-hydroxyvitamin D concentrations are associated with increased risk of stroke, but these studies had limited representation of black individuals., Methods: We examined the association of 25-hydroxyvitamin D with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults ≥45 years of age. Using a case-cohort study design, plasma 25-hydroxyvitamin D was measured in 610 participants who developed incident stroke (cases) and in 937 stroke-free individuals from a stratified cohort random sample of REGARDS participants (comparison cohort)., Results: In multivariable models adjusted for socio-demographic factors, co-morbidities and laboratory values including parathyroid hormone, lower 25-hydroxyvitamin D concentrations were associated with higher risk of stroke (25-hydroxyvitamin D >30 ng/mL reference; 25-hydroxyvitamin D concentrations 20-30 ng/mL, hazard ratio 1.33, 95% confidence interval (95% CI) 0.89,1.96; 25-hydroxyvitamin D <20 ng/mL, hazard ratio 1.85, 95% CI 1.17, 2.93). There were no statistically significant differences in the association of lower 25-hydroxyvitamin D with higher risk of stroke in black vs. white participants in fully adjusted models (hazard ratio comparing lowest vs. highest 25-hydroxyvitamin D category 2.62, 95% CI 1.18, 5.83 in blacks vs. 1.64, 95% CI 0.83, 3.24 in whites, P(interaction) = 0.82). The associations were qualitatively unchanged when restricted to ischemic or hemorrhagic stroke subtypes or when using race-specific cut-offs for 25-hydroxyvitamin D categories., Conclusions: Vitamin D deficiency is a risk factor for incident stroke and the strength of this association does not appear to differ by race., (© 2016 World Stroke Organization.)

Background: The association between waist circumference and end-stage renal disease (ESRD) remains poorly explored., Study Design: Longitudinal population-based cohort., Setting & Participants: Participants in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study (n=30,239) with information for body mass index (BMI), waist circumference, spot urine albumin-creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR; n=26,960)., Predictor: Elevated waist circumference or BMI., Outcomes & Measurements: Incident cases of ESRD were identified through linkage of REGARDS participants with the US Renal Data System., Results: Mean baseline age was 64.8 years, 45.8% were men, and 40.3% were black. Overall, 297 (1.1%) individuals developed ESRD during a median of 6.3 years. After adjustment for all covariates including waist circumference, no significant association was noted between BMI categories and ESRD incidence compared to BMI of 18.5 to 24.9 kg/m2 (referent). Higher waist circumference categories showed significantly increased hazard rates of ESRD, with waist circumference ≥ 108 cm in women and ≥122 cm in men (highest category) showing a 3.97-fold higher hazard rate (95% CI, 2.10-6.86) for ESRD compared to waist circumference < 80 cm in women and <94 cm in men (referent) after adjusting for demographic factors and BMI. However, no significant association was noted between any waist circumference category and ESRD incidence after adjustment for obesity-associated comorbid conditions and baseline ACR and eGFR., Limitations: Short follow-up period (6.3 years) to assess ESRD risk among adults with eGFRs>60 mL/min/1.73 m2., Conclusions: In this cohort of older adults, obesity as measured by waist circumference is associated with higher ESRD risk even with adjustment for BMI, whereas obesity as measured by BMI is not associated with higher ESRD risk after adjustment for waist circumference. However, no significant association is noted between increased waist circumference and ESRD risk after adjustment for obesity-related comorbid conditions, eGFR, and ACR., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

We have developed the web-based Michigan Proteome Visualization Tool (MI-PVT) to visualize and compare protein expression and isoform-level function across human chromosomes and tissues (http://guanlab.ccmb.med.umich.edu/mipvt). As proof of principle, we have populated the tool with Human Proteome Map (HPM) data. We were able to observe many biologically interesting features. From the vantage point of our chromosome 17 team, for example, we found more than 300 proteins from chromosome 17 expressed in each of the 30 tissues and cell types studied, with the highest number of expressed proteins being 685 in testis. Comparisons of expression levels across tissues showed low numbers of proteins expressed in esophagus, but esophagus had 12 cytoskeletal proteins coded on chromosome 17 with very high expression (>1000 spectral counts). This customized MI-PVT should be helpful for biologists to browse and study specific proteins and protein data sets across tissues and chromosomes. Users can upload any data of interest in MI-PVT for visualization. Our aim is to integrate extensive mass-spectrometric proteomic data into the tool to facilitate finding chromosome-centric protein expression and correlation across tissues.