Metabolic regulation in progression to autoimmune diabetes

Recent evidence from serum metabolomics indicates that specific metabolic disturbances precede β-cell autoimmunity in humans and can be used to identify those children who subsequently progress to type 1 diabetes. The mechanisms behind these disturbances are unknown. Here we show the specificity of the pre-autoimmune metabolic changes, as indicated by their conservation in a murine model of type 1 diabetes. We performed a study in non-obese prediabetic (NOD) mice which recapitulated the design of the human study and derived the metabolic states from longitudinal lipidomics data. We show that female NOD mice who later progress to autoimmune diabetes exhibit the same lipidomic pattern as prediabetic children. These metabolic changes are accompanied by enhanced glucose-stimulated insulin secretion, normoglycemia, upregulation of insulinotropic amino acids in islets, elevated plasma leptin and adiponectin, and diminished gut microbial diversity of the Clostridium leptum group. Together, the findings indicate that autoimmune diabetes is preceded by a state of increased metabolic demands on the islets resulting in elevated insulin secretion and suggest alternative metabolic related pathways as therapeutic targets to prevent diabetes.     

Histopathological diagnosis of myocarditis in a dengue outbreak in Sri Lanka, 2009

Background

In 2009, an outbreak of dengue caused high fatality in Sri Lanka. We conducted 5 autopsies of clinically suspected myocarditis cases at the General Hospital, Peradeniya to describe the histopathology of the heart and other organs.

Methods

The diagnosis of dengue was confirmed with specific IgM and IgG ELISA, HAI and RT-PCR techniques. The histology was done in tissue sections stained with hematoxylin and eosin.

Results

Of the 319 cases of dengue fever, 166(52%) had severe infection. Of them, 149 patients (90%) had secondary dengue infection and in 5 patients, DEN-1 was identified as the causative serotype. The clinical diagnosis of myocarditis was considered in 45(27%) patients. The autopsies were done in 5 patients who succumbed to shock (3 females and 2 males) aged 13- 31 years. All had pleural effusions, ascites, bleeding patches in tissue planes and histological evidence of myocarditis. The main histological findings of the heart were interstitial oedema with inflammatory cell infiltration and necrosis of myocardial fibers. One patient had pericarditis. The concurrent pulmonary abnormalities were septal congestion, pulmonary haemorrhage and diffuse alveolar damage; one case showed massive necrosis of liver.

Conclusions

The histology supports occurrence of myocarditis in dengue infection.

     

Correction to: Patterns and trends in two decades of research on Nepal’s mammalian fauna (2000–2019): examining the past for future implications

Biodiversity and Conservation -     

Two-stage fermentation process for enhanced mannitol production using Candida magnoliae mutant R9

Mutants of Candida magnoliae NCIM 3470 were generated by treatment of ultra-violet radiations, ethyl methyl sulphonate and N-methyl-N′-nitro-N-nitrosoguanidine. Mutants with higher reductase activity were screened by means of 2,3,5-triphenyl tetrazolium chloride agar plate assay. Among the screened mutants, the mutant R9 produced maximum mannitol (i.e. 46 g l^?1) in liquid fermentation medium containing 250 g l^?1 glucose and hence was selected for further experiments. Preliminary optimization studies were carried out on shake-flask level which increased the mannitol production to 60 g l^?1 in liquid fermentation medium containing 300 g l^?1 glucose. A two-stage fermentation process comprising of growth phase and production phase was employed. During the growth phase, glucose was supplemented and aerobic conditions were maintained. Thereafter, the production phase was initiated by supplementing fructose and switching to anaerobic conditions by discontinuing aeration and decreasing the speed of agitation. The strategy of two-stage fermentation significantly enhanced the production of mannitol up to 240 g l^?1, which is the highest among all fermentative production processes and corresponds to 81 % yield and 4 g l^?1 h^?1 productivity without formation of any by-product.     

Telomeric injury by KML001 in human T cells induces mitochondrial dysfunction through the p53-PGC-1α pathway

Telomere erosion and mitochondrial dysfunction are prominent features of aging cells with progressive declines of cellular functions. Whether telomere injury induces mitochondrial dysfunction in human T lymphocytes, the major component of adaptive host immunity against infection and malignancy, remains unclear. We have recently shown that disruption of telomere integrity by KML001, a telomere-targeting drug, induces T cell senescence and apoptosis via the telomeric DNA damage response (DDR). In this study, we used KML001 to further investigate the role and mechanism of telomere injury in mitochondrial dysregulation in aging T cells. We demonstrate that targeting telomeres by KML001 induces mitochondrial dysfunction, as evidenced by increased mitochondrial swelling and decreased mitochondrial membrane potential, oxidative phosphorylation, mitochondrial DNA content, mitochondrial respiration, oxygen consumption, glycolysis, and ATP energy production. Mechanistically, we found that the KML001-induced telomeric DDR activated p53 signaling, which in turn repressed the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and nuclear respiratory factor 1 (NRF-1), leading to T cell mitochondrial dysfunction. These results, forging a direct link between telomeric and mitochondrial biology, shed new light on the human T cell aging network, and demonstrate that the p53-PGC-1α-NRF-1 axis contributes to mitochondrial dysfunction in the setting of telomeric DDR. This study suggests that targeting this axis may offer an alternative, novel approach to prevent telomere damage-mediated mitochondrial and T cell dysfunctions to combat a wide range of immune aging-associated human diseases.Subject terms: Immunology, Diseases     

New bithiazolyl hydrazones: Novel synthesis,characterization and antitubercular evaluation

New bithiazolyl hydrazones (6a–l) have been first time synthesized by carrying novel one pot cyclocondensation of 5-acyl thiazoles (1a–b), thiosemicarbazide (2) and substituted phenacyl chlorides (4a–f) in freshly prepared ionic liquid, diisopropyl ethyl ammonium acetate (DIPEAc) at room temperature. The newly synthesized compounds have been evaluated for their antitubercular activity and the compounds 3b, 6a, 6b, 6d, 6e, 6f, 6g, and 6l have displayed noticeable antitubercular activity compared to Rifampicin with tolerable cytotoxicity. All these compounds were also screened for their antibacterial activity and found that, compounds 6j and 6k have exhibited a very good antibacterial activity. Molecular docking study has shown better harmony with the evaluation trend shown by these compounds under in vitro antitubercular screening.     

Interaction of quantitative trait loci for resistance to common bacterial blight and pathogen isolates in <Emphasis Type="Italic">Phaseolus vulgaris</Emphasis> L.

Common bacterial blight (CBB) is a major disease of common bean (Phaseolus vulgaris L.) worldwide. Genetic resistance is the most effective and environmentally safe approach for controlling CBB, and identification of resistance quantitative trait loci (QTL) can improve response to selection when breeding for CBB resistance. Interactions of CBB resistance QTL and pathogen isolates with different levels of aggressiveness were studied using an F _4:5 recombinant inbreed line (RIL) population, derived from a cross between the susceptible cultivar “Sanilac” and the resistant breeding line “OAC 09-3.” Disease phenotyping was performed under field and growth room conditions using multiple bacterial isolates with differential levels of aggressiveness. QTL analysis was performed with 237 molecular markers. The effect of pathogen isolate on the average phenotypic value in the RIL population and the interaction of RILs and the pathogen isolates were highly significant. Two QTL underlying CBB resistance were detected on Pv08 and Pv03. A major QTL (R ² _p between 15 and 56%) was identified in a 5-cM (380 kbp) interval in the distal end of the long arm of Pv08. This genomic region was significantly associated with multiple disease evaluation traits in field and growth room assays and against different isolates of the pathogen, which included the previously known CBB marker SU91. A new QTL on Pv03 (Xa3.3^SO), associated with the PvSNP85p745405 allele from the susceptible parent, Sanilac, appeared to be an isolate-specific QTL against the aggressive fuscans isolate ISO118. Interaction between the SU91 and Xa3.3^SO QTL resulted in a significant reduction in mean disease severity for almost all disease evaluation traits after plants were challenged with the isolate ISO118. The 7.92 and 7.79% diseased areas in RILs with both QTL, compared with 14.92 and 13.81% in RILs without either in test1 and in test2 quantified by image analysis, showed a 44 and 47% reduction of percent diseased areas, indicating that the two QTL interact to limit the expansion of CBB symptoms after infection by ISO118. The information obtained in this study indicates that while the broad-spectrum SU91 QTL is useful in breeding programs, isolate-specific QTL, such as Xa3.3^SO, will aid in breeding bean varieties with enhanced resistance against aggressive regional isolates.     

Differential responses of the enzymes involved in proline biosynthesis and degradation in drought tolerant and sensitive cotton genotypes during drought stress and recovery

The relative water content (RWC), free proline levels and the activities of enzymes involved in proline metabolism were studied in drought tolerant (Ca/H 680) and drought sensitive (Ca/H 148) genotypes of cotton (Gossypium hirsutum L.) during induction of water stress and posterior recovery. Water stress caused a significant increase in proline levels and P5CS activity in leaves of both tolerant and sensitive genotypes, whereas the activity of P5CR increased minimally and the activity of OAT remains unchanged. The activity of PDH decreased under drought stress in both the genotypes. The leaf of tolerant genotype maintained higher RWC, photosynthetic activity and proline levels, as well as higher P5CS and P5CR activities under water stress than that of drought sensitive genotype. The drought induced proline levels and activities of P5CS and P5CR declined and tend to be equal to their respective controls, during recovery, whereas the PDH activity tends to increase. These results indicate that induction of proline levels by up regulation of P5CS and down regulation of PDH may be involved in the development of drought tolerance in cotton.