PubMed Health⌕ Search

Biomedical subjects

S K Nair

Publications and source records attributed to S K Nair.

At least 19 recordsLinked to original sources
PubMed2007

Coverage, utilization and barriers to cataract surgical services in rural South India: results from a population-based study.

OBJECTIVES: To determine the cataract surgical coverage, utilization and barriers to cataract surgery in a rural taluk of south India. STUDY DESIGN: A cross-sectional, community-based survey. METHODS: A house-to-house survey was carried out in 15 villages that were selected by cluster sampling during January to October, 2002. A total of 1505 people aged 50 years and above were tested for visual acuity (VA) and their eyes examined. Cataract surgical coverage was calculated for people and eyes, and for VA levels of <3/60 and <6/60. Information about details of cataract surgery and barriers to cataract surgery were collected using a pre-designed proforma. RESULTS: Cataract surgical coverage was 63% (people) and 51% (eyes) for VA<3/60 compared with 49% (people) and 36% (eyes) for VA<6/60. Of 109 operated eyes, 51.2% of operations were carried out in private hospitals and 33.3% in voluntary/charitable hospitals. Inability to afford the operation (22.9%) and fear of the operation (19.2%) were the main barriers to cataract surgery. CONCLUSIONS: The reasons for underutilization of government hospitals are to be investigated. Awareness of low-cost cataract intraocular lens (IOL) non-governmental organization (NGO) surgery and free-of-cost NGO services available in the region needs to be raised. Barriers to cataract surgical services should be addressed by community-based health-education programmes to improve the uptake of existing services.

Aged↗
PubMed2006

Mapping QTLs for popping ability in a popcorn x flint corn cross.

Popping expansion volume (PEV) in popcorn (Zea mays L.) is a distinct heritable character and defined as the ratio of the volume after popping to the volume before popping. PEV is quantitatively inherited and 3-4 genes/quantitative trait loci (QTLs) have been implicated. In the present study, we have dissected the quantitative PEV into two component traits, viz., flake volume (FV) and percent unpopped kernels (UPK), and mapped QTLs using SSR markers for all three traits with 194 F3 families derived from a popcorn (A-1-6) x flint corn (V273) cross. Heritability (broad sense) estimates for PEV, FV and UPK based on F3 mean bases were 0.72, 0.54 and 0.68, respectively. The QTL analyses for the three traits based on combined environment data were performed by composite interval mapping using QTL cartographer. Four QTLs were identified for PEV on chromosomes 1, 3, 8 and 10, which together explained 62% of the phenotypic variance (sigma2p). Four QTLs were found on chromosomes 1, 5, 9 and 10 for FV (explaining 44% of sigma2p) and five QTLs for UPK on chromosomes 1, 3, 4, 5 and 9 (explaining 57% of sigma2p). The relative efficiency estimates of marker-based selection in comparison to phenotypic selection for PEV (1.10), FV (1.22) and UPK (1.11) indicated that marker-based selection could be relatively more efficient. The QTL on chromosome 1S for PEV was found to be most significant, where QTLs for hard endosperm starch concentration had been detected earlier.

Alleles↗
PubMed2006

Structural aspects of interactions within the Myc/Max/Mad network.

Recently determined structures of a number of Myc family proteins have provided significant insights into the molecular nature of complex assembly and DNA binding. These structures illuminate the details of specific interactions that govern the assembly of nucleoprotein complexes and, in doing so, raise more questions regarding Myc biology. In this review, we focus on the lessons provided by these structures toward understanding (1) interactions that govern transcriptional repression by Mad via the Sin3 pathway, (2) homodimerization of Max, (3) heterodimerization of Myc-Max and Mad-Max, and (4) DNA recognition by each of the Max-Max, Myc-Max, and Mad-Max dimers.

Animals↗
PubMed2005

Two-generation marker-aided backcrossing for rapid conversion of normal maize lines to quality protein maize (QPM).

The low nutritive value of maize endosperm protein is genetically corrected in quality protein maize (QPM), which contains the opaque 2 gene along with numerous modifiers for kernel hardness. We report here a two generation marker-based backcross breeding program for incorporation of the opaque 2 gene along with phenotypic selection for kernel modification in the background of an early maturing normal maize inbred line, V25. Using the flanking marker distances from opaque 2 gene in the cross V 25 xCML 176, optimum population size for the BC(2) generation was computed in such a way that at least one double recombinant could be obtained. Whole genome background selection in the BC(2) generation identified three plants with 93 to 96% recurrent parent genome content. The three BC(2)F(2) families derived from marker identified BC(2) individuals were subjected to foreground selection and phenotypic selection for kernel modification. The tryptophan concentration in endosperm protein was significantly enhanced in all the three classes of kernel modification viz., less than 25%, 25--50% and more than 50% opaqueness. BC(2)F(3) lines developed from the hard endosperm kernels were evaluated for desirable agronomic and biochemical traits in replicated trials and the best line was chosen to represent the QPM version of V25, with tryptophan concentration of 0.85% in protein. The integrated breeding strategy reported here can be applied to reduce genetic drag as well as the time involved in a conventional line conversion program, and would prove valuable in rapid development of specialty corn germ plasm.

Crosses, Genetic↗
PubMed2005

Identification and validation of QTLs conferring resistance to sorghum downy mildew (Peronosclerospora sorghi) and Rajasthan downy mildew (P. heteropogoni) in maize.

We have mapped the quantitative trait loci (QTLs) conferring resistance to sorghum downy mildew (Peronosclerospora sorghi; SDM) and Rajasthan downy mildew (P. heteropogoni; RDM), two species of DM prevalent throughout India. QTL mapping was carried out on a backcross population of 151 individuals derived from a cross between CM139 (susceptible parent) and NAI116 (highly resistant to both SDM and RDM). Heritability estimates were 0.74 for SDM and 0.67 for RDM. Composite interval mapping combined with a linkage map constructed with 80 simple sequence repeat (SSR) markers resulted in the identification of three QTLs (one each on chromosomes 2, 3 and 6) for SDM resistance and two QTLs (one each on chromosomes 3 and 6) for RDM resistance, all of which were contributed by NAI116. The significance of the major QTL on chromosome 6 (bin 6.05) that confers resistance to diverse DMs in tropical Asia, including SDM and RDM in India, was also verified. The results confirmed that some common QTLs contribute to both SDM and RDM resistance, while additional loci might specifically govern resistance to SDM. The QTL information generated in this study provide information that will aid in undertaking an integrated breeding strategy for the transfer of resistance to SDM and RDM in maize lines using marker-assisted selection.

Breeding↗
PubMed2005

Conformational dynamics of estrogen receptors alpha and beta as revealed by intrinsic tryptophan fluorescence and circular dichroism.

Estrogen receptors (ER alpha and ER beta) are ligand-activated nuclear receptors that mediate the action of estrogens. These receptors activate transcription by similar mechanism(s), although the overall amino acid sequence identity is only 47%. In order to compare the structural and conformational features of ER alpha and ER beta, we monitored their intrinsic tryptophan fluorescence during thermal unfolding. The 50% unfolding temperatures (T(M)) of ER alpha and ER beta were 39+/-1 and 40+/-2 degrees C, respectively. Estradiol had no significant effect on the T(M) of ER alpha or ER beta. In contrast, binding of the estrogen-response element increased the T(M) of ER alpha and ER beta by 10 degrees C. Thermal unfolding of estradiol-bound ER alpha and ligand-free ER beta showed two-step transitions, with the formation of intermediates that were stable between 36-48 and 34-42 degrees C, respectively. We confirmed the presence of intermediate states during thermal unfolding by circular dichroism spectroscopy. Atomic force microscopy showed that the ER beta intermediate consisted of discrete globular particles, whereas the ER alpha intermediate showed a speckled appearance, with sparse well-defined particles. Fluorescence-quenching studies showed the presence of two classes of tryptophan in unliganded ER alpha and ER beta. Binding of estradiol to ER beta exposed its tryptophans, whereas estradiol reduced the accessibility of the tryptophans of ER alpha. Our results illustrate the differential effects of ligands on the unfolding of ER alpha and ER beta, and identify partially unfolded intermediates. Differences in the conformational flexibility and stability of ER alpha and ER beta may represent functional differences of ligand-bound ERs in recruiting coactivator proteins and initiating transcription.

Acrylamide↗
PubMed2001

Rapid entry into the cryptophycin core via an acyl-beta-lactam macrolactonization: total synthesis of cryptophycin-24.

[see structure]. An efficient, concise approach to the macrolide core of the cryptophycins, potent antimitotic agents, has been achieved. The reaction sequence features a novel macrolactonization utilizing a reactive acyl-beta-lactam intermediate that incorporates the beta-amino acid moiety within the 16-membered macrolide core. This highly modular approach, which allows for multiple alterations throughout the structure, was successfully applied to the total synthesis of cryptophycin-24.

Depsipeptides↗
PubMed2001

Induction of polyclonal prostate cancer-specific CTL using dendritic cells transfected with amplified tumor RNA.

Polyvalent cancer vaccines targeting the entire antigenic spectrum on tumor cells may represent a superior therapeutic strategy for cancer patients than vaccines solely directed against single Ags. In this study, we show that autologous dendritic cells (DC) transfected with RNA amplified from microdissected tumor cells are capable of stimulating CTL against a broad set of unidentified and critical prostate-specific Ags. Although the polyclonal CTL responses generated with amplified tumor RNA-transfected DC encompassed as a subcomponent a response against prostate-specific Ag (PSA) as well as against telomerase reverse transcriptase, the tumor-specific CTL were consistently more effective than PSA or telomerase reverse transcriptase CTL to lyse tumor targets, suggesting the superiority of the polyclonal response. Although tumor RNA-transfected DC stimulated CTL, which recognized not only tumor but also self-Ags expressed by benign prostate tissue, these cross-reactive CTL were exclusively specific for the PSA, indicating an immunodominant role of PSA in the prostate cancer-specific immune response. Our data suggest that tumor RNA-transfected DC may represent a broadly applicable, potentially clinically effective vaccine strategy for prostate cancer patients, which is not limited by tumor tissue availability for Ag preparation and may minimize the risk of clonal tumor escape.

Adjuvants, Immunologic↗
PubMed2000

Total synthesis of cryptophycin-24 (Arenastatin A) amenable to structural modifications in the C16 side chain.

Two efficient protocols for the synthesis of tert-butyl (5S,6R,2E, 7E)-5-[(tert-butyldimethylsilyl)oxy]-6-methyl-8-phenyl-2, 7-octadienoate, a major component of the cryptophycins, are reported. The first utilized the Noyori reduction and Frater alkylation of methyl 5-benzyloxy-3-oxopentanoate to set two stereogenic centers, which became the C16 hydroxyl and C1' methyl of the cryptophycins. The second approach started from 3-p-methoxybenzyloxypropanal and a crotyl borane reagent derived from (-)-alpha-pinene to set both stereocenters in a single step and provided the dephenyl analogue, tert-butyl (5S,6R,2E)-5-[(tert-butyldimethylsilyl)oxy]-6-methyl-2, 7-octadienoate, in five steps. This compound was readily converted to the 8-phenyl compound via Heck coupling. The silanyloxy esters were efficiently deprotected and coupled to the C2-C10 amino acid fragment to provide desepoxyarenastatin A and its dephenyl analogue. The terminal olefin of the latter was further elaborated via Heck coupling. Epoxidation provided cryptophycin-24 (arenastatin A).

Antineoplastic Agents↗
PubMed2000

A subset of human monocyte-derived dendritic cells expresses high levels of interleukin-12 in response to combined CD40 ligand and interferon-gamma treatment.

Dendritic cells (DCs) may arise from multiple lineages and progress through a series of intermediate stages until fully mature, at which time they are capable of optimal antigen presentation and T-cell activation. High cell surface expression of CD83 is presumed to correlate with full maturation of DCs, and a number of agents have been shown to increase CD83 expression on DCs. We hypothesized that interleukin 12 (IL-12) expression would be a more accurate marker of functionally mature DCs capable of activating antigen-specific T cells. We used combinations of signaling through CD40, using CD40 ligand trimer (CD40L), and interferon gamma to demonstrate that CD83 expression is necessary but not sufficient for optimal production of IL-12 by DCs. Phenotypically mature DCs could be induced to produce high levels of IL-12 p70 only when provided 2 simultaneous stimulatory signals. By intracellular cytokine detection, we determined that only a subset of cells that express high levels of CD80 and CD83 generate large amounts of IL-12. DCs matured with both signals are superior to DCs stimulated with the individual agents in activating antigen-specific T cell in vitro. These findings have important implications regarding the identification, characterization, and clinical application of functionally mature DCs.

Adjuvants, Immunologic↗
PubMed2000

Phenotypic and functional maturation of dendritic cells mediated by heparan sulfate.

Primary immune responses are thought to be induced by dendritic cells. To promote such responses, dendritic cells must be activated by exogenous agonists, such as LPS, or by products of activated leukocytes, such as TNF-alpha and IL-1. How dendritic cells might be activated in the absence of exogenous stimuli, or without the immediate presence of activated leukocytes, as might occur in immunity to tumor cells or transplants, is unknown. We postulated that heparan sulfate, an acidic, biologically active polysaccharide associated with cell membranes and extracellular matrices, which is rapidly released under conditions of inflammation and tissue damage, might provide such a stimulus. Incubation of immature murine dendritic cells with heparan sulfate induced phenotypic maturation evidenced by up-regulation of I-A, CD40, CD54 (ICAM-1), CD80 (B7-1), and CD86 (B7-2). Dendritic cells exposed to heparan sulfate exhibited a markedly lowered rate of Ag uptake and increased allostimulatory capacity. Stimulation of dendritic cells with heparan sulfate induced release of TNF-alpha, IL-1beta, and IL-6, although the maturation of dendritic cells was independent of these cytokines. These results suggest that soluble heparan sulfate chains, as products of the degradation of heparan sulfate proteoglycan, might induce maturation of dendritic cells without exogenous stimuli, thus contributing to the generation and maintenance of primary immune responses.

Animals↗
PubMed2000

Involvement of an ATP-dependent peptide chaperone in cross-presentation after DNA immunization.

Immunization with plasmid DNA holds promise as a vaccination strategy perhaps useful in situations that currently lack vaccines, since the major means of immune induction may differ from more conventional approach. In the present study, we demonstrate that exposure of macrophages to plasmid DNA encoding viral proteins or OVA generates Ag-specific material that, when presented in vitro by dendritic cells to naive T cells, induces primary CTL response or elicits IL-2 production from an OVA peptide-specific T-T hybridoma. The immunogenic material released was proteinaceous in nature, free of apoptotic bodies, and had an apparent m.w. much larger than a 9-11-aa CTL-recognizable peptide. The macrophage-released factor(s) specifically required a hydrolyzable ATP substrate and was inhibited by procedures that removed or hydrolyzed ATP; in addition, anti-heat-shock protein 70 antiserum abrogated the activity to a large extent. These results indicate the possible involvement of a heat-shock protein 70-linked peptide chaperone in a cross-priming method of immune induction by DNA vaccination. Such a cross-priming process may represent a principal mechanism by which plasmid DNA delivered to cells such as myocytes effectively shuttle Ag to DC or other APC to achieve CTL induction in vivo.

Adenosine Triphosphate↗
PubMed2000

Human dendritic cells transfected with RNA encoding prostate-specific antigen stimulate prostate-specific CTL responses in vitro.

Although immunological tolerance to self Ags represents an important mechanism to prevent normal tissue injury, there is growing evidence that tolerance to tumor Ags, which often represent normal peripherally expressed proteins, is not absolute and can be effectively reverted. Prostate-specific Ag (PSA) is a self Ag expressed by both normal and malignant prostatic epithelium, and therefore offers a unique opportunity to examine the ability of self Ags to serve as specific CTL targets. In this study, we investigated the efficacy of autologous dendritic cells (DC) transfected with mRNA encoding PSA to stimulate CTL against PSA Ags in vitro. Ag in form of RNA carries the advantage to encode multiple epitopes for many HLA alleles, thus permitting induction of CTL responses among many cancer patients independent of their HLA repertoire. In this study, we show that PSA mRNA-transfected DC were capable of stimulating primary CTL responses against PSA Ags in vitro. The PSA-specific CTL did not cross-react with kallikrein Ags, a protein, which shares significant homology with PSA, suggesting that harmful autoimmune toxicity may not represent a significant problem with this approach. PSA RNA-transfected DC generated from male or female healthy volunteers or from cancer patients were equally effective in stimulating PSA-specific CTL in vitro, implying that neither natural tolerance to PSA Ags nor tumor-mediated T cell anergy may represent major barriers for CTL generation against the self Ag PSA. This study provides a preclinical rationale for using PSA RNA-transfected DC in active or adoptive immunization protocols.

Cell Differentiation↗
PubMed2000

Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells.

Unique patient-specific tumor antigens may constitute the dominant antigens in the antitumor immune response. Hence, vaccination with the patient's own repertoire of tumor antigens may offer a superior strategy to elicit protective immunity. We have shown previously that dendritic cells transfected with mRNA isolated from tumor cells stimulate potent CTL responses and engender protective immunity in tumor-bearing mice. In the current study, we demonstrate that tumor mRNA, isolated from murine tumor cell lines or from primary human tumor cells microdissected from frozen tissue sections, can be amplified without loss of function. This study provides the foundations for an effective and broadly applicable treatment that does not require the characterization of the relevant antigenic profile in each patient and will not be limited by tumor tissue availability for antigen preparation.

Animals↗
PubMed2000

Induction of cytotoxic T cell responses and tumor immunity against unrelated tumors using telomerase reverse transcriptase RNA transfected dendritic cells.

The polypeptide component of telomerase (TERT) is an attractive candidate for a broadly expressed tumor rejection antigen because telomerase is silent in normal tissues but is reactivated in more than 85% of cancers. Here we show that immunization against TERT induces immunity against tumors of unrelated origin. Immunization of mice with TERT RNA-transfected dendritic cells (DC) stimulated cytotoxic T lymphocytes (CTL), which lysed melanoma and thymoma tumor cells and inhibited the growth of three unrelated tumors in mice of distinct genetic backgrounds. TERT RNA-transfected human DC stimulated TERT-specific CTL in vitro that lysed human tumor cells, including Epstein Barr virus (EBV)-transformed B cells as well as autologous tumor targets from patients with renal and prostate cancer. Tumor RNA-transfected DC were used as surrogate targets in the CTL assays, obviating the difficulties in obtaining tumor cells from cancer patients. In one instance, where a tumor cell line was successfully established in culture from a patient with renal cancer, the patient's tumor cells were efficiently lysed by the CTL. Immunization with tumor RNA was generally more effective than immunization with TERT RNA, suggesting that an optimal immunization protocol may have to include TERT as well as additional tumor antigens.

Animals↗
PubMed2000

A radioiodine speciation, deposition, and dispersion model with uncertainty propagation for the Oak Ridge dose reconstruction.

Between 1944 and 1956, radioactive 131I was released into the atmosphere from operations at the Oak Ridge National Laboratory in Oak Ridge, TN. The releases occurred from stacks and from building vents and openings in three different chemical forms: elemental, organic, and particulate. During their transport in the atmosphere, different forms of iodine react differently with other atmospheric chemicals and moisture, and are removed from the plume at different rates by the processes of dry and wet deposition. A modified Gaussian plume model was developed to address the processes of radioiodine speciation, deposition, depletion, and dispersion in the atmosphere, and to propagate uncertainties in input parameter values through to the ground-level concentrations of 131I in air. A unique approach was used to develop an implicitly correlated set of hourly meteorological parameters for any day of a month for each month of the year from ten years of available data between 1987 and 1996. The model was validated for both annual average and short-term releases. For the annual average releases, the predictions of ground-level concentrations of 131I from the model were within a factor of 2 of measured field data. For two of the three sets of available weekly data, the measurements fell within the 95% subjective confidence interval of model predictions. Predictions of ground-level air concentrations were made on an annual average basis for the entire period of release and on a short-term, episodic basis for a 1954 accident.

Atmosphere↗
PubMed2000

External exposure to radionuclides accumulated in shoreline sediments with an application to the lower Clinch River.

A simple analytical method was developed to estimate external doses from exposure to contaminated riverine shorelines. The method consists of deriving an adjustment factor that accounts for the geometry of the riverine shoreline; the adjustment factor is applied to the dose-rate coefficients already available for infinite contaminated surfaces. Such a geometry factor circumvents very complex radiation transport calculations which would otherwise be necessary to model exposures to a finite contaminated surface. For instance, for radionuclides emitting gamma rays of energies above 600 keV (e.g., 137Cs), the published dose-rate coefficients must be reduced by 75%, 60%, 50%, and 33% for shoreline widths of 4, 10, 20, and 50 m, respectively. The geometry factor changes only mildly with the energy of the gamma radiation. This property allows for the geometry factor to be used for radionuclides emitting multiple gamma rays of various energies. If a quick analysis is desired, the geometry factors derived for 137Cs can be used for all radionuclides. More refined analysis can be performed by deriving geometry factors for each radionuclide according to its gamma spectrum. Also, the mild variation with energy allows the geometry factors to be applied to the case when radionuclides are accumulated in layers under the soil surface, and not only to the case when radionuclides are deposited onto the soil surface. Empirical relationships between the geometry factor and the dimension of the shoreline were provided so that one can obtain values of the geometry factor for any shoreline width. These relationships can be easily used to account for the uncertainty in the dimension of the shoreline. The method was applied to derive similar adjustment factors for contaminated surfaces of other simple geometries (e.g., circular surfaces). An example of how this method can be applied to its full extent is presented for the case of external exposure to the shores of the lower Clinch River. This river received large amounts of 137Cs, 60Co, 106Ru, 95Zr, 95Nb, 144Ce, and 90Sr released during 1944-1991 from the Oak Ridge Reservation in Oak Ridge, Tennessee.

Adult↗