Self-reactive human CD4 T cell clones form unusual immunological synapses

Recognition of self–peptide-MHC (pMHC) complexes by CD4 T cells plays an important role in the pathogenesis of many autoimmune diseases. We analyzed formation of immunological synapses (IS) in self-reactive T cell clones from patients with multiple sclerosis and type 1 diabetes. All self-reactive T cells contained a large number of phosphorylated T cell receptor (TCR) microclusters, indicative of active TCR signaling. However, they showed little or no visible pMHC accumulation or transport of TCR–pMHC complexes into a central supramolecular activation cluster (cSMAC). In contrast, influenza-specific T cells accumulated large quantities of pMHC complexes in microclusters and a cSMAC, even when presented with 100-fold lower pMHC densities. The self-reactive T cells also maintained a high degree of motility, again in sharp contrast to virus-specific T cells. 2D affinity measurements of three of these self-reactive T cell clones demonstrated a normal off-rate but a slow on-rate of TCR binding to pMHC. These unusual IS features may facilitate escape from negative selection by self-reactive T cells encountering very small amounts of self-antigen in the thymus. However, these same features may enable acquisition of effector functions by self-reactive T cells encountering large amounts of self-antigen in the target organ of the autoimmune disease

Hypoglycemia and the Origin of Hypoxia-Induced Reduction in Human Fetal Growth

The most well known reproductive consequence of residence at high altitude (HA >2700 m) is reduction in fetal growth. Reduced fetoplacental oxygenation is an underlying cause of pregnancy pathologies, including intrauterine growth restriction and preeclampsia, which are more common at HA. Therefore, altitude is a natural experimental model to study the etiology of pregnancy pathophysiologies. We have shown that the proximate cause of decreased fetal growth is not reduced oxygen availability, delivery, or consumption. We therefore asked whether glucose, the primary substrate for fetal growth, might be decreased and/or whether altered fetoplacental glucose metabolism might account for reduced fetal growth at HA.Doppler and ultrasound were used to measure maternal uterine and fetal umbilical blood flows in 69 and 58 residents of 400 vs 3600 m. Arterial and venous blood samples from mother and fetus were collected at elective cesarean delivery and analyzed for glucose, lactate and insulin. Maternal delivery and fetal uptakes for oxygen and glucose were calculated.The maternal arterial – venous glucose concentration difference was greater at HA. However, umbilical venous and arterial glucose concentrations were markedly decreased, resulting in lower glucose delivery at 3600 m. Fetal glucose consumption was reduced by >28%, but strongly correlated with glucose delivery, highlighting the relevance of glucose concentration to fetal uptake. At altitude, fetal lactate levels were increased, insulin concentrations decreased, and the expression of GLUT1 glucose transporter protein in the placental basal membrane was reduced.Our results support that preferential anaerobic consumption of glucose by the placenta at high altitude spares oxygen for fetal use, but limits glucose availability for fetal growth. Thus reduced fetal growth at high altitude is associated with fetal hypoglycemia, hypoinsulinemia and a trend towards lactacidemia. Our data support that placentally-mediated reduction in glucose transport is an initiating factor for reduced fetal growth under conditions of chronic hypoxemia

Mitochondrial and Plasma Membrane Pools of Stomatin-Like Protein 2 Coalesce at the Immunological Synapse during T Cell Activation

Stomatin-like protein 2 (SLP-2) is a member of the stomatin – prohibitin – flotillin – HflC/K (SPFH) superfamily. Recent evidence indicates that SLP-2 is involved in the organization of cardiolipin-enriched microdomains in mitochondrial membranes and the regulation of mitochondrial biogenesis and function. In T cells, this role translates into enhanced T cell activation. Although the major pool of SLP-2 is associated with mitochondria, we show here that there is an additional pool of SLP-2 associated with the plasma membrane of T cells. Both plasma membrane-associated and mitochondria-associated pools of SLP-2 coalesce at the immunological synapse (IS) upon T cell activation. SLP-2 is not required for formation of IS nor for the re-localization of mitochondria to the IS because SLP-2-deficient T cells showed normal re-localization of these organelles in response to T cell activation. Interestingly, upon T cell activation, we found the surface pool of SLP-2 mostly excluded from the central supramolecular activation complex, and enriched in the peripheral area of the IS where signalling TCR microclusters are located. Based on these results, we propose that SLP-2 facilitates the compartmentalization not only of mitochondrial membranes but also of the plasma membrane into functional microdomains. In this latter location, SLP-2 may facilitate the optimal assembly of TCR signalosome components. Our data also suggest that there may be a net exchange of membrane material between mitochondria and plasma membrane, explaining the presence of some mitochondrial proteins in the plasma membrane

Strategies to Target Tumor Immunosuppression

The tumor microenvironment is currently in the spotlight of cancer immunology research as a key factor impacting tumor development and progression. While antigen-specific immune responses play a crucial role in tumor rejection, the tumor hampers these immune responses by creating an immunosuppressive microenvironment. Recently, major progress has been achieved in the field of cancer immunotherapy, and several groundbreaking clinical trials demonstrated the potency of such therapeutic interventions in patients. Yet, the responses greatly vary among individuals. This calls for the rational design of more efficacious cancer immunotherapeutic interventions that take into consideration the “immune signature” of the tumor. Multimodality treatment regimens that aim to enhance intratumoral homing and activation of antigen-specific immune effector cells, while simultaneously targeting tumor immunosuppression, are pivotal for potent antitumor immunity

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Not AvailableEighty-nine accessions collected from North-east India were studied for genetic divergence and potentiality for yield and other economic traits. A number of accessions were identified as sources of traits of breeders' interest. Sources of resistance to fusarium wilt, jassids and serpentine leaf miner were identified. Eighty-nine accessions were grouped into six clusters. The diverse clusters derived could be used in hybridization programme to generate a wide range of transgressive segregates in populations for development of high yielding, disease and insect resistant castor varieties.Not Availabl

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Not AvailableThe development of extra-early genepool in castor (Ricinus communis L.) was aimed at enhancing the genetic base for developing extra-early maturing lines with enhanced seed yield and other desirable traits. Based on evaluation for four contiguous years, 21 stable extra-early maturing (75-110 days) accessions were selected and were random mated for five generations in isolation. Consequently the range and mean of the major yield contributing traits and yield were considerably while the days to 50% flowering and days to maturity and node number to primary spike were comparable to parents. The genetically enhanced genepool of castor would certainly provide board base for developing diverse high yielding extra-early maturing cultivars.Not Availabl

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Standarad operational procedure of Keshanjana – An Ayurvedic formulation

Masi Kalpana is one of the pharmaceutical formulations in Ayurvedic pharmacy used in variety of pathological conditions mainly in external/local applications. Keshamasi has been propounded in Anjana (collyrium) dosage form mixed with Goghrita as Keshanjana in the treatment of Sukshakshipaka (Dry Eye Syndrome) by Acharya Vagabhatta. This preparation is not in practice; & owing to the sensitivity of ocular therapeutics issue as the method of preparation and quantity of its ingredients is in obscure manner in the literature, this formulation - Keshanjana was taken up for developing Standard Operative Procedure / standardization and clinical evaluation in Dry Eye Syndrome in an EMR project after a pilot study in a PG thesis work.&nbsp

Association between fetal interleukin-1 receptor antagonist gene polymorphism and unexplained fetal death

OBJECTIVE: In spite of extensive clinical examinations or autopsies, as many as 15% to 40% of stillbirths remain unexplained. A systemic fetal inflammatory response is an independent risk factor for severe neonatal morbidity, mediated by proinflammatory cytokines. As a major anti-inflammatory cytokine, interleukin-1 receptor antagonist (IL-1ra) plays a crucial role modulating the proinflammatory response. The gene coding for IL-1ra (IL1RN) is polymorphic. We hypothesized that fetal possession of a specific allele, IL-1RN*2, associated with increased proinflammatory responses, may increase susceptibility to intrauterine fetal death. STUDY DESIGN: Fetal kidney cells were obtained from paraffin blocks of 27 unexplained stillbirths. DNA was isolated and tested for IL-1RN genotypes by polymerase chain reaction. As a control group, DNA from 302 live births was also tested. RESULTS: There was an enhanced rate of IL-1RN*2 homozygocity, 41%, among unexplained stillbirths compared with the control group, 8.6% (P < .001). Histologic analysis of fetal tissues demonstrated a predominant proinflammatory response in IL-1RN*2 homozygote fetuses. Extensive screening (microbiology, maternal serology, placenta histology) did not identify any specific trigger agent. CONCLUSION: There is an association between unexplained stillbirth and fetal homozygous IL1RN*2 carriage

Subcutaneous and omental fat expression of adiponectin and leptin in women with polycystic ovary syndrome

To assess message expression of adiponectin and leptin in visceral and SC fat in women with polycystic ovary syndrome (PCOS) and in control women. Design: Prospective clinical trial. Setting: Academic medical centers in Mexico City, Mexico and New York, New York. Patient(s): Women with PCOS and control women. Intervention(s): Surgical biopsies of visceral (omental) and subcutaneous (SC) adipose tissue, fasting blood samples, and ultrasound measurements of visceral and SC fat. Main Outcome Measure(s): Messenger RNA assessment of adiponectin and leptin in adipose tissue samples; serum measurements of adiponectin, leptin, glucose, insulin, and hormone levels; measurements of fat quantity by ultrasound. Correlative analyses as well as comparisons between women with PCOS and control women were performed. Result(s): Confirming previous data, women with PCOS had more insulin resistance, similar serum leptin, but lower serum adiponectin compared with control women. When control women were divided into quartiles by body mass index (BMI), messenger RNA expression of leptin and adiponectin decreased with increasing BMI. Adiponectin and leptin expression was significantly lower in women with PCOS; in weight-matched patients and control women, leptin and adiponectin expression was statistically significantly lower in SC tissue, and adiponectin expression was statistically significantly lower in omental tissue in women with PCOS. In control women, there was greater expression in SC tissue compared with in visceral tissue. There were significant negative correlations between visceral and SC fat mass by both ultrasound as well as adiponectin and leptin expression in women with PCOS. Serum adiponectin correlated statistically significantly with visceral adiponectin expression (r = 0.64) in women with PCOS, and there was a statistically significant correlation between SC adiponectin expression and the Quantitative Insulin-Sensitivity Check Index as a marker of insulin resistance (r = 0.43). Conclusion(s): Adipocytokine expression in fat tissue appears to be down-regulated by an increased fat mass; this is particularly evident in the case of adiponectin expression in women with PCOS. It is probable that insulin resistance is a factor that may contribute, in part, to these finding