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1.  Bayesian Analysis of Climate Change Effects on Observed and Projected Airborne Levels of Birch Pollen 
A Bayesian framework is presented for modeling Effects of climate change on pollen indices such as annual birch pollen count, maximum daily birch pollen count, start date of birch pollen season and the date of maximum daily birch pollen count. Annual mean CO2 concentration, mean spring temperature and the corresponding pollen index of prior year were found to be statistically significant accounting for Effects of climate change on four pollen indices. Results suggest that annual productions and peak values from 2020 to 2100 under different scenarios will be 1.3-8.0 and 1.1-7.3 times higher respectively than the mean values for 2000, and start and peak dates will occur around two to four weeks earlier. These results have been partly confirmed by the available historical data. As a demonstration, the emission profiles in future years were generated by incorporating the predicted pollen indices into an existing emission model.
doi:10.1016/j.atmosenv.2012.11.028
PMCID: PMC3601922  PMID: 23526049
Climate change; Birch; Pollen; Bayesian analysis
2.  Age-Related Macular Degeneration and the Incidence of Cardiovascular Disease: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(3):e89600.
Importance
Research has indicated some shared pathogenic mechanisms between age-related macular degeneration (AMD) and cardiovascular disease (CVD). However, results from prior epidemiologic studies have been inconsistent as to whether AMD is predictive of future CVD risk.
Objective
To systematically review population-based cohort studies of the association between AMD and risk of total CVD and CVD subtypes, coronary heart disease (CHD) and stroke.
Data Sources
A systematic search of the PubMed and EMBASE databases and reference lists of key retrieved articles up to December 20, 2012 without language restriction.
Data Extraction
Two reviewers independently extracted data on baseline AMD status, risk estimates of CVD and methods used to assess AMD and CVD. We pooled relative risks using random or fixed effects models as appropriate.
Results
Thirteen cohort studies (8 prospective and 5 retrospective studies) with a total of 1,593,390 participants with 155,500 CVD events (92,039 stroke and 62,737 CHD) were included in this meta-analysis. Among all studies, early AMD was associated with a 15% (95% CI, 1.08–1.22) increased risk of total CVD. The relative risk was similar but not significant for late AMD (RR, 1.17; 95% CI, 0.98–1.40). In analyses restricted to the subset of prospective studies, the risk associated with early AMD did not appreciably change; however, there was a marked 66% (95% CI, 1.31–2.10) increased risk of CVD among those with late AMD.
Conclusion
Whereas the results from all cohort studies suggest that both early and late AMD are predictive of a small increase in risk of future CVD, subgroup analyses limited to prospective studies demonstrate a markedly increased risk of CVD among people with late AMD. Retrospective studies using healthcare databases may have inherent methodological limitations that obscure such association. Additional prospective studies are needed to further elucidate the associations between AMD and specific CVD outcomes.
doi:10.1371/journal.pone.0089600
PMCID: PMC3969321  PMID: 24681973
3.  Exposure indices for the National Children's Study: application to inhalation exposures in Queens County, NY 
Characterization of environmental exposures to population subgroups within the National Children's Study (NCS), or other large-scale human environmental health studies is essential for developing a high-quality data platform for subsequent investigations. A computational formulation utilizing the tiered exposure ranking framework is presented for calculating inhalation exposure indices (EIs) for population subgroups. This formulation employs a probabilistic approach and combines information from diverse, publicly available exposure-relevant databases and information on biological mechanisms, for ranking study locations or population subgroups with respect to potential for specific end point-related environmental exposures. These EIs capture and summarize, within a set of numerical values/ranges, complex distributions of potential exposures to multiple airborne contaminants. These estimates capture spatial and demographic variability within each study segment, and allow for the relative comparison of study locations based on different statistical metrics of exposures. The EI formulation was applied to characterize and rank segments within Queens County, NY, which is one of the Vanguard centers for the NCS. Inhalation EI estimates relevant to respiratory outcomes, and potentially to pregnancy outcomes (low birth weight and preterm birth rates) were calculated at the study segment level. Results indicate that there is substantial variability across the study segments in Queens County, NY, and within segments, and showed an exposure gradient across the study segments that can help guide and target environmental and personal exposure sampling efforts in this county. The results also serve as an example application of the EI for use in other exposure and outcome studies.
doi:10.1038/jes.2012.99
PMCID: PMC3961756  PMID: 23072768
National Children's Study; exposure index; birth outcomes; inhalation exposures
4.  Sublingual Vaccination Induces Mucosal and Systemic Adaptive Immunity for Protection against Lung Tumor Challenge 
PLoS ONE  2014;9(3):e90001.
Sublingual route offers a safer and more practical approach for delivering vaccines relative to other systemic and mucosal immunization strategies. Here we present evidence demonstrating protection against ovalbumin expressing B16 (B16-OVA) metastatic melanoma lung tumor formation by sublingual vaccination with the model tumor antigen OVA plus synthetic glycolipid alpha-galactosylceramide (aGalCer) for harnessing the adjuvant potential of natural killer T (NKT) cells, which effectively bridge innate and adaptive arms of the immune system. The protective efficacy of immunization with OVA plus aGalCer was antigen-specific as immunized mice challenged with parental B16 tumors lacking OVA expression were not protected. Multiple sublingual immunizations in the presence, but not in the absence of aGalCer, resulted in repeated activation of NKT cells in the draining lymph nodes, spleens, and lungs of immunized animals concurrent with progressively increasing OVA-specific CD8+ T cell responses as well as serum IgG and vaginal IgA levels. Furthermore, sublingual administration of the antigen only in the presence of the aGalCer adjuvant effectively boosted the OVA-specific immune responses. These results support potential clinical utility of sublingual route of vaccination with aGalCer-for prevention of pulmonary metastases.
doi:10.1371/journal.pone.0090001
PMCID: PMC3943861  PMID: 24599269
5.  The effect of Hurricane Katrina on the prevalence of health impairments and disability among adults in New Orleans: Differences by age, race, and sex 
We examined the effects of Hurricane Katrina on disability-related measures of health among adults from New Orleans, U.S.A., in the year after the hurricane, with a focus on differences by age, race, and sex. Our analysis used data from the American Community Survey to compare disability rates between the pre-Katrina population of New Orleans with the same population in the year after Katrina (individuals were interviewed for the study even if they relocated away from the city). The comparability between the pre-and post-Katrina samples was enhanced by using propensity weights. We found a significant decline in health for the adult population from New Orleans in the year after the hurricane, with the disability rate rising from 20.6% to 24.6%. This increase in disability reflected a large rise in mental impairments and, to a lesser extent, in physical impairments. These increases were, in turn, concentrated among young and middle-aged black females. Stress-related factors likely explain why young and middle-aged black women experienced worse health outcomes, including living in dwellings and communities that suffered the most damage from the hurricane, household breakup, adverse outcomes for their children, and higher susceptibility.
doi:10.1016/j.socscimed.2012.12.009
PMCID: PMC3640812  PMID: 23321678
U.S.A; Disability; Demographic disparities; Hurricane Katrina; New Orleans; Natural disasters and health
6.  Evaluation of a robot-assisted video-assisted thoracoscopic surgery programme 
At present, there is increasing interest in surgical procedures using a robot-assisted device. The aim of this study was to investigate whether robot-assisted video-assisted thoracoscopic surgery (VATS) was more effective than conventional VATS. A total of 64 VATS lobectomies in Papworth Hospital (Cambridge, UK) were included in the study. In 34 cases the lobectomies were performed using conventional VATS (CV group), while in the remaining 30 cases the lobectomies were performed using robot-assisted VATS (Robotic group). In the robot-assisted VATS, FreeHand®, a thoracoscopic camera controller produced by Freehand 2010 Ltd. (Eastleigh, UK), was used. The duration of the thoracoscopic surgery in the Robotic group was 145.50±10.43 min, whereas in the CV group the duration was 162.79±9.40 min. The surgery duration in the Robotic group was 10.62% shorter than that in the CV group (P<0.05). The rates of bleeding, pulmonary infection, arrhythmia and prolonged air leak (≥5 days) in the Robotic group were 0, 3.33, 26.67 and 13.33%, respectively, while the corresponding rates in the CV group were 2.94, 5.88, 20.59 and 17.65%, respectively. No significant differences were identified in the postoperative complication rates between the two groups (P≥0.05). There was no perioperative mortality in the study. Compared with conventional VATS, FreeHand-assisted VATS provides a similar rate of postoperative complications and a reduced surgery duration, and may be beneficial for the recovery of the patients following VATS.
doi:10.3892/etm.2014.1532
PMCID: PMC3961121  PMID: 24669243
robot-assisted video-assisted thoracoscopic surgery; FreeHand; thoracoscopic camera holders
7.  Phenotypic and Functional Characterization of Lymphocytes from Different Age Groups of Bolivian Squirrel Monkeys (Saimiri boliviensis boliviensis) 
PLoS ONE  2013;8(11):e79836.
Due to many physiological and genetic characteristic similarities to humans, squirrel monkeys provide an ideal animal model specifically for studying malaria, and transmissible spongiform encephalopathies (Creutzfeldt-Jacob disease). While squirrel monkeys three years and older are generally considered adult subjects suitable for use in medical research studies, little is known about the functional properties of lymphocytes in relation to the age of these animals, which could significantly impact the quality and quantity of innate and adaptive immune responses. In this study, we investigated differences in the phenotype and function of lymphocytes subsets of young (3–4 years), adult (8–10 years) and aged (16–19 years) squirrel monkeys. In general, animals in all three age groups exhibited comparable numbers of different lymphocyte subsets except for CD20+ B cells that were significantly lower in aged relative to young animals and T cells subsets expressing both CD4 and CD8 (double positive) were significantly higher in aged relative to young animals. With increasing age, phenotypic differences in central and effector memory T cells subsets were observed, that were more pronounced for the CD8+ T cells. Despite equal proportions of CD3+ T cells among the three age groups, responses of peripheral blood mononuclear cells to T cell mitogens PHA and Con A showed lower IFN-γ producing cells in the aged group than that in the young group. Furthermore, aged animals showed significantly higher plasma levels of inflammatory cytokines IL-6, IFN-γ, TNF-α, IL-10 and IL-12. These findings suggest that while the squirrel monkeys in general share phenotypic and functional similarities of lymphocyte subsets with humans in relation to age, specific differences exist in immune function of lymphocytes between young and old animals that could potentially impact experimental outcomes for which the measurement of immunologic endpoints are critical.
doi:10.1371/journal.pone.0079836
PMCID: PMC3839916  PMID: 24282512
8.  Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Hyderabad cohort of the A1chieve study 
Background:
The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents.
Materials and Methods:
Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Hyderabad, India.
Results:
A total of 1249 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 893), insulin detemir (n = 158), insulin aspart (n = 124), basal insulin plus insulin aspart (n = 19) and other insulin combinations (n = 54). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 9.0%) and insulin user (mean HbA1c: 9.5%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naïve: −0.9%, insulin users: −1.1%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients.
Conclusion:
Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.
doi:10.4103/2230-8210.122130
PMCID: PMC3872909  PMID: 24404501
A1chieve study; Hyderabad; insulin analogues; type 2 diabetes mellitus
9.  Functional Analysis and Molecular Docking studies of Medicinal Compounds for AChE and BChE in Alzheimer’s Disease and Type 2 Diabetes Mellitus 
Aging and Disease  2013;4(4):186-200.
Acetylcholinesterase and Butyrylcholinesterase share unravelling link with components of metabolic syndromes that’s characterised by low levels of HDL cholesterol, obesity, high fast aldohexose levels, hyper-trigliceridaemia and high blood pressure, by regulation of cholinergic transmission and therefore the enzyme activity within a living system. The phosphomotifs associated with amino acid and tyrosine binding motifs in AChE and BChE were known to be common. Phylogenetic tree was constructed to these proteins usinf UPGMA and Maximum Likelihood methods in MEGA software has shown interaction of AChE and BChE with ageing diseases like Alzheimer’s disease and Diabetes. AChE has shown closely related to BChE, retinol dehydrogenase and β-polypeptide. The present studies is also accomplished that AChE, BChE, COLQ, HAND1, APP, NLGN2 and NGF proteins has interactions with diseases such as Alzheimer’s and D2M using Pathwaylinker and STRING. Medicinal compounds like Ortho-7, Dibucaine and HI-6 are predicted as good targets for modeled AChE and BChE proteins based on docking studies. Hence perceptive studies of cholinesterase structure and the biological mechanisms of inhibition are necessary for effective drug development.
PMCID: PMC3733582  PMID: 23936743
AChE; BChE; Protein interactions; Phylogeny; Docking
10.  Comparison of Systemic and Mucosal Immunization with Helper-Dependent Adenoviruses for Vaccination against Mucosal Challenge with SHIV 
PLoS ONE  2013;8(7):e67574.
Most HIV-1 infections are thought to occur at mucosal surfaces during sexual contact. It has been hypothesized that vaccines delivered at mucosal surfaces may mediate better protection against HIV-1 than vaccines that are delivered systemically. To test this, rhesus macaques were vaccinated by intramuscular (i.m.) or intravaginal (ivag.) routes with helper-dependent adenoviral (HD-Ad) vectors expressing HIV-1 envelope. Macaques were first immunized intranasally with species C Ad serotype 5 (Ad5) prior to serotype-switching with species C HD-Ad6, Ad1, Ad5, and Ad2 vectors expressing env followed by rectal challenge with CCR5-tropic SHIV-SF162P3. Vaccination by the systemic route generated stronger systemic CD8 T cell responses in PBMC, but weaker mucosal responses. Conversely, mucosal immunization generated stronger CD4 T cell central memory (Tcm) responses in the colon. Intramuscular immunization generated higher levels of env-binding antibodies, but neither produced neutralizing or cytotoxic antibodies. After mucosal SHIV challenge, both groups controlled SHIV better than control animals. However, more animals in the ivag. group had lower viral set points than in in the i.m. group. These data suggest mucosal vaccination may have improve protection against sexually-transmitted HIV. These data also demonstrate that helper-dependent Ad vaccines can mediate robust vaccine responses in the face of prior immunity to Ad5 and during four rounds of adenovirus vaccination.
doi:10.1371/journal.pone.0067574
PMCID: PMC3701068  PMID: 23844034
11.  PNUTS functions as a proto-oncogene by sequestering PTEN 
Cancer research  2012;73(1):205-214.
PTEN is a well-defined tumor suppressor gene that antagonizes the PI3K/Akt pathway to regulate a multitude of cellular processes such as survival, growth, motility, invasiveness and angiogenesis. While the functions of PTEN have been studied extensively, the regulation of its activity during normal and disease conditions still remains incompletely understood. In this study, we identified the protein phosphatase-1 nuclear targeting subunit PNUTS (PPP1R10) as a PTEN associated protein. PNUTS directly interacted with the lipid-binding domain (C2 domain) of PTEN and sequestered it in the nucleus. Depletion of PNUTS leads to increased apoptosis and reduced cellular proliferation in a PTEN-dependent manner. PNUTS expression was elevated in certain cancers compared to matched normal tissues. Collectively, our studies reveal PNUTS as a novel PTEN regulator and a likely oncogene.
doi:10.1158/0008-5472.CAN-12-1394
PMCID: PMC3538077  PMID: 23117887
12.  On the Equivalent Dose for Auger Electron Emitters 
Radiation research  1993;134(1):71-78.
Radionuclides that emit Auger electrons are widely used in nuclear medicine (e.g., 99mTc, 123I, 201T1) and biomedical research (e.g., 51Cr, 125I), and they are present in the environment (e.g., 40K, 55Fe). Depending on the subcellular distribution of the radionuclide, the biological effects caused by tissue-incorporated Auger emitters can be as severe as those from high-LET α particles. However, the recently adopted recommendations of the International Commission on Radiological Protection (ICRP) provide no guidance with regard to calculating the equivalent dose for these radionuclides. The present work, using spermatogenesis in mouse testis as the experimental model, shows that the lethality of the prolific Auger emitter 125I is linearly dependent on the fraction of the radioactivity in the organ that is bound to DNA. This suggests that the equivalent dose for Auger emitters may have a similar linear dependence. Accordingly, a formalism for calculating the equivalent dose for Auger emitters is advanced within the ICRP framework.
PMCID: PMC3690377  PMID: 8475256
13.  Nutritional and Toxicological Assessment of White-Rot Fermented Animal Feed 
Indian Journal of Microbiology  2011;52(2):185-190.
The fungal fermented wheat straws as animal feeds have been evaluated for its toxicological and nutritional status in male rats (Holtzman strain). Digestibility of dry matter and other nutrients as well as fiber fractions were found significantly higher (P < 0.05) in straw fermented with either Ganoderma sp. rckk02 (T3) or Crinipellis sp. RCK-1 (T4) than unfermented straw (T1) or straw fermented with Pycnoporus cinnabarinus (T2). The aflatoxin B1, B2, G1 and G2 were either absent or present in permissive levels in T3 and T4 diets and exhibited normal stress enzyme activity in case of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) enzymes whereas, rats fed on T2 diet showed elevated levels of stress enzymes (ALT, AST and LDH activity), 100% high morbidity and 8.3% mortality. This study suggests that Ganoderma sp. rckk02 and Crinipellis sp. RCK-1 are efficient in improving the nutritive value of poor quality straw and do not posses any threat for their subsequent use as ruminant feed.
doi:10.1007/s12088-011-0222-2
PMCID: PMC3386461  PMID: 23729880
Wheat straw; Solid-state fermentation; White-rot fungi; Aflatoxin
14.  Metabolite profiling and biological activities of bioactive compounds produced by Chrysosporium lobatum strain BK-3 isolated from Kaziranga National Park, Assam, India 
SpringerPlus  2013;2:122.
In an ongoing survey for bioactive potential of microorganisms from different biosphere zones of India, a new Chrysosporium lobatum strain BK-3 was isolated from soil sample collected from a biodiversity hotspot, Kaziranga National Park, Assam, India. Bioactivity-guided purification resulted in the isolation of two bioactive compounds whose chemical structures were elucidated by 1H and 13C Nuclear Magnetic Resonance (NMR), 2D-NMR, Fourier Transform Infra-red (FT-IR) and mass spectroscopic techniques, and were identified as α, β-dehydrocurvularin and curvularin. Only curvularin exhibited 80% acetylcholinesterase (AChE) inhibitory activity. Detailed ligand receptor binding interactions were studied for curvularin by molecular docking studies. Further, both curvularin and α, β-dehydrocurvularin had similar level of cytotoxicity against different human tumour cell lines like A549, HeLa, MDA-MB-231 and MCF-7, while α, β-dehydrocurvularin was active against COLO 205 with a IC50 of 7.9 μM, but curvularin was inactive. α, β-Dehydrocurvularin also showed good superoxide anion scavenging activity with an EC50 value of 16.71 μg ml-1. Hence, both these compounds exhibited differences in bioactive profiles and this was probably associated with their minor structural differences. This is a first report on bioactive compounds exhibiting AChE inhibitory, cytotoxicity and antioxidant activities from Chrysosporium lobatum strain BK-3.
Electronic supplementary material
The online version of this article (doi:10.1186/2193-1801-2-122) contains supplementary material, which is available to authorized users.
doi:10.1186/2193-1801-2-122
PMCID: PMC3616213  PMID: 23565355
Acetylcholinesterase inhibitors; Chrysosporium lobatum; Curvularin; α, β-Dehydrocurvularin; Molecular docking
15.  The Panel Study of Income Dynamics: Overview, Recent Innovations, and Potential for Life Course Research 
Spanning over four decades, the Panel Study of Income Dynamics (PSID) is the world's longest running household panel survey. The resulting data archive presents research opportunities for breakthroughs in understanding the connections between economic status, health and well-being across generations and over the life course. The long panel, genealogical design, and broad content of the data represent a unique opportunity for a multi-perspective study of life course evolution and change within families over multiple generations. Based on relational data structures and advanced web-based archiving and delivery tools, the PSID has a publicly available web-based facility for users worldwide to create customized data extracts and codebooks based on nearly 70,000 variables from over 70,000 individuals over 44 years. This paper provides an overview of the PSID and its supplemental studies, the Disability and Use of Time Supplement, the Child Development Supplement, and the Transition into Adulthood study, and describes features and recent enhancements that have increased the potential of the archive for studying life course development.
PMCID: PMC3591471  PMID: 23482334
panel study; life course; data collection; human development; time use; young adulthood; aging
16.  The Diagnostic Utility of Bact/ALERT and Nested PCR in the Diagnosis of Tuberculous Meningitis 
Objective: The early laboratory diagnosis of Tuberculous Meningitis (TBM) is crucial, to start the antitubercular chemotherapy and to prevent its complications. However, the conventional methods are either less sensitive or time consuming. Hence, the diagnostic potentials of BacT/ALERT and Polymerase Chain Reaction (PCR) was evaluated in this study.
Material and Method: The study group comprised of 62 cases and 33 controls. The cases were divided according to Ahuja’s criteria into the confirmed (two cases), highly probable (19 cases), probable (26 cases) and the possible (15 cases) subgroups. Ziehl Neelsen’s (ZN) and Auramine Phenol (AP) staining, Lowenstein Jensen (LJ) medium culture, BacT/ALERT and nested Polymerase Chain Reaction (PCR) which targeted IS6110 were carried out on all the patients.
Observation and Results: The sensitivity of the LJ culture was 3.22%. BacT/ALERT showed a sensitivity and a specificity of 25.80% and 100% and those of nested PCR were found to be 40.32% and 96.97% respectively. The mean detection time of growth of the LJ culture was 31.28 days, whereas that of BacT/ALERT was 20.68 days. The contamination rate in the LJ culture and BacT/ALERT were 7.2% and 5.8% respectively.
Conclusion: Nested PCR was found to be more sensitive, followed by BacT/ALERT as compared to the LJ culture and smear microscopy. As both false negative and false positive results have been reported for nested PCR, so it should not be used alone as a criterion for initiating or terminating the therapy, but it should be supported by clinical, radiological, cytological and other microbiological findings.
doi:10.7860/JCDR/2012/5098.2674
PMCID: PMC3576755  PMID: 23450650
Tuberculous meningitis; Sensitivity; Nested PCR; BacT/ALERT
17.  Middle-redox potential laccase from Ganoderma sp.: its application in improvement of feed for monogastric animals 
Scientific Reports  2013;3:1299.
The variables influencing laccase production by white-rot fungus Ganoderma sp. rckk-02 were optimized employing response surface methodology. Malt extract (6.0% w/v), lignin (0.5% w/v) and pH (5.5) were found to be the most significant factors for enhanced laccase production by 7 fold (226.0 U/ml) as compared to unoptimized growth conditions (32.0 U/ml). The N-terminal sequence of laccase revealed its distinct amino acid profile (S- I- R- N- S- G), which suggested it as a novel enzyme. The Far-UV CD spectrum of the laccase showed single broad negative trough at around 213 nm, a typical signature of all β proteins. The laccase was found to fall in the range of middle redox potential laccases. Purified laccase at dosage of 2.5 Ug−1 body weight when supplemented with pelleted diet of rats, a significant improvement (p < 0.05) in nutrients digestibility without causing any elevation of blood stress enzymes was observed.
doi:10.1038/srep01299
PMCID: PMC3575017  PMID: 23416696
18.  Allosteric Regulation of Serine Protease HtrA2 through Novel Non-Canonical Substrate Binding Pocket 
PLoS ONE  2013;8(2):e55416.
HtrA2, a trimeric proapoptotic serine protease is involved in several diseases including cancer and neurodegenerative disorders. Its unique ability to mediate apoptosis via multiple pathways makes it an important therapeutic target. In HtrA2, C-terminal PDZ domain upon substrate binding regulates its functions through coordinated conformational changes the mechanism of which is yet to be elucidated. Although allostery has been found in some of its homologs, it has not been characterized in HtrA2 so far. Here, with an in silico and biochemical approach we have shown that allostery does regulate HtrA2 activity. Our studies identified a novel non-canonical selective binding pocket in HtrA2 which initiates signal propagation to the distal active site through a complex allosteric mechanism. This non-classical binding pocket is unique among HtrA family proteins and thus unfolds a novel mechanism of regulation of HtrA2 activity and hence apoptosis.
doi:10.1371/journal.pone.0055416
PMCID: PMC3573033  PMID: 23457469
19.  Intranasal but not intravenous delivery of the adjuvant α-galactosylceramide permits repeated stimulation of natural killer T cells in the lung 
European journal of immunology  2011;41(11):3312-3322.
Efficient induction of antigen-specific immunity is achieved by delivering multiple doses of vaccine formulated with appropriate adjuvants that can harness the benefits of innate immune mediators. The synthetic glycolipid α-galactosylceramide (α-GalCer) is a potent activator of NKT cells, a major innate immune mediator cell type effective in inducing maturation of DCs for efficient presentation of co-administered antigens. However, systemic administration of α-GalCer results in NKT cell anergy in which the cells are unresponsive to subsequent doses of α-GalCer. We show here that α-GalCer delivered as an adjuvant by the intranasal route, as opposed to the intravenous route, enables repeated activation of NKT cells and DCs, resulting in efficient induction of cellular immune responses to co-administered antigens. We show evidence that after intranasal delivery, α-GalCer is selectively presented by DCs for the activation of NKT cells, not B cells. Furthermore, higher levels of PD-1 expression, a potential marker for functional exhaustion of the NKT cells when α-GalCer is delivered by the intravenous route, are not observed after intranasal delivery. These results support a mucosal route of delivery for the utility of α-GalCer as an adjuvant for vaccines, which often requires repeated dosing to achieve durable protective immunity.
doi:10.1002/eji.201041359
PMCID: PMC3568446  PMID: 21818755
Adjuvants; Anergy; DCs; α-GalCer; Mucosal immunity; NKT
20.  Increased activation and cytokine secretion in B cells stimulated with leptin in aged humans 
Aging is associated chronic inflammation and autoimmunity, and increased levels of leptin. Increased levels of leptin are associated with inflammation and autoimmunity. We have recently reported that leptin activates B cells to induce secretion of proinflammatory and anti-inflammatory cytokines. Role of B cells and leptin in inflammation associated with aging has not been explored. In this study we demonstrate that leptin activates and induces significantly greater amount of IL-6, TNF-α, and IL-10 by B cells from aged humans as compared to young controls. This is associated with increased leptin-induced phosphorylation of STAT3 (signal transducer and activator of transcription-3) in B cells from aged humans as compared to young subjects. These data suggest that leptin-induced B cell-derived proinflammatory cytokines may play a role in chronic inflammation associated with human aging.
doi:10.1186/1742-4933-10-3
PMCID: PMC3557206  PMID: 23343052
TNF-α; IL-6; IL-10; B cells
21.  Baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) 
McMurray, John J.V. | Anand, Inder S. | Diaz, Rafael | Maggioni, Aldo P. | O'Connor, Christopher | Pfeffer, Marc A. | Solomon, Scott D. | Tendera, Michal | van Veldhuisen, Dirk J. | Albizem, Moetaz | Cheng, Sunfa | Scarlata, Debra | Swedberg, Karl | Young, James B. | Amuchastegui, M. | Belziti, C. | Bluguermann, J. | Caccavo, M. | Cartasegna, L. | Colque, R. | Cuneo, C. | Fernandez, A. | Gabito, A. | Goicochea, R. | Gonzalez, M. | Gorosito, V. | Grinfeld, L. | Hominal, M. | Kevorkian, R. | Litvak Bruno, M. | Llanos, J. | Mackinnon, I. | Manuale, O. | Marzetti, E. | Nul, D. | Perna, E. | Riccitelli, M. | Sanchez, A. | Santos, D. | Schygiel, P. | Toblli, J. | Vogel, D. | Aggarwal, A. | Amerena, J. | De Looze, F. | Fletcher, P. | Hare, D. | Ireland, M. | Krum, H. | Lattimore, J. | Marwick, T. | Sindone, A. | Thompson, P. | Waites, J. | Altenberger, J. | Ebner, C. | Lenz, K. | Pacher, R. | Poelzl, G. | Charlier, F. | de Ceuninck, M. | De Keulenaer, G. | Dendale, P. | Maréchal, P. | Mullens, W. | Thoeng, J. | Vanderheyden, M. | Vanhaecke, J. | Weytjens, C. | Wollaert, B. | Albuquerque, D. | Almeida, D. | Aspe y Rosas, J. | Bocchi, E. | Bordignon, S. | Clausell, N. | Kaiser, S. | Leaes, P. | Martins Alves, S. | Montera, M. | Moura, L. | Pereira de Castro, R. | Rassi, S. | Reis, A. | Saraiva, J. | Simões, M. | Souza Neto, J. | Teixeira, M. | Benov, H. | Chompalova, B. | Donova, T. | Georgiev, P. | Gotchev, D. | Goudev, A. | Grigorov, M. | Guenova, D. | Hergeldjieva, V. | Ivanov, D. | Kostova, E. | Manolova, A. | Marchev, S. | Nikolov, F. | Popov, A. | Raev, D. | Tzekova, M. | Czarnecki, W. | Giannetti, N. | Haddad, H. | Heath, J. | Huynh, T. | Lepage, S. | Liu, P. | Lonn, E. | Ma, P. | Manyari, D. | Moe, G. | Parker, J. | Pesant, Y. | Rajda, M. | Ricci, J. | Roth, S. | Sestier, F. | Sluzar, V. | Sussex, B. | Vizel, S. | Antezana, G. | Bugueno, C. | Castro, P. | Conejeros, C. | Manriquez, L. | Martinez, D. | Potthoff, S. | Stockins, B. | Vukasovic, J. | Gregor, P. | Herold, M. | Jerabek, O. | Jirmar, R. | Kuchar, R. | Linhart, A. | Podzemska, B. | Soucek, M. | Spac, J. | Spacek, R. | Vodnansky, P. | Bronnum-Schou, J. | Clemmensen, K. | Egstrup, K. | Jensen, G. | Kjoller-Hansen, L. | Kober, L. | Markenvard, J. | Rokkedal, J. | Skagen, K. | Torp-Pedersen, C. | Tuxen, C. | Videbak, L. | Laks, T. | Vahula, V. | Harjola, V. | Kettunen, R. | Kotila, M. | Bauer, F. | Cohen Solal, A. | Coisne, D. | Davy, J. | De Groote, P. | Dos Santos, P. | Funck, F. | Galinier, M. | Gibelin, P. | Isnard, R. | Neuder, Y. | Roul, G. | Sabatier, R. | Trochu, J. | Anker, S. | Denny, S. | Dreykluft, T. | Flesch, M. | Genth-Zotz, S. | Hambrecht, R. | Hein, J. | Jeserich, M. | John, M. | Kreider-Stempfle, H. | Laufs, U. | Muellerleile, K. | Natour, M. | Sandri, M. | Schäufele, T. | von Hodenberg, E. | Weyland, K. | Winkelmann, B. | Tse, H. | Yan, B. | Barsi, B. | Csikasz, J. | Dezsi, C. | Edes, I. | Forster, T. | Karpati, P. | Kerekes, C. | Kis, E. | Kosa, I. | Lupkovics, 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A. | Berk, M. | Berry, B. | Bethala, V. | Bilazarian, S. | Bisognano, J. | Bleyer, F. | Blum, M. | Boehmer, J. | Bouchard, A. | Boyle, A. | Bozkurt, B. | Brown, C. | Burlew, B. | Burnham, K. | Butler, J. | Call, J. | Cambier, P. | Cappola, T. | Carlson, R. | Chandler, B. | Chandra, R. | Chandraratna, P. | Chernick, R. | Colan, D. | Colfer, H. | Colucci, W. | Connelly, T. | Costantini, O. | Dadkhah, S. | Dauber, I. | Davis, J. | Davis, S. | Denning, S. | Drazner, M. | Dunlap, S. | Egbujiobi, L. | Elkayam, U. | Elliott, J. | El-Shahawy, M. | Essandoh, L. | Ewald, G. | Fang, J. | Farhoud, H. | Felker, G. | Fernandez, J. | Festin, R. | Fishbein, G. | Florea, V. | Flores, E. | Floro, J. | Gabris, M. | Garg, M. | Gatewood, R. | Geller, M. | Ghali, J. | Ghumman, W. | Gibbs, G. | Gillespie, E. | Gilmore, R. | Gogia, H. | Goldberg, L. | Gradus-Pizlo, I. | Grainger, T. | Gudmundsson, G. | Gunawardena, D. | Gupta, D. | Hack, T. | Hall, S. | Hamroff, G. | Hankins, S. | Hanna, M. | Hargrove, J. | Haught, W. | Hauptman, P. | Hazelrigg, M. | Herzog, C. | Heywood, J. | Hill, T. | Hilton, T. | Hirsch, H. | Hunter, J. | Ibrahim, H. | Imburgia, M. | Iteld, B. | Jackson, B. | Jaffrani, N. | Jain, D. | Jain, A. | James, M. | Jimenez, J. | Johnson, E. | Kale, P. | Kaneshige, A. | Kapadia, S. | Karia, D. | Karlsberg, R. | Katholi, R. | Kerut, E. | Khoury, W. | Kipperman, R. | Klapholz, M. | Kosinski, E. | Kozinn, M. | Kraus, D. | Krueger, S. | Krum, H. | Kumar, S. | Lader, E. | Lee, C. | Levy, W. | Lewis, E. | Light-McGroary, K. | Loh, I. | Lombardi, W. | Machado, C. | Maislos, F. | Mancini, D. | Markus, T. | Mather, P. | McCants, K. | McGrew, F. | McLaurin, B. | McMillan, E. | McNamara, D. | Meyer, T. | Meymandi, S. | Miller, A. | Minami, E. | Modi, M. | Mody, F. | Mohanty, P. | Moscoso, R. | Moskowitz, R. | Moustafa, M. | Mullen, M. | Naz, T. | Noonan, T. | O'Brien, T. | Oellerich, W. | Oren, R. | Pamboukian, S. | Pereira, N. | Pitt, W. | Porter, C. | Prabhu, S. | Promisloff, 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European Journal of Heart Failure  2013;15(3):334-341.
Aims
This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes.
Methods and results
Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate <60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106–117) g/L.
Conclusion
The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity.
doi:10.1093/eurjhf/hfs204
PMCID: PMC3576902  PMID: 23329651
Heart failure; Anaemia
22.  Mechanism of S-oxygenation by a cysteine dioxygenase model complex 
In this work we present the first computational study on a biomimetic cysteine dioxygenase model complex, [FeII(LN3S)]+ where LN3S is a tetradentate ligand with a bis(imino)pyridyl scaffold and a pendant arylthiolate group. The reaction mechanism of sulfur dioxygenation with O2 was examined by density functional theory (DFT) methods, and compared to results obtained for cysteine dioxygenase. The reaction proceeds via multistate reactivity patterns on competing singlet, triplet and quintet spin state surfaces. The reaction mechanism is analogous to that found for cysteine dioxygenase enzymes [Kumar, D.; Thiel, W.; de Visser, S. P. J. Am. Chem. Soc. 2011, 133, 3869–3882], hence the computations indicate that this complex can closely mimic the enzymatic process. The catalytic mechanism starts from an iron(III)-superoxo complex and the attack of the terminal oxygen atom of the superoxo group on the sulfur atom of the ligand. Subsequently, the dioxygen bond breaks to form an iron(IV)-oxo complex with a bound sulfenato group. After reorganization the second oxygen atom is transferred to the substrate to give a sulfinic acid product. An alternative mechanism involving the direct attack of dioxygen on the sulfur, without involving any iron-oxygen intermediates, was also examined. Importantly, a significant energetic preference for dioxygen coordinating to the iron center prior to attack at sulfur was discovered and serves to elucidate the function of the metal ion in the reaction process. The computational results are in good agreement with experimental observations, and the differences and similarities of the biomimetic complex and the enzymatic CDO center are highlighted.
doi:10.1021/jp208230g
PMCID: PMC3267236  PMID: 22091701
23.  Lessons on Non-Progression of HIV Disease from Monkeys 
doi:10.3389/fimmu.2013.00064
PMCID: PMC3595530  PMID: 23495354
24.  Effect of salinity on tomato (Lycopersicon esculentum Mill.) during seed germination stage 
A study was conducted using ten genetically diverse genotypes along with their 45F1 (generated by diallel mating) under normal and salt stress conditions. Although, tomato (Lycopersicon esculentum Mill.) is moderately sensitive to salinity but more attention to salinity is yet to be required in the production of tomato. In present study, germination rate, speed of germination, dry weight ratio and Na+/K+ ratio in root and shoot, were the parameters assayed on three salinity levels; control, 1.0 % NaCl and 3.0 % NaCl with Hoagland’s solution. Increasing salt stress negatively affected growth and development of tomato. When salt concentration increased, germination of tomato seed was reduced and the time needed to complete germination lengthened, root/shoot dry weight ratio was higher and Na+ content increased but K+ content decreased. Among the varieties, Sel-7 followed by Arka Vikas and crosses involving them as a parent were found to be the more tolerant genotypes in the present study on the basis of studied parameters.
doi:10.1007/s12298-011-0097-z
PMCID: PMC3550529  PMID: 23573039
Lycopersicon esculentum; Growth parameters; Salinity stress; Tomato; Effect of salinity
25.  Glutamic acid decarboxylase (anti-GAD) & tissue transglutaminase (anti-TTG) antibodies in patients with thyroid autoimmunity 
Background & objectives:
Several autoimmune disorders have been reported to be associated with autoimmune thyroiditis and may coexist with other organ-specific autoantibodies. The aim of the present study was to evaluate the presence of tissue transglutaminase (anti-TTG) and glutamic acid decarboxylase (anti-GAD) antibodies in patients suffering from autoimmune thyroiditis as diagnosed by anti-thyroid peroxidase (anti-TPO) antibodies, which may indicate high risk for developing celiac disease or type 1 diabetes mellitus.
Methods:
Five thousand children and 2800 adults were screening as part of a general health examination done on a voluntary basis in four different parts of Delhi. A total of 577 subjects positive for anti-TPO antibody constituted the cases. Equal number of age and sex matched anti-TPO antibody negative controls were randomly selected from the same cohort to form paired case control study. The cases and controls were further divided into two groups as follows: group-1 (children and adolescent <18 yr), group-2 (adults >18 yr). Serum samples of cases and controls were analysed for thyroid function test (FT3, FT4, and TSH), anti-TTG and anti-GAD antibodies.
Results:
A total of 1154 subjects (577 cases and 577 controls) were included in this study. Hypothyroidism was present in 40.2 per cent (232) cases compared to only 4.7 per cent (27) in controls (P<0.001). Anti-TTG and anti-GAD antibodies were present in 6.9 and 12.5 per cent subjects among cases compared to 3.5 per cent (P=0.015) and 4.3 per cent (P=0.001) in controls, respectively. Only anti-GAD antibody were significantly positive in cases among children and adolescents (P =0.0044) and adult (P=0.001) compared to controls. Levels of anti-TTG and anti-GAD antibodies increased with increasing titre of anti-TPO antibody.
Interpretation & conclusions:
Our findings showed high positivity of anti-GAD and anti-TTG antibodies among subjects with thyroid autoimmunity. It is, therefore, important to have high clinical index of suspicion for celiac disease or type 1 diabetes mellitus in patients with autoimmune thyroiditis.
PMCID: PMC3657903  PMID: 23481055
Anti-GAD antibody; anti-TPO antibody; anti-TTG antibody; thyroid autoimmunity

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