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1.  Preparation of low galactose yogurt using cultures of Gal+Streptococcus thermophilus in combination with Lactobacillus delbrueckii ssp. bulgaricus 
Streptococcus thermophilus is an important lactic starter used in the production of yogurt. Most strains of S. thermophilus are galactose negative (Gal−) and are able to metabolize only glucose portion of lactose and expel galactose into the medium. This metabolic defect leads to the accumulation of free galactose in yogurt, resulting in galactosemia among consumers. Hence there is an absolute need to develop low galactose yogurt. Therefore, in this study, three galactose positive (Gal+) S. thermophilus strains from National Collection of Dairy Cultures (NCDC) viz. NCDC 659 (AJM), NCDC 660 (JM1), NCDC 661 (KM3) and a reference galactose negative (Gal−) S. thermophilus NCDC 218 were used for preparation of low galactose yogurt. In milk fermented using S. thermophilus isolates alone, NCDC 659 released less galactose (0.27 %) followed by NCDC 661 (0.3 %) and NCDC 660 (0.45 %) after 10 h at 42 °C. Milk was fermented in combination with Gal−L. delbrueckii subsp. bulgaricus NCDC 04, in which NCDC 659 released least galactose upto 0.49 % followed by NCDC 661 (0.51 %) and NCDC 660 (0.60 %) than reference Gal− NCDC 218(0.79 %). Low galactose yogurt was prepared following standard procedure using Gal+S. thermophilus isolates and Gal−L. delbrueckii subsp. bulgaricus NCDC 04 in 1:1 ratio. Among which low galactose yogurt by NCDC 659 combination contained less galactose 0.37 % followed by NCDC 661 (0.51 %), NCDC 660 (0.65 %) and reference Gal− NCDC 218 (0.98 %) after 4 h of fermentation. This study clearly reveals that Gal+S. thermophilus isolates can be paired with Gal−L. delbrueckii subsp. bulgaricus for developing low galactose yogurt.
PMCID: PMC4152513  PMID: 25190881
Galactose; S. thermophilus; Low galactose yogurt; L. delbrueckii subsp. bulgaricus
2.  Patients with irritable bowel syndrome-diarrhea have lower disease-specific quality of life than irritable bowel syndrome-constipation 
AIM: To determine effect of irritable bowel syndrome (IBS) subtype on IBS-specific quality of life (QOL) questionnaire and its subscales.
METHODS: We studied IBS patients visiting our functional gastroenterology disorder clinic at a tertiary care center of Unites States. IBS and IBS subtype were diagnosed using Rome-III questionnaire. QOL was assessed using IBS-QOL questionnaire. IBS-QOL assesses quality of life along eight subscales: dysphoria, interference with activities, body image, health worry, food avoidance, social reactions, sexual health, and effect on relationships. IBS-QOL and its subscales were both scored on a range of 0-100 with higher scores suggestive of better QOL. Results of overall IBS-QOL scores and subscale scores are expressed as means with 95%CI. We compared mean IBS-QOL score and its subscales among various IBS-subtypes. Analysis of variance (ANOVA) was used to compare the mean difference between more than two groups after controlling for age and gender. A post-hoc analysis using Bonferroni correction was used only when P value for ANOVA was less than 0.05.
RESULTS: Of 542 patients screened, 243 had IBS as per Rome-III criteria. IBS-mixed (IBS-M) was the most common IBS subtype (121 patients, 49.8%) followed by IBS- diarrhea (IBS-D) (56 patients, 23.1%), IBS-constipation (IBS-C) (54 patients, 22.2%) and IBS-unspecified (IBS-U) (12 patients, 4.9%). Overall IBS-QOL scores were significantly different among various IBS-subtypes (P = 0.01). IBS-QOL of patients with IBS-D (61.6, 95%CI: 54.0-69.1) and IBS-M (63.0, 95%CI: 58.1-68.0) was significantly lower than patients with IBS-C (74.5, 95%CI: 66.9-82.1) (P = 0.03 and 0.02 respectively). IBS-D patients scored significantly lower than IBS-C on food avoidance (45.0, 95%CI: 34.8-55.2 vs 61.1, 95%CI: 50.8-71.3, P = 0.04) and interference with activity (59.6, 95%CI: 51.4-67.7 vs 82.3, 95%CI: 74.1-90.6, P < 0.001). IBS-M patients had more interference in their activities (61.6, 95%CI: 56.3-66.9 vs 82.3, 95%CI: 74.1-90.6, P = 0.001) and greater impact on their relationships (73.3, 95%CI: 68.4-78.2 vs 84.7, 95%CI: 77.2-92.2, P = 0.02) than IBS-C patients. Patients with IBS-M also scored significantly lower than IBS-C on food avoidance (47.2, 95%CI: 40.7-53.7 vs 61.1, 95%CI: 50.8-71.3, P = 0.04) and social reaction (66.1, 95%CI: 61.1-71.1 vs 80.0, 95%CI: 72.1-87.7, P = 0.005).
CONCLUSION: IBS-D and IBS-M patients have lower IBS-QOL than IBS-C patients. Clinicians should recognize food avoidance, effects on daily activities and relationship problems in these patients.
PMCID: PMC4499353  PMID: 26185382
Irritable bowel syndrome; Irritable bowel syndrome subtype; Quality of life; Irritable bowel syndrome-quality of life; Constipation; Diarrhea
3.  Phylogenetic analysis of heterocystous cyanobacteria (Subsections IV and V) using highly iterated palindromes as molecular markers 
Highly iterated palindromes (HIP) have been used as high resolution molecular markers for assessing the genetic variability and phylogenetic relatedness of heterocystous cyanobacteria (subsections IV and V) representing 12 genera of heterocystous cyanobacteria, collected from different geographical areas of India. DNA fingerprints generated using four HIP markers viz. HIP-AT, HIP-CA, HIP-GC, and HIP-TG showed 100 % polymorphism in all the heterocystous cyanobacteria studied and each marker produced unique and strain-specific banding pattern. Furthermore, phylogenetic affinities based on the dendrogram constructed using HIP DNA profiles of heterocystous cyanobacteria suggest the monophyletic origin of this entire heterocystous clade along with a clear illustration of the polyphyletic origin of the branched Stigonematalean order (Subsection V). In addition, phylogenetic affinities were validated by principal component analysis of the HIP fingerprints. The overall data obtained by both the phylogeny and principal component assessments proved that the entire heterocystous clade was intermixed, and there are immediate needs for classificatory reforms that satisfy morphological plasticity and environmental concerns.
PMCID: PMC4101137  PMID: 25049460
Heterocystous cyanobacteria; Highly iterated palindromes; Phylogeny; Principal component analysis
4.  Integrative genomic analysis in K562 chronic myelogenous leukemia cells reveals that proximal NCOR1 binding positively regulates genes that govern erythroid differentiation and Imatinib sensitivity 
Nucleic Acids Research  2015;43(15):7330-7348.
To define the functions of NCOR1 we developed an integrative analysis that combined ENCODE and NCI-60 data, followed by in vitro validation. NCOR1 and H3K9me3 ChIP-Seq, FAIRE-seq and DNA CpG methylation interactions were related to gene expression using bootstrapping approaches. Most NCOR1 combinations (24/44) were associated with significantly elevated level expression of protein coding genes and only very few combinations related to gene repression. DAVID's biological process annotation revealed that elevated gene expression was uniquely associated with acetylation and ETS binding. A matrix of gene and drug interactions built on NCI-60 data identified that Imatinib significantly targeted the NCOR1 governed transcriptome. Stable knockdown of NCOR1 in K562 cells slowed growth and significantly repressed genes associated with NCOR1 cistrome, again, with the GO terms acetylation and ETS binding, and significantly dampened sensitivity to Imatinib-induced erythroid differentiation. Mining public microarray data revealed that NCOR1-targeted genes were significantly enriched in Imatinib response gene signatures in cell lines and chronic myelogenous leukemia (CML) patients. These approaches integrated cistrome, transcriptome and drug sensitivity relationships to reveal that NCOR1 function is surprisingly most associated with elevated gene expression, and that these targets, both in CML cell lines and patients, associate with sensitivity to Imatinib.
PMCID: PMC4551916  PMID: 26117541
5.  Epigenetic distortion to VDR transcriptional regulation in prostate cancer cells 
The current study aimed to examine the gene specific mechanisms by which the actions of the vitamin D receptor (VDR) are distorted in prostate cancer. Transcriptional responses toward the VDR ligand, 1α,25(OH)2D3, were examined in non-malignant prostate epithelial cells (RWPE-1) and compared to the 1α,25(OH)2D3-recalcitrant prostate cancer cells (PC-3). Time resolved transcriptional studies for two VDR target genes revealed selective attenuation and repression of VDR transcriptional responses in PC-3 cells. For example, responses in PC-3 cells revealed suppressed responsiveness of IGFBP3 and G0S2. Furthermore, Chromatin Immunoprecipitation (ChIP) assays revealed that suppressed transcriptional responses in PC-3 cells of IGFBP3 and G0S2 were associated with selective VDR-induced NCOR1 enrichment at VDR-binding regions on target-gene promoter regions. We propose that VDR inappropriately recruits co-repressors in prostate cancer cells. Subsequent direct and indirect mechanisms may induce local DNA methylation and stable transcriptional silencing. Thus a transient epigenetic process mediated by co-repressor binding, namely, the control of H3K9 acetylation, is distorted to favor a more stable epigenetic event, namely DNA methylation.
PMCID: PMC4429754  PMID: 23098689
NCOR1; Prostate cancer; Epigenetics; VDR
6.  Predictors of Time to Recovery in Infants with Probable Serious Bacterial Infection 
PLoS ONE  2015;10(4):e0124594.
Serious bacterial infections continue to be an important cause of death and illness among infants in developing countries. Time to recovery could be considered a surrogate marker of severity of the infection. We therefore aimed to identify clinical and laboratory predictors of time to recovery in infants with probable serious bacterial infection (PSBI).
We used the dataset of 700 infants (7-120 days) enrolled in a randomised controlled trial in India in which 10mg of oral zinc or placebo was given to infants with PSBI. PSBI was defined as signs/symptoms of possible serious bacterial infection along with baseline C-reactive protein(CRP) level >12mg/L. Time to recovery was defined as time from enrolment to the end of a 2-day period with no symptoms/signs of PSBI and daily weight gain of at least 10g over 2 succesive days on exclusive oral feeding. Cox proportional hazard regression was used to measure the associations between relevant variables and time to recovery.
Infants who were formula fed prior to illness episode had 33% longer time to recovery (HR-0.67, 95%CI-0.52, 0.87) than those who were not. Being underweight (HR-0.84, 95%CI-0.70, 0.99), lethargic (HR-0.77, 95%CI-0.62, 0.96) and irritable (HR-0.81, 95%CI-0.66, 0.99) were independent predictors of time to recovery. Baseline CRP was significantly associated with time to recovery (P<0.001), higher CRP was associated with longer time to recovery and this association was nearly linear.
Simple clinical and laboratory parameters such as formula feeding prior to the illness, being underweight, lethargic, irritable and having elevated CRP levels could be used for early identification of infants with PSBI at risk for protracted illness and could guide prompt referral to higher centers in resource limited settings. This also provides prognostic information to clinicians and family as longer recovery time has economic and social implications on the family in our setting.
Trial Registration NCT00347386
PMCID: PMC4409397  PMID: 25909192
7.  Plasma Deactivation of Oral Bacteria Seeded on Hydroxyapatite Disks as Tooth Enamel Analogue 
American journal of dentistry  2014;27(2):84-90.
To study the plasma treatment effects on deactivation of oral bacteria seeded on a tooth enamel analogue.
A non-thermal atmospheric pressure argon plasma brush was used to treat two different Gram-positive oral bacteria including Lactobacillus acidophilus (L. acidophilus) and Streptococcus mutans (S. mutans). The bacteria were seeded on hydroxyapatite (HA) disks used as tooth enamel analogue with three initial bacterial seeding concentrations: a low inoculum concentration between 2.1×108 and 2.4×108 cfu/mL, a medium inoculum concentration between 9.8×108 and 2.4×109 cfu/mL, and a high inoculum concentration between 1.7×1010 and 3.5×1010 cfu/mL. The bacterial survivability upon plasma exposure was examined in terms of plasma exposure time and oxygen addition into the plasmas. SEM was performed to examine bacterial morphological changes after plasma exposure.
The experimental data indicated that 13 second plasma exposure time completely killed all the bacteria when initial bacterial seeding density on HA surfaces were less than 6.9×106 cfu/cm2 for L. acidophilus and 1.7×107 cfu/cm2 for S. mutans, which were resulted from low initial seeding inoculum concentration between 2.1×108 and 2.4×108 cfu/mL. Plasma exposure of the bacteria at higher initial bacterial seeding density obtained with high initial seeding inoculum concentration, however, only resulted in ~ 1.5 to 2 log reduction and ~ 2 to 2.5 log reduction for L. acidophilus and S. mutans, respectively. It was also noted that oxygen addition into the argon plasma brush did not affect the plasma deactivation effectiveness. SEM images showed that plasma deactivation mainly occurred with the top layer bacteria, while shadowing effects from the resulting bacterial debris reduced the plasma deactivation of the underlying bacteria.
Clinical Significance
The experimental results indicate that, with direct contact, nonthermal atmospheric pressure argon plasmas could rapidly and effectively deactivate oral bacteria seeded on HA surfaces and thus could be a promising technique in various dental clinical applications.
PMCID: PMC4090609  PMID: 25000666
Atmospheric plasmas; bacterial deactivation; glow discharge; hydroxyapatite disc; oral bacteria
8.  Proteome mapping of epidermal growth factor induced hepatocellular carcinomas identifies novel cell metabolism targets and mitogen activated protein kinase signalling events 
BMC Genomics  2015;16(1):124.
Hepatocellular carcinoma (HCC) is on the rise and the sixth most common cancer worldwide. To combat HCC effectively research is directed towards its early detection and the development of targeted therapies. Given the fact that epidermal growth factor (EGF) is an important mitogen for hepatocytes we searched for disease regulated proteins to improve an understanding of the molecular pathogenesis of EGF induced HCC. Disease regulated proteins were studied by 2DE MALDI-TOF/TOF and a transcriptomic approach, by immunohistochemistry and advanced bioinformatics.
Mapping of EGF induced liver cancer in a transgenic mouse model identified n = 96 (p < 0.05) significantly regulated proteins of which n = 54 were tumour-specific. To unravel molecular circuits linked to aberrant EGFR signalling diverse computational approaches were employed and this defined n = 7 key nodes using n = 82 disease regulated proteins for network construction. STRING analysis revealed protein-protein interactions of > 70% disease regulated proteins with individual proteins being validated by immunohistochemistry. The disease regulated network proteins were mapped to distinct pathways and bioinformatics provided novel insight into molecular circuits associated with significant changes in either glycolysis and gluconeogenesis, argine and proline metabolism, protein processing in endoplasmic reticulum, Hif- and MAPK signalling, lipoprotein metabolism, platelet activation and hemostatic control as a result of aberrant EGF signalling. The biological significance of the findings was corroborated with gene expression data derived from tumour tissues to evntually define a rationale by which tumours embark on intriguing changes in metabolism that is of utility for an understanding of tumour growth. Moreover, among the EGF tumour specific proteins n = 11 were likewise uniquely expressed in human HCC and for n = 49 proteins regulation in human HCC was confirmed using the publically available Human Protein Atlas depository, therefore demonstrating clinical significance.
Novel insight into the molecular pathogenesis of EGF induced liver cancer was obtained and among the 37 newly identified proteins several are likely candidates for the development of molecularly targeted therapies and include the nucleoside diphosphate kinase A, bifunctional ATP-dependent dihydroyacetone kinase and phosphatidylethanolamine-binding protein1, the latter being an inhibitor of the Raf-1 kinase.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1312-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4357185  PMID: 25872475
Epidermal growth factor; Transgenic mice; Hepatocellular carcinoma; 2D-PAGE; MALDI-TOF/TOF; Immunhistochemistry; Computational biology
9.  Genetic variants in microRNAs and breast cancer risk in African American and European American women 
MicroRNAs (miRNAs) are an integral part of the post-transcriptional machinery of gene expression and have been implicated in the carcinogenic cascade. Single nucleotide polymorphisms (SNPs) in miRNAs and risk of breast cancer have been evaluated in populations of European or Asian ancestry, but not among women of African ancestry. Here we examined 145 SNPs in 6 miRNA processing genes and in 78 miRNAs which target genes known to be important in breast cancer among 906 African American (AA) and 653 European American (EA) cases and controls enrolled in the Women’s Circle of Health Study (WCHS). Allele frequencies of most SNPs (87%) differed significantly by race. We found a number of SNPs in miRNAs and processing genes in association with breast cancer overall or stratified by estrogen receptor (ER) status. Several associations were significantly different by race, with none of the associations being significant in both races. Using a polygenic risk score to combine the effects of multiple SNPs, we found significant associations with the score in each subgroup analysis. For ER-positive cancer, each unit increment of the risk score was associated with a 51% increased risk in AAs (OR=1.51, 95% CI=1.30–1.74, p=3.3*10−8) and a 73% increased risk in EAs (OR=1.73, 95% CI=1.45–2.06, p=1.4*10−9). These data show, for the first time, that miRNA-related genetic variations may underlie the etiology of breast cancer in both populations of African and European ancestries. Future studies are needed to validate our findings and to explore the underlying mechanisms.
PMCID: PMC3856568  PMID: 24062209
microRNA; SNP; breast cancer; epidemiology; estrogen receptor; polygenic risk score
10.  Multiple Shocks, Coping and Welfare Consequences: Natural Disasters and Health Shocks in the Indian Sundarbans 
PLoS ONE  2014;9(8):e105427.
Based on a household survey in Indian Sundarbans hit by tropical cyclone Aila in May 2009, this study tests for evidence and argues that health and climatic shocks are essentially linked forming a continuum and with exposure to a marginal one, coping mechanisms and welfare outcomes triggered in the response is significantly affected.
Data & Methods
The data for this study is based on a cross-sectional household survey carried out during June 2010. The survey was aimed to assess the impact of cyclone Aila on households and consequent coping mechanisms in three of the worst-affected blocks (a sub-district administrative unit), viz. Hingalganj, Gosaba and Patharpratima. The survey covered 809 individuals from 179 households, cross cutting age and gender. A separate module on health-seeking behaviour serves as the information source of health shocks defined as illness episodes (ambulatory or hospitalized) experienced by household members.
Key findings
Finding reveals that over half of the households (54%) consider that Aila has dealt a high, damaging impact on their household assets. Result further shows deterioration of health status in the period following the incidence of Aila. Finding suggests having suffered multiple shocks increases the number of adverse welfare outcomes by 55%. Whereas, suffering either from the climatic shock (33%) or the health shock (25%) alone increases such risks by a much lesser extent. The multiple-shock households face a significantly higher degree of difficulty to finance expenses arising out of health shocks, as opposed to their counterparts facing only the health shock. Further, these households are more likely to finance the expenses through informal loans and credit from acquaintances or moneylenders.
This paper presented empirical evidence on how natural and health shocks mutually reinforce their resultant impact, making coping increasingly difficult and present significant risks of welfare loss, having short as well as long-run development manifestations.
PMCID: PMC4149427  PMID: 25170846
11.  Cofactor Independent Phosphoglycerate Mutase of Brugia malayi Induces a Mixed Th1/Th2 Type Immune Response and Inhibits Larval Development in the Host 
BioMed Research International  2014;2014:590281.
Lymphatic filariasis is a major debilitating disease, endemic in 72 countries putting more than 1.39 billion people at risk and 120 million are already infected. Despite the significant progress in chemotherapeutic advancements, there is still need for other measures like development of an effective vaccine or discovery of novel drug targets. In this study, structural and immunological characterization of independent phosphoglycerate mutase of filarial parasite Brugia malayi was carried out. Protein was found to be expressed in all major parasite life stages and as an excretory secretory product of adult parasites. Bm-iPGM also reacted to all the categories of human bancroftian patient's sera including endemic normals. In vivo immunological behaviour of protein was determined in immunized BALB/c mice followed by prophylactic analysis in BALB/c mice and Mastomys coucha. Immunization with Bm-iPGM led to generation of a mixed Th1/Th2 type immune response offering 58.2% protection against larval challenge in BALB/c and 65–68% protection in M. coucha. In vitro studies confirmed participation of anti-Bm-iPGM antibodies in killing of B. malayi infective larvae and microfilariae through ADCC mechanism. The present findings reveal potential immunoprotective nature of Bm-iPGM advocating its worth as an antifilarial vaccine candidate.
PMCID: PMC4100390  PMID: 25061608
12.  Two functional serotonin polymorphisms moderate the effect of food reinforcement on BMI 
Behavioral neuroscience  2013;127(3):387-399.
Food reinforcement, or the motivation to eat, has been associated with increased energy intake, greater body weight and prospective weight gain. Much of the previous research on the reinforcing value of food has focused on the role of dopamine, but it may be worthwhile to examine genetic polymorphisms in the serotonin and opioid systems as these neurotransmitters have been shown to be related to reinforcement processes and to influence energy intake. We examined the relationship among 44 candidate genetic polymorphisms in the dopamine, serotonin and opioid systems, and food reinforcement and body mass index (BMI) in a sample of 245 individuals. Polymorphisms in the Monoamine oxidase A (MAOA-LPR) and serotonin receptor 2A genes (rs6314) moderated the effect of food reinforcement on BMI, accounting for an additional 5-10% variance and revealed a potential role of the single nucleotide polymorphism, rs6314 in the serotonin 2A receptor as a differential susceptibility factor for obesity. Differential susceptibility describes a factor that can confer either risk or protection depending on a second variable, such that rs6314 is predictive of both high and low BMI based on the level of food reinforcement, while the diathesis stress or dual-gain model influences only one end of the outcome measure. The interaction with MAOA-LPR better fit the dual-risk or diathesis stress model, with the 3.5R/4R allele conferring protection for individuals low in food reinforcement. These results provide new insight into genes theoretically involved in obesity and support the hypothesis that genetics moderate the association between food reinforcement on BMI.
PMCID: PMC4049455  PMID: 23544600
Obesity; dopamine; serotonin; food reinforcement; differential susceptibility
13.  Recruitment of NCOR1 to VDR target genes is enhanced in prostate cancer cells and associates with altered DNA methylation patterns 
Carcinogenesis  2012;34(2):248-256.
The current study investigated transcriptional distortion in prostate cancer cells using the vitamin D receptor (VDR) as a tool to examine how epigenetic events driven by corepressor binding and CpG methylation lead to aberrant gene expression. These relationships were investigated in the non-malignant RWPE-1 cells that were 1α,25(OH)2D3 responsive (RWPE-1) and malignant cell lines that were 1α,25(OH)2D3 partially responsive (RWPE-2) and resistant (PC-3). These studies revealed that selective attenuation and repression of VDR transcriptional responses in the cancer cell lines reflected their loss of antiproliferative sensitivity. This was evident in VDR target genes including VDR, CDKN1A (encodes p21(waf1/cip1)) and GADD45A; NCOR1 knockdown alleviated this malignant transrepression. ChIP assays in RWPE-1 and PC-3 cells revealed that transrepression of CDKN1A was associated with increased NCOR1 enrichment in response to 1α,25(OH)2D3 treatment. These findings supported the concept that retained and increased NCOR1 binding, associated with loss of H3K9ac and increased H3K9me2, may act as a beacon for the initiation and recruitment of DNA methylation. Overexpressed histone methyltransferases (KMTs) were detectable in a wide panel of prostate cancer cell lines compared with RWPE-1 and suggested that generation of H3K9me2 states would be favored. Cotreatment of cells with the KMT inhibitor, chaetocin, increased 1α,25(OH)2D3-mediated induction of CDKN1A expression supporting a role for this event to disrupt CDKN1A regulation. Parallel surveys in PC-3 cells of CpG methylation around the VDR binding regions on CDKN1A revealed altered basal and VDR-regulated DNA methylation patterns that overlapped with VDR-induced recruitment of NCOR1 and gene transrepression. Taken together, these findings suggest that sustained corepressor interactions with nuclear-resident transcription factors may inappropriately transform transient-repressive histone states into more stable and repressive DNA methylation events.
PMCID: PMC3564435  PMID: 23087083
14.  Serum microRNA expression patterns that predict early treatment failure in prostate cancer patients 
Oncotarget  2014;5(3):824-840.
We aimed to identify microRNA (miRNA) expression patterns in the serum of prostate cancer (CaP) patients that predict the risk of early treatment failure following radical prostatectomy (RP). Microarray and Q-RT-PCR analyses identified 43 miRNAs as differentiating disease stages within 14 prostate cell lines and reflectedpublically available patient data. 34 of these miRNA were detectable in the serum of CaP patients. Association with time to biochemical progression was examined in a cohort of CaP patients following RP. A greater than two-fold increase in hazard of biochemical progression associated with altered expression of miR-103, miR-125b and miR-222 (p <.0008) in the serum of CaP patients. Prediction models based on penalized regression analyses showed that the levels of the miRNAs and PSA together were better at detecting false positives than models without miRNAs, for similar level of sensitivity. Analyses of publically available data revealed significant and reciprocal relationships between changes in CpG methylation and miRNA expression patterns suggesting a role for CpG methylation to regulate miRNA. Exploratory validation supported roles for miR-222 and miR-125b to predict progression risk in CaP. The current study established that expression patterns of serum-detectable miRNAs taken at the time of RP are prognostic for men who are at risk of experiencing subsequent early biochemical progression. These non-invasive approaches could be used to augment treatment decisions.
PMCID: PMC3996656  PMID: 24583788
Prostate cancer; microRNA; biochemical progression; miR-103; miR-125b; miR-222; cancer epigenetics
15.  Evaluation of Phytase Producing Bacteria for Their Plant Growth Promoting Activities 
Bacterial inoculants are known to possess plant growth promoting abilities and have potential as liquid biofertilizer application. Four phytase producing bacterial isolates (phytase activity in the range of 0.076–0.174 U/mL), identified as Advenella species (PB-05, PB-06, and PB-10) and Cellulosimicrobium sp. PB-09, were analyzed for their plant growth promoting activities like siderophore production, IAA production, HCN production, ammonia production, phosphate solubilization, and antifungal activity. All isolates were positive for the above characteristics except for HCN production. The solubilization index for phosphorus on Pikovskaya agar plates was in the range of 2–4. Significant amount of IAA (7.19 to 35.03 μg/mL) production and solubilized phosphate (189.53 to 746.84 μg/mL) was noticed by these isolates at different time intervals. Besides that, a greenhouse study was also conducted with Indian mustard to evaluate the potential of these isolates to promote plant growth. Effect of seed bacterization on various plant growth parameters and P uptake by plant were used as indicators. The plant growth promoting ability of bacterial isolates in pot experiments was correlated to IAA production, phosphate solubilization, and other in vitro tests. On the basis of present findings, isolate PB-06 was most promising in plant growth promotion with multiple growth promoting characteristics.
PMCID: PMC3941791  PMID: 24669222
16.  Equity in maternal, newborn, and child health care coverage in India 
Global Health Action  2013;6:10.3402/gha.v6i0.22217.
Addressing inequitable coverage of maternal and child health care services among different socioeconomic strata of population and across states is an important part of India's contemporary health program. This has wide implications for the achievement of the Millennium Development Goal targets.
This paper assesses the inequity in coverage of maternal, newborn, and child health (MNCH) care services across household wealth quintiles in India and its states.
Utilizing the District Level Household and Facility Survey conducted during 2007–08, this paper has constructed a Composite Coverage Index (CCI) in MNCH care.
The mean overall coverage of 45% was estimated at the national level, ranging from 31% for the poorest to 60% for the wealthiest quintile. Moreover, a massive state-wise difference across wealth quintiles was observed in the mean overall CCI. Almost half of the Indian states and union territories recorded a ≤50% coverage in MNCH care services, which demands special attention.
India needs focused efforts to address the inequity in coverage of health care services by recognising or defining underserved people and pursuing well-planned time-oriented health programs committed to ameliorate the present state of MNCH care.
PMCID: PMC3772319  PMID: 24119659
maternal; newborn and child health; composite coverage index; household economic status; states; India; millennium development goals
17.  Trends in Child Immunization across Geographical Regions in India: Focus on Urban-Rural and Gender Differentials 
PLoS ONE  2013;8(9):e73102.
Although child immunization is regarded as a highly cost-effective lifesaver, about fifty percent of the eligible children aged 12–23 months in India are without essential immunization coverage. Despite several programmatic initiatives, urban-rural and gender difference in child immunization pose an intimidating challenge to India’s public health agenda. This study assesses the urban-rural and gender difference in child immunization coverage during 1992–2006 across six major geographical regions in India.
Data and Methods
Three rounds of the National Family Health Survey (NFHS) conducted during 1992–93, 1998–99 and 2005–06 were analyzed. Bivariate analyses, urban-rural and gender inequality ratios, and the multivariate-pooled logistic regression model were applied to examine the trends and patterns of inequalities over time.
Key Findings
The analysis of change over one and half decades (1992–2006) shows considerable variations in child immunization coverage across six geographical regions in India. Despite a decline in urban-rural and gender differences over time, children residing in rural areas and girls remained disadvantaged. Moreover, northeast, west and south regions, which had the lowest gender inequality in 1992 observed an increase in gender difference over time. Similarly, urban-rural inequality increased in the west region during 1992–2006.
This study suggests periodic evaluation of the health care system is vital to assess the between and within group difference beyond average improvement. It is essential to integrate strong immunization systems with broad health systems and coordinate with other primary health care delivery programs to augment immunization coverage.
PMCID: PMC3762848  PMID: 24023816
18.  Immunization of Mastomys coucha with Brugia malayi Recombinant Trehalose-6-Phosphate Phosphatase Results in Significant Protection against Homologous Challenge Infection 
PLoS ONE  2013;8(8):e72585.
Development of a vaccine to prevent or reduce parasite development in lymphatic filariasis would be a complementary approach to existing chemotherapeutic tools. Trehalose-6-phosphate phosphatase of Brugia malayi (Bm-TPP) represents an attractive vaccine target due to its absence in mammals, prevalence in the major life stages of the parasite and immunoreactivity with human bancroftian antibodies, especially from endemic normal subjects. We have recently reported on the cloning, expression, purification and biochemical characterization of this vital enzyme of B. malayi. In the present study, immunoprophylactic evaluation of Bm-TPP was carried out against B. malayi larval challenge in a susceptible host Mastomys coucha and the protective ability of the recombinant protein was evaluated by observing the adverse effects on microfilarial density and adult worm establishment. Immunization caused 78.4% decrease in microfilaremia and 71.04% reduction in the adult worm establishment along with sterilization of 70.06% of the recovered live females. The recombinant protein elicited a mixed Th1/Th2 type of protective immune response as evidenced by the generation of both pro- and anti-inflammatory cytokines IL-2, IFN-γ, TNF-α, IL-4 and an increased production of antibody isotypes IgG1, IgG2a, IgG2b and IgA. Thus immunization with Bm-TPP conferred considerable protection against B. malayi establishment by engendering a long-lasting effective immune response and therefore emerges as a potential vaccine candidate against lymphatic filariasis (LF).
PMCID: PMC3755969  PMID: 24015262
19.  The Interactions of microRNA and Epigenetic Modifications in Prostate Cancer 
Cancers  2013;5(3):998-1019.
Epigenetic modifiers play important roles in fine-tuning the cellular transcriptome. Any imbalance in these processes may lead to abnormal transcriptional activity and thus result in disease state. Distortions of the epigenome have been reported in cancer initiation and progression. DNA methylation and histone modifications are principle components of this epigenome, but more recently it has become clear that microRNAs (miRNAs) are another major component of the epigenome. Interactions of these components are apparent in prostate cancer (CaP), which is the most common non-cutaneous cancer and second leading cause of death from cancer in the USA. Changes in DNA methylation, altered histone modifications and miRNA expression are functionally associated with CaP initiation and progression. Various aspects of the epigenome have also been investigated as biomarkers for different stages of CaP detection, though with limited success. This review aims to summarize key aspects of these mechanistic interactions within the epigenome and to highlight their translational potential as functional biomarkers. To this end, exploration of TCGA prostate cancer data revealed that expression of key CaP miRNAs inversely associate with DNA methylation. Given the importance and prevalence of these epigenetic events in CaP biology it is timely to understand further how different epigenetic components interact and influence each other.
PMCID: PMC3795376  PMID: 24202331
epigenetics; DNA methylation; histone modifications; microRNA; prostate cancer; cancer
20.  Socioeconomic Disparities in Maternity Care among Indian Adolescents, 1990–2006 
PLoS ONE  2013;8(7):e69094.
India, with a population of more than 1.21 billion, has the highest maternal mortality in the world (estimated to be 56000 in 2010); and adolescent (aged 15–19) mortality shares 9% of total maternal deaths. Addressing the maternity care needs of adolescents may have considerable ramifications for achieving the Millennium Development Goal (MDG)–5. This paper assesses the socioeconomic differentials in accessing full antenatal care and professional attendance at delivery by adolescent mothers (aged 15–19) in India during 1990–2006.
Methods and Findings
Data from three rounds of the National Family Health Survey of India conducted during 1992–93, 1998–99, and 2005–06 were analyzed. The Cochran-Armitage and Chi-squared test for linear and non-linear time trends were applied, respectively, to understand the trend in the proportion of adolescent mothers utilizing select maternity care services during 1990–2006. Using pooled multivariate logistic regression models, the probability of select maternal healthcare utilization among women by key socioeconomic characteristics was appraised. After adjusting for potential socio-demographic and economic characteristics, the likelihood of adolescents accessing full antenatal care increased by only 4% from 1990 to 2006. However, the probability of adolescent women availing themselves of professional attendance at delivery increased by 79% during the same period. The study also highlights the desolate disparities in maternity care services among adolescents across the most and the least favoured groups.
Maternal care interventions in India need focused programs for rural, uneducated, poor adolescent women so that they can avail themselves of measures to delay child bearing, and for better antenatal consultation and delivery care in case of pregnancy. This study strongly advocates the promotion of a comprehensive ‘adolescent scheme’ along the lines of ‘Continuum of Maternal, Newborn and Child health Care’ to address the unmet need of reproductive and maternal healthcare services among adolescent women in India.
PMCID: PMC3720871  PMID: 23894412
21.  The Arabidopsis LECTIN RECEPTOR KINASE-VI.2 is a functional protein kinase and is dispensable for basal resistance to Botrytis cinerea 
Plant Signaling & Behavior  2012;8(1):e22611.
Sensing of microbial pathogens by pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs) elicits a defense program known as PAMP-triggered immunity (PTI). Recently, we have shown that the Arabidopsis thaliana L-TYPE LECTIN RECEPTOR KINASE-VI.2 (LecRK-VI.2) positively regulates bacterial PTI. In this report, we suggest by in silico analysis that the kinase domain of LecRK-VI.2 is functional. LecRK-VI.2 also demonstrated auto-phosphorylation activity in vitro in the presence of divalent metal cations indicating that LecRK-VI.2 has the ability to auto-phosphorylate. We further investigate the role of LecRK-VI.2 in Arabidopsis resistance to the necrotrophic fungal pathogen Botrytis cinerea. Disruption of LecRK-VI.2 did not affect Arabidopsis resistance to B. cinerea. Accordingly, wild-type upregulation levels of PTI-responsive WRKY53, FRK1, NHL10, CYP81F2 and CBP60 g after treatment with the fungal PAMP chitin were observed in lecrk-VI.2-1. These data provide evidences that the kinase domain of LecRK-VI.2 is active and show that LecRK-VI.2 is not critical for resistance to the fungal pathogen B. cinerea.
PMCID: PMC3745566  PMID: 23221759
Arabidopsis thaliana; lectin receptor kinase; innate immunity; protein kinase; botrytis cinerea; chitin
22.  Chronic meningitis with multiple cranial neuropathies: A rare initial presentation of Wegener's granulomatosis 
Wegener's granulomatosis (WG) is a systemic necrotizing vasculitis that affects the small blood vessels. It mainly affects the upper and lower respiratory tract and kidneys. Central nervous system (CNS) involvement is rare, and has been reported only in about 8% of cases during the course of illness. Initial presentation with neurologic affection, particularly chronic hypertrophic meningitis is very unusual. We report the case of a 34 year old male who presented with chronic hypertrophic meningitis and multiple cranial nerve involvement as the initial manifestation, without respiratory and renal symptoms. This case highlights the difficulties in diagnosing a rare disease with rarer presentation, and at the same time illustrates that Wegener's granulomatosis should be considered in the differential diagnosis of chronic meningitis.
PMCID: PMC3788296  PMID: 24101832
Chronic meningitis; cranial neuropathies; Wegener's granulomatosis
23.  In vitro gene silencing of independent phosphoglycerate mutase (iPGM) in the filarial parasite Brugia malayi 
The phosphoglycerate mutase (PGM) enzyme catalyzes the interconversion of 2- and 3-phosphoglycerate in the glycolytic /gluconeogenic pathways that are present in the majority of cellular organisms. They can be classified as cofactor-dependent PGM (dPGM) or cofactor-independent PGM (iPGM). Vertebrates, yeasts, and many bacteria have only dPGM, while higher plants, nematodes, archaea, and many other bacteria have only iPGM. A small number of bacteria, including Escherichia coli and certain archaea and protozoa, contain both forms. The silencing of ipgm in Caenorhabditis elegans (C. elegans) has demonstrated the importance of this enzyme in parasite viability and, therefore, its potential as an anthelmintic drug target. In this study, the role of the Brugia malayi (B. malayi) ipgm in parasite viability, microfilaria release, embryogenesis, and in vivo development of infective larvae post-gene silencing was explored by applying ribonucleic acid (RNA) interference studies.
The in vitro ipgm gene silencing by small interfering RNA (siRNA) leads to severe phenotypic deformities in the intrauterine developmental stages of female worms with a drastic reduction (~90%) in the motility of adult parasites and a significantly reduced (80%) release of microfilariae (mf) by female worms in vitro. Almost half of the in vitro-treated infective L3 displayed sluggish movement. The in vivo survival and development of siRNA-treated infective larvae (L3) was investigated in the peritoneal cavity of jirds where a ~45% reduction in adult worm establishment was observed.
The findings clearly suggest that iPGM is essential for both larval and adult stages of B. malayi parasite and that it plays a pivotal role in female worm embryogenesis. The results thus validate the Bm-iPGM as a putative anti-filarial drug target.
PMCID: PMC3707094  PMID: 23849829
siRNA; Lymphatic filariasis; Drug target; RNAi; Embryogenesis
24.  Serum Vitamin D Metabolites in Colorectal Cancer Patients Receiving Cholecalciferol Supplementation: Correlation with Polymorphisms in the Vitamin D Genes 
Hormones & Cancer  2013;4(4):242-250.
Cholecalciferol (D3) supplementation results in variable increases in serum 25(OH)D3 levels, however, the influence of genetic polymorphisms on these variable responses is unclear. We measured serum 25(OH)D3, 24,25(OH)2D3, 1,25(OH)2D3 and VDBP levels in 50 colorectal cancer (CRC) patients before and during 2,000 IU daily oral D3 supplementation for six months and in 263 archived CRC serum samples. Serum PTH levels and PBMC 24-OHase activity were also measured during D3 supplementation. TagSNPs in CYP2R1, CYP27A1, CYP27B1, CYP24A1, VDR, and GC genes were genotyped in all patients, and the association between these SNPs and serum vitamin D3 metabolites levels before and after D3 supplementation was analyzed. The mean baseline serum 25(OH)D3 level was less than 32 ng/mL in 65 % of the 313 CRC patients. In the 50 patients receiving D3 supplementation, serum levels of 25(OH)D3 increased (p = 0.008), PTH decreased (p = 0.036) and 24,25(OH)2D3, 1,25(OH)2D3, VDBP levels and PBMC 24-OHase activity were unchanged. GC SNP rs222016 was associated with high 25(OH)D3 and 1,25(OH)2D3 levels at baseline while rs4588 and rs2282679 were associated with lower 25(OH)D3 and 1,25(OH)2D3 levels both before and after D3 supplementation. CYP2R1 rs12794714 and rs10500804 SNPs were significantly associated with low 25(OH)D3 levels after supplementation but not with baseline 25(OH)D3. Our results show that D3 supplementation increased 25(OH)D3 levels in all patients. GC rs4588 and rs2283679 SNPs were associated with increased risk of vitamin D3 insufficiency and suboptimal increase in 25(OH)D3 levels after D3 supplementation. Individuals with these genotypes may require higher D3 supplementation doses to achieve vitamin D3 sufficiency.
PMCID: PMC3689467  PMID: 23456391
25.  Lectin receptor kinases in plant innate immunity 
A key feature of innate immunity is the ability to recognize and respond to potential pathogens in a highly sensitive and specific manner. In plants, the first layer of defense is induced after recognition by pattern recognition receptors of microbe-associated molecular patterns. This recognition elicits a defense program known as pattern-triggered immunity. Pathogen entry into host tissue is a critical early step in causing infection. For foliar bacterial pathogens, natural surface openings such as stomata, are important entry sites. Stomata in contact with bacteria rapidly close and can thus restrict bacterial entry into leaves. The molecular mechanisms regulating stomatal closure upon pathogen perception are not yet well-understood. Plant lectin receptor kinases are thought to play crucial roles during development and in the adaptive response to various stresses. Although the function of most plant lectin receptor kinases is still not clear, a role for this kinase family in plant innate immunity is emerging. Here, we summarize recent progresses in the identification of lectin receptor kinases involved in plant innate immunity. We also discuss the role of lectin receptor kinases in stomatal innate immunity signaling.
PMCID: PMC3646242  PMID: 23675375
plant; receptor-like kinase; lectin receptor kinase; innate immunity; stomatal innate immunity; bacteria

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