ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome.

Genome-wide association studies in inflammatory bowel disease have identified risk loci in the orosomucoid-like protein 3/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) gene to confer susceptibility to ulcerative colitis (UC), but the underlying functional relevance remains unexplored. Here, we found that a subpopulation of the UC patients who had higher disease activity shows enhanced expression of ORMDL3 compared to the patients with lower disease activity and the non-UC controls. We also found that the patients showing high ORMDL3 mRNA expression have elevated interleukin-1ß cytokine levels indicating positive correlation. Further, knockdown of ORMDL3 in the human monocyte-derived macrophages resulted in significantly reduced interleukin-1ß release. Mechanistically, we report for the first time that ORMDL3 contributes to a mounting inflammatory response via modulating mitochondrial morphology and activation of the NLRP3 inflammasome. Specifically, we observed an increased fragmentation of mitochondria and enhanced contacts with the endoplasmic reticulum (ER) during ORMDL3 over-expression, enabling efficient NLRP3 inflammasome activation. We show that ORMDL3 that was previously known to be localized in the ER also becomes localized to mitochondria-associated membranes and mitochondria during inflammatory conditions. Additionally, ORMDL3 interacts with mitochondrial dynamic regulating protein Fis-1 present in the mitochondria-associated membrane. Accordingly, knockdown of ORMDL3 in a dextran sodium sulfate -induced colitis mouse model showed reduced colitis severity. Taken together, we have uncovered a functional role for ORMDL3 in mounting inflammation during UC pathogenesis by modulating ER-mitochondrial contact and dynamics.

A fluorophore anchored MOF for fast and sensitive sensing of Cu(II) and 3-nitrotyrosine in a physiological medium.

We report the solvothermal synthesis of a dansyl anchored hafnium based fluorescent metal-organic framework (MOF) having the formula [Hf6O4(OH)4(L)6]·H2O·6DMF (H2L = 2-((5-(dimethylamino)naphthalene)-1-sulfonamido)terephthalic acid). The synthesized material showed high fluorescence emission properties as well as high thermal (stable up to 330 °C) and chemical stability. It also exhibited a wide range of pH tolerance as well as a high BET surface area of 703 m2 g-1. The activated MOF showed ultra-fast (detection time < 10 s) and ultra-sensitive sensing properties towards Cu(II) and the biologically important biomarker 3-nitrotyrosine (3-NTyr) in a HEPES medium at a physiological pH of 7.4. Along with high selectivity, very low detection limits of 229 nM and 539 nM were obtained for Cu(II) and 3-NTyr respectively. Furthermore, this probe was utilised for the detection and quantification of Cu(II) and 3-NTyr in biosamples (urine and serum) with very low RSD values (2.3-4.8%). Additionally, this probe was employed to detect the presence of Cu(II) as a pollutant in various environmental water samples. Furthermore, for rapid economic detection of Cu(II), a MOF coated fluorescent paper strip was demonstrated. Thorough mechanistic investigations displayed that a complexometric interaction between Cu(II) and the probe is the main reason for the quenching of fluorescence intensity. This proposed mechanism was well supported by experimental evidence. On the other hand, the FRET mechanism is proposed based on the experimental observations for dynamic quenching of the fluorescence intensity of the probe in the presence of 3-NTyr.

Impact of population density on Covid-19 infected and mortality rate in India.

The Covid-19 is a highly contagious disease which becomes a serious global health concern. The residents living in areas with high population density, such as big or metropolitan cities, have a higher probability to come into close contact with others and consequently any contagious disease is expected to spread rapidly in dense areas. However, recently, after analyzing Covid-19 cases in the USA researchers at the Johns Hopkins Bloomberg School of Public Health, London school of economics, and IZA-Institute of Labour Economics conclude that the spread of Covid-19 is not linked with population density. Here, we investigate the influence of population density on Covid-19 spread and related mortality in the context of India. After a detailed correlation and regression analysis of infection and mortality rates due to Covid-19 at the district level, we find moderate association between Covid-19 spread and population density.