Murine Herpetic Stromal Keratitis: Elucidating the Early Events Involved in its Pathogenesis

Herpes simplex viruses (HSV) infection is a common cause of ocular disease and can result in a chronic inflammatory reaction that impairs vision. This latter manifestation is called herpetic stromal keratitis (HSK) and usually occurs as a consequence of virus reactivation from latency in the trigeminal ganglion. The pathogenesis process involves complex interactions of cellular and molecular events. HSK in humans, and certainly its murine experimental model, appears to be an immunopathologic disease process. The crucial cell type orchestrating the inflammation is a CD4+ Tcell that has a Thl cytokineproducing profile. However, prior to this immunoinflammatory phase, multiple events occur that set the stage for subsequent pathology. These include production of cytokines and chemokines, infiltration of innate immune cells and neovascularization of the avascular cornea. Current understanding about human and murine HSK pathogenesis is reviewed in Part I. Part II progresses this knowledge using knockout and transgenic mice. Results in Part II clarify the essential role of IL-l, a proinflammtory cytokine, produced as a consequence of virus replication, in HSK pathogenesis. Part III, in addition to Part II, elucidate the mechanisms involved in IL-l and IL-6 mediated polymorphonuclear leukocyte (PMN) influx and neovascularization of cornea following virus infection. These cytokines were shown to be produced quite early after infection and capable of inducing angiogenic factors, resulting in angiogenesis of the cornea. In addition, the role of IL-l in inducing proinflammatory arachidonic acid metabolites has been discussed in PART IV. Cycloxygenase 2 enzyme produced from resident corneal cells in presence of IL-l was shown to be crucial for creating an inflammatory milieu and facilitate early PMN influx in murine cornea. These results provide novel insights into the link between viral infections, pro-inflammatory mediators, PMN migration, angiogenesis and HSK development. Our understanding about the role of IL-l in HSK pathogenesis was evaluated clinically in Part V using an IL-l receptor antagonist (IL-l ra) protein. Mice receiving IL-l ra h~d diminished disease severity. The administration of IL-l ra was shown to reduce the influx into the cornea of cells of both the innate and adaptive immune response. In addition, the treatment also diminished corneal VEGF levels resulting reduced angiogenic response. Our results show the iluportance of targeting early proinflammatory molecules such as IL-l to counteract HSK and advocate IL-l ra as an effective agent to achieve this. In Part VI, a novel flow cytometry based assay has been used to quantify corneal angiogenesis following ocular HSV infection. Our results indicate that, this assay was sensitive enough to able to pick up the difference in angiogenic response between mice. Thus, estimation of angiogenesis on the basis of number of endothelial cells proved to be a useful approach to quantify corneal neovascularization. This dissertation presents research aimed at elucidating both molecular and cellular events in HSK pathogenesis. These results will serve as guidelines for future development of more efficient prophylactic and therapeutic strategies

Analysis of Fermi-LAT data from Tucana-II: Possible constraints on the Dark Matter models with an intriguing hint of a signal

Tucana-II (Tuc-II), a recently discovered and confirmed Ultra Faint Dwarf Spheroidal galaxy, has a high mass to light ratio as well as a large line-of-sight stellar velocity dispersion, thus making it an ideal candidate for an indirect dark matter (DM) search. In this paper, we have analyzed nine years of $\gamma$-ray data obtained from the \textit{Fermi}-LAT instrument from the direction of Tuc-II. The fact that a very weak significant $\gamma$-ray excess ($2.2\sigma$) over the background of Tuc-II have been detected from the location of this galaxy. We have observed that this excess of $\gamma$-ray emission from the of location Tuc-II rises with longer periods of data. If WIMP pair annihilation is assumed for this faint emission, for $b\bar{b}$ annihilation channel the test statistics (TS) value peaks at DM mass $\sim$ 14 GeV and for $\tau^{+}\tau^{-}$ annihilation channel it peaks at DM mass 4 GeV. It is then called for an estimation of the $95\%$ confidence level upper limit of the possible velocity weighted self-annihilation cross-section of the DM particles (WIMPs) within Tuc-II by fitting the observed $\gamma$-ray flux with spectra expected for DM annihilation. The estimated upper limits of the cross-sections from Tuc-II are then compared with two other dwarf galaxies that are considered to be good DM candidates in several studies. We have also compared our results with the cross-sections obtained in various popular theoretical models of the WIMPs to find that our results impose reasonable tight constraints on the parameter spaces of those DM models. In the concluding section, we compared our results with the similar results obtained from a combined dSph analysis by the \textit{Fermi}-LAT collaboration as well as the results obtained from the studies of DM in the dwarf galaxies by the major ground-based Cherenkov experiments.Comment: 23 pages, 16 figures, 7 table

Enhancing genetic gain through the application of genomic selection in developing irrigated rice for the favorable ecosystem in Bangladesh

Increasing selection differential and decreasing cycle time, the rate of genetic improvement can be accelerated. Creating and capturing higher genetic with higher accuracy within the shortest possible time is the prerequisite for enhancing genetic gain for any trait. Comprehensive yield testing at multi-locations at early generations together with the shortest line fixation time can expedite the rapid recycling of parents in the breeding program through recurrent selection. Genomic selection is efficient in capturing high breeding value individuals taking additive genetic effects of all genes into account with and without extensive field testing, thus reducing breeding cycle time enhances genetic gain. In the Bangladesh Rice Research Institute, GS technology together with the trait-specific marker-assisted selection at the early generation of RGA-derived breeding lines showed a prediction accuracy of 0.454–0.701 with 0.989–2.623 relative efficiency over the four consecutive years of exercise. This study reports that the application of GS together with trait-specific MAS has expedited the yield improvement by 117 kg ha−1·year−1, which is around seven-fold larger than the baseline annual genetic gain and shortened the breeding cycle by around 1.5 years from the existing 4.5 years

A Novel Intracellular Isoform of Matrix Metalloproteinase-2 Induced by Oxidative Stress Activates Innate Immunity

Experimental and clinical evidence has pinpointed a critical role for matrix metalloproteinase-2 (MMP-2) in ischemic ventricular remodeling and systolic heart failure. Prior studies have demonstrated that transgenic expression of the full-length, 68 kDa, secreted form of MMP-2 induces severe systolic failure. These mice also had unexpected and severe mitochondrial structural abnormalities and dysfunction. We hypothesized that an additional intracellular isoform of MMP-2, which affects mitochondrial function is induced under conditions of systolic failure-associated oxidative stress.Western blots of cardiac mitochondria from the full length MMP-2 transgenics, ageing mice and a model of accelerated atherogenesis revealed a smaller 65 kDa MMP-2 isoform. Cultured cardiomyoblasts subjected to transient oxidative stress generated the 65 kDa MMP-2 isoform. The 65 kDa MMP-2 isoform was also induced by hypoxic culture of cardiomyoblasts. Genomic database analysis of the MMP-2 gene mapped transcriptional start sites and RNA transcripts induced by hypoxia or epigenetic modifiers within the first intron of the MMP-2 gene. Translation of these transcripts yields a 65 kDa N-terminal truncated isoform beginning at M(77), thereby deleting the signal sequence and inhibitory prodomain. Cellular trafficking studies demonstrated that the 65 kDa MMP-2 isoform is not secreted and is present in cytosolic and mitochondrial fractions, while the full length 68 kDa isoform was found only in the extracellular space. Expression of the 65 kDa MMP-2 isoform induced mitochondrial-nuclear stress signaling with activation of the pro-inflammatory NF-κB, NFAT and IRF transcriptional pathways. By microarray, the 65 kDa MMP-2 induces an innate immunity transcriptome, including viral stress response genes, innate immunity transcription factor IRF7, chemokines and pro-apoptosis genes.A novel N-terminal truncated intracellular isoform of MMP-2 is induced by oxidative stress. This isoform initiates a primary innate immune response that may contribute to progressive cardiac dysfunction in the setting of ischemia and systolic failure

Synthesis beyond limit

<p>Rice production needs to increase in the future in order to meet increasing demands. The development of new improved and higher yielding varieties more quickly will be needed to meet this demand. However, most rice breeding programmes in the world have not changed in several decades. In this article, we revisit the evidence in favour of using rapid generation advance (RGA) as a routine breeding method. We describe preliminary activities at the International Rice Research Institute (IRRI) to re-establish RGA on a large scale as the main breeding method for irrigated rice breeding. We also describe experiences from the early adoption at the Bangladesh Rice Research Institute. Evaluation of RGA breeding lines at IRRI for yield, flowering time and plant height indicated transgressive segregation for all traits. Some RGA lines were also higher yielding than the check varieties. The cost advantages of using RGA compared to the pedigree method were also empirically determined by performing an economic analysis. This indicated that RGA is several times more cost effective and advantages will be realized after 1 year even if facilities need to be built. Based on our experience, and previous independent research empirically testing the RGA method in rice, we recommend that this method should be implemented for routine rice breeding in order to improve breeding efficiency.</p

Dynamics of Hot QCD Matter -- Current Status and Developments

The discovery and characterization of hot and dense QCD matter, known as Quark Gluon Plasma (QGP), remains the most international collaborative effort and synergy between theorists and experimentalists in modern nuclear physics to date. The experimentalists around the world not only collect an unprecedented amount of data in heavy-ion collisions, at Relativistic Heavy Ion Collider (RHIC), at Brookhaven National Laboratory (BNL) in New York, USA, and the Large Hadron Collider (LHC), at CERN in Geneva, Switzerland but also analyze these data to unravel the mystery of this new phase of matter that filled a few microseconds old universe, just after the Big Bang. In the meantime, advancements in theoretical works and computing capability extend our wisdom about the hot-dense QCD matter and its dynamics through mathematical equations. The exchange of ideas between experimentalists and theoreticians is crucial for the progress of our knowledge. The motivation of this first conference named "HOT QCD Matter 2022" is to bring the community together to have a discourse on this topic. In this article, there are 36 sections discussing various topics in the field of relativistic heavy-ion collisions and related phenomena that cover a snapshot of the current experimental observations and theoretical progress. This article begins with the theoretical overview of relativistic spin-hydrodynamics in the presence of the external magnetic field, followed by the Lattice QCD results on heavy quarks in QGP, and finally, it ends with an overview of experiment results.Comment: Compilation of the contributions (148 pages) as presented in the `Hot QCD Matter 2022 conference', held from May 12 to 14, 2022, jointly organized by IIT Goa & Goa University, Goa, Indi

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era