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S Jayaraman

Publications and source records attributed to S Jayaraman.

At least 19 recordsLinked to original sources
PubMed2026

A novel reusable transcriptome-wide association study workflow used to map key genes linked to important cattle traits.

Transcriptome-wide association studies (TWAS) are a powerful approach for studying the genes underlying complex traits by directly integrating GWAS and gene expression datasets. In cattle, they have been previously applied to identify genes driving fertility, milk production, and health. However, these studies have also highlighted several challenges, from difficulties in reproducing these complex analyses to limitations from poor genotype calls, especially when called directly from RNA sequencing data. To address these and other challenges, for the H2020 BovReg Project, we have developed a streamlined, species-agnostic, and reusable Nextflow TWAS workflow to integrate transcriptomic and GWAS summary statistic datasets. Our workflow first generates accurate genotype calls and gene expression prediction models from transcriptomic datasets and then applies these tools to impute gene expression levels into GWAS cohorts, enabling the association of genes with traits of interest. We explore optimal strategies for calling genetic variants directly from transcriptomic data and illustrate that using imputation approaches specifically designed for low-pass sequencing data can improve variant calling over previously adopted methods. We demonstrate the utility of our TWAS workflow by applying it to both novel and publicly available GWAS cohorts for cattle, detecting novel gene-trait associations for complex traits. Using a new transcriptome annotation of the cattle genome generated for the BovReg project we also illustrate how previously un-assayable associations can be detected. The results and the workflow we present, provide a new resource for the community and contribute to a better understanding of the molecular drivers of complex traits in cattle with the goal of eventually leveraging this information in future breeding decisions.

Animals↗
PubMed1992

Tolerance induction in T helper (Th1) cells by thymic macrophages.

Most macrophages in the peripheral tissues present Ag optimally to a variety of functionally distinct Th cells. Although thymic macrophages have been implicated in deleting autoreactive thymocytes, their role in influencing the functional capacities of mature T cells is not clear. We have established a normal untransformed macrophage cell line, named TMC, from the mouse thymus. The TMC line presents protein Ag to an IL-4-producing Th2 type Th clone after IFN-gamma treatment as evidence by T cell proliferation and the release of IL-3 and IL-4. However, these thymic macrophages are inefficient at stimulating a well characterized cytochrome C-specific IL-2-producing Th1 clone, A.E7. Ag presentation by TMC results in the production of IL-3 but not IL-2 production or proliferation of A.E7 cells. This selective Ag presentation defect to Th1 cells is corrected by the addition of live but not fixed allogeneic irradiated spleen cells, suggesting that the thymic macrophages lack the expression of costimulatory activity required for Th1 activation. This is further demonstrated by the failure of live thymic macrophages to provide costimulatory activity to A.E7 cells stimulated with fixed spleen cells plus the antigenic peptide 81-104. Exposure of A.E7 cells to paraformaldehyde-treated TMC in the presence of 81-104 peptide induces specific hyporesponsiveness, anergy. These data demonstrate that thymic macrophages can have a profound influence on the response of selected T cells to Ag. Furthermore, the nature of the T cell stimulus is also critical because Th1 and Th2 cells responded equally well to the T cell mitogen, Con A, and a bacterial superantigen presented by the thymic macrophages.

Animals↗
PubMed1992

Influence of nutritional factors on growth and hydrolytic enzyme production in Nocardia asteroides.

The growth and production of hydrolytic enzymes such as alpha-amylase, esterase and peroxidase as influenced by the type of media, carbon and nitrogen sources and C:N ratio were monitored in Nocardia asteroides at 37 degrees C. Sabouraud dextrose and the synthetic media yielded maximum growth compared with tryptic soy broth. Among the carbon sources (dextrose, fructose, sucrose, maltose, starch and citrate), monosaccharides supported maximum growth and induced higher alpha-amylase activity but repressed the peroxidase activity. On the other hand, the disaccharides and starch produced less growth but induced maximum esterase and peroxidase activities. Glutamate among the nitrogen sources (nitrate, nitrite, ammonium, hydroxylamine, glutamate and casein) supported maximum growth. Glutamate, nitrate and casein induced alpha-amylase and esterase activities but suppressed peroxidase activity. Nitrite, ammonium and hydroxylamine stimulated peroxidase activity to the maximum but repressed alpha-amylase and esterase activities. Low, medium and high C:N ratios induced maximum peroxidase, esterase and alpha-amylase activities, respectively.

Caseins↗
PubMed1991

Involvement of protein kinase C in competence induction of macrophages to generate T suppressor cells.

We have previously described an Ia-expressing macrophage hybridoma clone, termed clone 59, which attains the ability to induce Ts cells after activation with murine rIFN-gamma. In this report, we show that a protein kinase C (PKC) activator, PMA (10 ng/ml) can replace IFN-gamma in inducing this form of macrophage competence. IFN-gamma-induced cellular competence was abrogated specifically by a PKC inhibitor but not by inhibitors that have specificity for cyclic nucleotide-dependent protein kinases. Furthermore, PGE2 known to induce protein kinase A in murine macrophages also failed to induce competence. In contrast, the ability to induce Th responses was neither dependent on IFN-gamma nor inhibited by prior treatment with protein kinase inhibitors. Furthermore, PKC depletion of macrophages by treatment with high doses (100 ng/ml) of PMA abrogated their ability to induce Ts cells. In addition, PKC-depleted macrophages failed to regain the ability to stimulate Ts cells after further treatment with IFN-gamma. The ability of IFN-gamma to modulate macrophage-mediated induction of Ts cells does not clearly correlate with an increased Ia expression as inducible expression of Ia was not consistently abrogated by PKC inhibitor treatment. In addition, PKC inhibitors failed to prevent the production of the cytokines IL-1 and IL-6. However, incubation of IFN-gamma or PMA-treated macrophages with antibodies recognizing the putative IJ ligand blocked the ability to induce Ts cells, suggesting the expression of these determinants on accessory cells is responsible for Ts induction.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Prostatic hypoplasia in bonnet monkeys following active immunization with semisynthetic anti-LHRH vaccine.

An active immunization study using semisynthetic anti-luteinizing hormone releasing hormone (LHRH) vaccine was undertaken in adult male bonnet monkeys (Macaca radiata). Four male bonnet monkeys were immunized with LHRH-DT vaccine (100 micrograms/monkey). When the elevation of serum anti-LHRH titers reached an effective concentration, a remarkable decrease in serum testosterone level was observed. The sperm counts at 12 and 20 weeks following immunization in all immunized monkeys were reduced markedly. One representative animal with high antibody titer along with an age-matched control animal was sacrificed 20 weeks following primary immunization. The prostate weight of the immunized monkey was reduced to one-third (0.027) of the control (0.085). A reduction was also observed in other reproductive organs. Remaining animals are being studied for a reversible effect of immunization. Thus the study demonstrates that the size of the prostate can be reduced significantly by inhibition of hypothalamic-pituitary-testicular axis using this anti-LHRH vaccine.

Acid Phosphatase↗
PubMed1990

Relationships between antigen-specific helper and inducer suppressor T cell hybridomas.

Ts1, or inducer suppressor T cells, share many phenotypic and functional characteristics with helper/inducer subset of T cells. In order to evaluate the relationship between these cell types, we made a series of new Ts1 hybridomas by the fusion of Ts1 cells with the functionally TCR alpha/beta-negative BW thymoma (BW 1100). Three Ts1 hybridomas (CKB-Ts1-38, CKB-Ts1-53, and CKB-Ts1-81) were established that express TCR and produce Ag-specific suppressor factors constitutively, thus making it possible to study the nature and specificity of Ag receptors, MHC restriction, and lymphokine production by the Ts1 hybridomas. Results presented in this report demonstrate that all the Ts1 hybridomas described here express CD3-associated TCR-alpha beta. These three Ts1 hybridomas recognize Ag (NP-KLH) specifically in a growth inhibition assay and this recognition is restricted by IE molecules. Two of the hybridomas also produce IL-2 or IL-2 and IL-4 upon Ag-specific activation. Thus, by these three criteria the Ts1 hybridomas appear indistinguishable from Th cells. These three Ts1 hybridomas, however, release suppressor factors (TsF1) in the supernatant that suppress both in vivo DTH and in vitro PFC responses in an Ag-specific manner. Like the TsF1 factors characterized previously, the suppression mediated by these factors are Igh restricted and lack H-2 restriction. These factors mediate suppression when given in the induction phase but not during the effector phase of the immune response. The TsF1 factors are absorbed by Ag (NP-BSA), and anti-TCR affinity columns and the suppressor activity can be recovered by elution. The data are consistent with the interpretation that Ts1 inducer-suppressor T cells are related to Th cells; the feature that distinguishes these cells is the ability to produce Ag-binding factors that specifically suppress immune responses.

Animals↗
PubMed1990

Characterization of T cell clones from an athymic mouse.

Although Thy-1+ lymphocytes have been observed in lymphoid tissues of athymic mice, attempts to analyze these cells on the clonal level have previously yielded only populations of CD4-CD8+ cytolytic T cells. Furthermore, studies of responses of these cells to various mitogenic stimuli have demonstrated significant defects in the ability of these cells to proliferate in culture. We report here on the cloning and maintenance in long term culture of T cells from an athymic mouse stimulated in vitro with allogeneic spleen cells. Of 10 Thy-1+ clones, 7 CD4+CD8- and 3 CD4-CD8+ Ag-specific cells were obtained. Among the CD4+ T cells, we observed a variety of specificities, including an autoreactive I-Aq specific clone, a minor lymphocyte stimulating determinant (Mls)-reactive clone, and five allo-I-Ad-specific CD4+ clones; a class II-specific CD4-CD8+ clone was also obtained. In addition, we observed two Thy-1-CD3+ clones (one of which is also CD4+ and expresses V beta 8) which are constitutively responsive to the lymphokines IL-2 and IL-4. Of 11 clones tested, 7 produce IL-2 and/or IL-4 lymphokines after stimulation through the TCR, whereas 4 do not, requiring exogenous lymphokines for optimal responses to Ag. Of 10 clones tested for IL-2R expression, 3 had notably low levels, correlating with low proliferative responses to IL-2. The results reveal the spectrum of T cells available to a mouse which is congenitally athymic and describe the heterogeneity of immune defects expressed in such cells at the clonal level.

Animals↗
PubMed1990

Enhancement of in vivo cell-mediated immune responses by three distinct cytokines.

The ability of recombinant/purified cytokines to augment delayed-type hypersensitivity (DTH) responses was investigated. Suboptimal doses of haptenized SC were treated in vitro with purified or recombinant derived cytokines and tested for their ability to enhance DTH in vivo. With the use of this protocol, it was shown that both human and mouse rIL-6, as well as mouse rTNF-alpha, potentiated DTH in a dose-dependent manner. In accordance with these data, IL-6/TNF-alpha-containing supernatant from long term nonlymphoid cell lines also possessed the ability to augment DTH. By using the same protocol, we have also identified T cell hybridomas that produce DTH-augmenting activity constitutively. The hybridoma-derived factor, termed the T cell enhancing factor (TCEF), was functionally distinguishable from the defined cytokines IL-1 through IL-6, IFN-gamma, and TNF by bioassay. Furthermore, RNA derived from the hybridoma failed to hybridize with cDNA probes specific for IL-1 to IL-6, IFN-gamma, TNF-alpha, and granulocyte-macrophage CSF. Further characterization of the serum-free conditioned media derived from the hybridoma indicated that the TCEF was a soluble acid labile glycoprotein (Mr greater than 30,000). Finally, we investigated the cellular requirements for DTH augmentation by IL-6, TNF-alpha, and TCEF; all are dependent upon the presence of T cells in the immunizing inoculum. We propose that these cytokines play a critical role in the development of DTH responses in vivo.

Animals↗
PubMed1990

Histopathological changes in reproductive organs of male Wistar rats following active immunization against LHRH.

Histopathological changes induced by immune responses generated against luteinizing hormone releasing hormone (LHRH) were studied in adult male Wistar rats. Active immunization with a semisynthetic anti-LHRH vaccine, LHRH D-Lys6, (10, 40, and 80 micrograms/animal) conjugated with diphtheria toxoid, produced bioeffective antibodies as indicated by significant reduction in circulating testosterone levels. At the 14th week after immunization the animals were sacrificed and reproductive organs were evaluated. These organs were studied for histopathological changes and compared with those of nonimmunized control rats. Marked hypoplastic changes were observed in the genital organs. Testicular changes such as arrest of spermatogenesis at the spermatocyte level and atrophic changes in the interstitial Leydig cells were noticed in treated animals. Similarly attenuation of secretory epithelial cells with substantial increase in the stromal tissues was observed in the prostate and seminal vesicles. The current observation suggests the possible usefulness of this anti-LHRH vaccine under clinical conditions where reduction in androgenic response is desired as in the case of hormone-dependent prostatic carcinoma.

Animals↗
PubMed1989

Functional analysis of cloned macrophage hybridomas. VII. Modulation of suppressor T cell-inducing activity.

We have previously characterized a macrophage hybridoma clone, termed clone 59, which induced immunity but consistently failed to induce Ts responses. Macrophage 59 cells were cultured with supernatants from several activated T cell clones to determine if lymphokines could modulate the activity of this macrophage hybridoma to generate effector Ts. Culture supernatants from Th1 clones and from one atypical IL-4 and IFN-gamma-producing T cell clone successfully modulated clone 59 cells to induce effector Ts cells. In contrast, supernatants from activated Th2 cells failed to generate Ts-inducing activity in macrophage 59 cells. Culture with recombinant derived IFN-gamma was sufficient to cause modulation of Ts-inducing activity in macrophage 59 cells. The data imply that the differential functional activities ascribed to various macrophage hybridoma clones reflect macrophage heterogeneity instead of independent macrophage lineages. The suppression induced by clone 59 macrophages was genetically restricted to the putative I-J region. The ability of IFN-gamma containing supernatants to endow macrophage 59 with the capacity to induce effector suppressor cells was specifically abrogated by addition of an anti-IJk-idiotype antibody, which also reacts with IJ-interaction molecules, indicating that the mechanism of modulation most likely involves expression of IJ-interaction molecule determinants on antigen presenting cells.

Animals↗
PubMed1989

Interleukin 3-dependent and -independent mast cells stimulated with IgE and antigen express multiple cytokines.

In response to IgE and specific multivalent antigen, mast cell lines (both growth factor-dependent and -independent) induce the transcription and/or secretion of a number of cytokines having a wide spectrum of activities. We have identified IL-1, IL-3, IL-5, IL-6, IFN-gamma, GM-CSF, JE, MIP1 alpha, MIP1 beta, and TCA3 RNA in at least two of four mast cell clones. The production of these products (except JE) is activation-associated and can be induced by IgE plus antigen. In selected instances cytokine expression can also be induced by activation with Con A or phorbol ester plus ionophore, albeit to levels less than those observed with IgE plus antigen. In addition, long-term mast cell clones and primary cultures of bone marrow-derived mast cells specifically release IL-1, IL-4, and/or IL-6 bioactivity after activation. These findings suggest that in addition to their inflammatory effector function mast cells may serve as a source of growth and regulatory factors. The relationship of mast cells to cells of the T lymphocyte lineage is discussed.

Animals↗
PubMed1989

A monoclonal antibody raised to lipomodulin recognizes T suppressor factors in two independent hapten-specific suppressor networks.

Five different Ag-binding suppressor factors from two types of hapten-specific Ts cell hybridomas (TsF1 inducer and TsF3 effector factors) were bound by an anti-lipomodulin mAb (141-B9), that crossreacts with rodent glycosylation inhibition factor (GIF). The Ag-specific suppressor activity in these hybridoma supernatants was bound by anti-lipomodulin columns and could be recovered by elution at acid pH. Additional evidence for the expression of lipomodulin/GIF activity on these TsF molecules was demonstrated by the ability of the eluted fractions to inhibit the glycosylation of IgE-binding peptides during their biosynthesis. The same biologic activity is associated with GIF and lipomodulin. The relationship between TsF and lipomodulin/GIF was confirmed in a serologic assay, which showed that TsF1 and TsF3 molecules, whether purified over Ag, anti-IJ or anti-TsF columns, are recognized by the mAb. 141-B9. The combined results indicate that Ag-binding Ts factors share a common antigenic determinant with phospholipase inhibitory proteins such as lipomodulin and GIF. In addition, the demonstration of glycosylation regulatory activity carried on these TsF molecules suggests a possible mode for their bioactivity.

Animals↗
PubMed1989

Variation of lung density corrections in a typical patient population.

The correction factors to allow for the excess transmission through the lung were worked out for 25 patients who underwent radiation treatment of lesions in thorax. The geometrical arrangements of the beams used for the treatments were reconstructed on the CT scans to identify the amount of lung that intervened. The lung transmission correction factors were worked out for four possible photon energies Cobalt-60, 6 MV, 10 MV, and 20 MV. Isocentric treatment was considered throughout and the isocenter was regarded as the point of dose prescription as is done in normal practice. Correction factors were based on published experimental data for situations that had the isocenter inside the lung. Ratio of TAR (or TMR) method and Batho's power law of TAR (or TMR) method were used if the isocenter was behind the lung. It was observed that the average increase in the total dose after lung corrections were 11.5 +/- 6%, 8.5 +/- 5%, 5.5 +/- 3%, and 4.0 +/- 2% at the energies of Cobalt-60, 6 MV, 10 MV, and 20 MV, respectively. This proves the importance of carrying out the lung transmission corrections to achieve a greater consistency in the doses delivered between groups of patients treated with different photon energies.

Humans↗
PubMed1989

Role of adjuvants in inhibitory influence of immunization with porcine zona pellucida antigen (ZP-3) on ovarian folliculogenesis in bonnet monkeys: a morphological study.

Female bonnet monkeys were immunized with 55 kDa porcine zona antigen (ZP-3), with either complete Freund's adjuvant (CFA) or sodium phthalylated lipopolysaccharide (SPLPS) as adjuvant. Anti-ZP-3 antibody titers were monitored and the effect of immunization on the ovarian morphology was assessed by high-resolution light microscopy. The study demonstrated that both adjuvants used were equally potent in eliciting antibody response against ZP-3. Although no morphological damage to ovarian components was observed in animals immunized with SPLPS as adjuvant, immunization using CFA resulted in profound ovarian follicular atrophy, sparing only the primordial follicles. The atrophic phenomenon involved those follicles that either already had or were in the process of forming zona pellucida. The results of this study indicate that choice of adjuvant may be an important consideration for immunization against zona antigens. These findings encourage further investigations for developing better immunization regimen aimed at using zona antigens for immunocontraception.

Adjuvants, Immunologic↗
PubMed1988

Effect of antiprogestin ZK 98.734 on the ovarian cycle, early pregnancy, and on its binding to progesterone receptors in the myometrium of marmoset Callithrix jacchus.

The antiprogestin ZK 98.734 (11 beta-(4-dimethylaminophenyl-17 beta-hydroxy-17 alpha-(3-hydroxy-prop-1(Z)-enyl-4,9(10)-estradien-3-one) was administered i.m. (5 mg/day) for three consecutive days to two groups of common marmosets. In one group (nonpregnant, n = 6), it was injected during the luteal phase, and to the second group (pregnant, n = 7), it was injected during early pregnancy, on Days 24-26 of the mid-cycle estradiol peak. Administration of ZK 98.734 during the luteal phase caused a sharp drop in plasma progesterone levels. The luteal phase was shortened whether the drug was administered during the early or the late luteal phase. Similarly, administration of ZK 98.734 during early pregnancy caused a significant drop in progesterone levels, and pregnancy was terminated in all of the animals. The post-treatment cycles in both groups of animals were ovulatory and of normal duration. 3H-ZK 98.734 showed specific binding to myometrial cytosol fraction. ZK 98.734 also displaced the binding of 3H-progesterone to progesterone receptors. However, progesterone had higher binding affinity than did ZK 98.734. The antifertility action of ZK 98.734 could be a result either of its luteolytic action or of its blocking the progesterone receptors in the target tissue. This study, therefore, indicates that in the common marmoset ZK 98.734 is a progesterone antagonist with a potential to terminate early pregnancy.

Animals↗
PubMed1987

The use of nonspecific T acceptor cells to overcome the aberrant function of antigen-specific third-order T suppressor cells.

Earlier studies in the phenyltrimethylamino (TMA) hapten system demonstrated that under certain conditions idiotype-specific second-order T suppressor (Ts2)-bearing mice fail to suppress TMA-specific delayed-type hypersensitivity. This was due to a functional deletion in the third-order T suppressor (Ts3) subset. In this report we have confirmed and extended these findings to show that only homologous TMA-specific Ts3 can restore suppressor function, both heterologous Ts3 and unprimed T-cell populations failed to do so. Furthermore, attempts to induce Ts3 function in the defective mice after reconstitution with normal precursor Ts3 cells also failed. In contrast, protocols which induce heterologous contact and cutaneous hypersensitivity reactions readily induced cell populations capable of restoring suppression in the Ts3-defective mice. Analysis of the lymphoid populations from the contact-sensitized defective mice revealed that these cells were not the prototypical Ts3 but were similar to the previously reported nonspecific T acceptor cell. The results further indicated that the T acceptor cell functioned as the active terminal-phase Ts subset, and this could be used as an alternative to the TMA-specific Ts3. The importance of multiple suppressor pathways at the terminal phase of immune suppression is discussed.

Animals↗