54 research outputs found

    Two Genes on A/J Chromosome 18 Are Associated with Susceptibility to Staphylococcus aureus Infection by Combined Microarray and QTL Analyses

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    Although it has recently been shown that A/J mice are highly susceptible to Staphylococcus aureus sepsis as compared to C57BL/6J, the specific genes responsible for this differential phenotype are unknown. Using chromosome substitution strains (CSS), we found that loci on chromosomes 8, 11, and 18 influence susceptibility to S. aureus sepsis in A/J mice. We then used two candidate gene selection strategies to identify genes on these three chromosomes associated with S. aureus susceptibility, and targeted genes identified by both gene selection strategies. First, we used whole genome transcription profiling to identify 191 (56 on chr. 8, 100 on chr. 11, and 35 on chr. 18) genes on our three chromosomes of interest that are differentially expressed between S. aureus-infected A/J and C57BL/6J. Second, we identified two significant quantitative trait loci (QTL) for survival post-infection on chr. 18 using N2 backcross mice (F1 [C18A]×C57BL/6J). Ten genes on chr. 18 (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTL regions and were also identified by the expression array selection strategy. Using real-time PCR, 6 of these 10 genes (Chmp1b, Dtwd2, Isoc1, Lman1, Tnfaip8, and Seh1l) showed significantly different expression levels between S. aureus-infected A/J and C57BL/6J. For two (Tnfaip8 and Seh1l) of these 6 genes, siRNA-mediated knockdown of gene expression in S. aureus–challenged RAW264.7 macrophages induced significant changes in the cytokine response (IL-1 β and GM-CSF) compared to negative controls. These cytokine response changes were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18 mice (which contain A/J chromosome 18 but are otherwise C57BL/6J), but not C57BL/6J mice. These findings suggest that two genes, Tnfaip8 and Seh1l, may contribute to susceptibility to S. aureus in A/J mice, and represent promising candidates for human genetic susceptibility studies

    Can we prevent or treat multiple sclerosis by individualised vitamin D supply?

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    Apart from its principal role in bone metabolism and calcium homeostasis, vitamin D has been attributed additional effects including an immunomodulatory, anti-inflammatory, and possibly even neuroprotective capacity which implicates a possible role of vitamin D in autoimmune diseases like multiple sclerosis (MS). Indeed, several lines of evidence including epidemiologic, preclinical, and clinical data suggest that reduced vitamin D levels and/or dysregulation of vitamin D homeostasis is a risk factor for the development of multiple sclerosis on the one hand, and that vitamin D serum levels are inversely associated with disease activity and progression on the other hand. However, these data are not undisputable, and many questions regarding the preventive and therapeutic capacity of vitamin D in multiple sclerosis remain to be answered. In particular, available clinical data derived from interventional trials using vitamin D supplementation as a therapeutic approach in MS are inconclusive and partly contradictory. In this review, we summarise and critically evaluate the existing data on the possible link between vitamin D and multiple sclerosis in light of the crucial question whether optimization of vitamin D status may impact the risk and/or the course of multiple sclerosis

    Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

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    In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

    Prevalence of, and antigenic variation in, serotype G10 rotaviruses and detection of serotype G3 strains in diarrheic calves: Implications for the origin of G10P11 or P11 type reassortant asymptomatic strains in newborn children in India

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    Previous studies have shown predominant association of G10P11 type bovine rotavirus-derived reassortant strains with asymptomatic infections in newborn children in India. To understand the epidemiological and genetic basis for the origin of these strains in humans, the relative frequencies of different serotypes among bovine rotaviruses (BRVs) isolated from southern, western and central regions of the country were determined by subgroup and serotype analysis as well as nucleotide (nt) sequence analysis of the genes encoding the outer capsid proteins VP4 and VP7. Since the human G10P11 asymptomatic neonatal strain I321 possessed NSP1 from a human rotavirus, to determine its genetic origin in the bovine strains, comparative analysis of partial gene sequences from representative G10P11 strains was also carried out. The following observations were of great epidemiological significance, (i) G10P11 strains predominated in all the three regions with frequencies ranging between 55.6% and 85.2%. In contrast to the high prevalence of G6 strains in other countries, only one G6 strain was detected in this study and G8 strains represented 5.8% of the isolates, (ii) among the G10 strains, in serotyping ELISA, four patterns of reactivity were observed that appeared to correlate with the differences in electropherotypic patterns and amino acid (aa) sequence of the VP7, (iii) surprisingly, strains belonging to serotype G3 were detected more frequently (10.7%) than those of serotypes G6 and G8 combined, while strains representing the new serotype (G15) were observed in a single farm in Bangalore, and (iv) about 3.9% of the isolates were nontypeable as they exhibited high cross-reactivity to the serotyping MAbs used in the study. Comparative analysis of the VP7 gene sequence from the prototype G3 MAb-reactive bovine strain J63 revealed greatest sequence relatedness (87.6% nt and 96.0% aa) with that of serotype G3 rhesus-monkey strain RRV. It also exhibited high sequence homology with the VP7 from several animal and animal rotavirus-related human G3 strains (Simian SA11; equine ERV316 and FI-14. canine CU-1 and K9; porcine 4F; Feline Cat2 and human HCR3, YO and AU1). Partial nucleotide sequence analysis of the NSP1 gene of J63 showed greatest nt sequence homology (95.9%) to the NSP1 gene allele of the Indian G8 strain, isolated from a diarrheic child, which is likely to have been transmitted directly from cattle and 92.6% homology to that of the bovine G8 strain A5-10 suggesting the likely origin of J63 by gene reassortment between a bovine G8 strain and a G3 animal strain. Prevalence of G10P11 strains in cattle and G10P11 or P11 type reassortant strains in asymptomatic neonates as well as detection of G8P[1] strains in diarrheic children support our hypothesis for bidirectional transmission of rotaviruses between humans and cattle and origin of novel strains catalyzed by the age-old traditions and socio-economic conditions in India

    Thyristor Controlled Series Capacitor with Automatic Control

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    An increasingly competitive market where economic and environmental pressures limit their scope to expand transmission facilities.The optimization of transmission corridors for power transfer has become a great importance. In this scenario, the FACTS technology is an attractive option for increasing system operation flexibility [1] , New developments in high-current, high-power electronics are making it possible to control electronically the power flows on the high voltage side of the network during both steady state and transient operation

    Expression, purification, crystallization and preliminary crystallographic analysis of the diarrhoea-causing and virulence-determining region of rotaviral nonstructural protein NSP4

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    The region spanning the tetrameric coiled-coil domain and the interspecies-variable virulence-determining region of the cytoplasmic tail of rotaviral nonstructural protein NSP4 has been crystallized. The crystals belong to space group I222, with unit-cell parameters a = 30.70, b = 38.07, c = 181.62 A˚\AA , and contain two molecules in the asymmetric unit. Diffraction data have been collected utilizing a MAR imaging plate to a resolution of 2.2 A˚\AA . The tetramer is generated by the crystallographic dyad along the c axis

    Genomic Diversity Through Gene Reassortment and Antigenic Drift and Molecular Epidemiology of Rotaviruses in India

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    A review. Long term epidemiol. studies on both symptomatic and asymptomatic rotavirus infections during the period 1988 to 1999 in Bangalore revealed a consistently high rate (.apprx.60%) of asymptomatic infection of neonates born in hospitals/clinics by unusual P[11]G10 type strains. The prototype neonatal strain I321 was shown to be a reassortant between a P[11]G10 bovine rotavirus and a human rotavirus with all the genes, except for two genes encoding the nonstructural proteins NSP1 and NSP3, derived from the bovine parent. Neonatal infections were totally dominated by I321-like strains. Neonatal infections appear to confer protection against subsequent rotavirus illness as evident from the two-year follow-up study of I321-infected newborn children as well as by the significant reduction in rotavirus illness in Bangalore for the last 8 years. Another reassortant neonatal strain 116E (P[11]G9) was also isolated in New Delhi. G3 type strains were more prevalent in symptomatic infections in Bangalore throughout the study period. The order of prevalence was G3 (36.6) > G2 (22.0%) > G1 (17.1%) > G4 (6.0%). There was no change in the epidemiology situation during this period. In contrast, serotype G1 was found to be more prevalent in other regions of the country. Majority of the G2-like strains were nontypeable in serotyping ELISA due to broad cross-reactivity to serotyping mAbs. This appears to be due to amino acid substitutions in the antigenic regions of VP7 as well as in VP4 and these strains probably represent a G2 subtype. An unusual G2 strain assocd. with diarrhoea, having 'long' e-type and SG1 specificity has been isolated in Manipur and appears to have been evolved by gene reassortment between a P[4]G2 human strain and a porcine strain. Direct transmission of bovine G8 strains from cattle was observed to cause severe diarrhoea in children in Mysore. Serotype G10 was found to dominate infections in cattle in India and represented 55.0% - 85.0% of the isolates in different farms across the country. Serotype G6 was negligible in Indian cattle and G8 strains were detected in all the regions (5.8%). Another surprising observation was the presence of G3 strains in significant nos. (10.7%) in all the regions. The prototype bovine G3 strain G3 was shown to be a reassortant between a bovine G8 strain and an animal G3 strain (simian, canine or equine). A novel rotavirus was isolated from a single farm in Bangalore and was shown to represent the new serotype P[21]G15. The findings from our lab. are of great significance since they provided strong epidemiol. basis for the origin of P[11]G10 and P[11]G9 reassortant asymptomatic neonatal strains in different regions of the country. Age-old Indian traditions, close proximity of majority of the Indian population with cattle, and environmental conditions appear to facilitate inter-species transmission of rotaviruses between humans and cattle and cattle and animals and evolution of novel strains in India
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