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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]

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.)