Population structure, biogeography and transmissibility of mycobacterium tuberculosis

Mycobacterium tuberculosis is a clonal pathogen proposed to have co-evolved with its human host for millennia, yet our understanding of its genomic diversity and biogeography remains incomplete. Here we use a combination of phylogenetics and dimensionality reduction to reevaluate the population structure of M. tuberculosis, providing an in-depth analysis of the ancient Indo-Oceanic Lineage 1 and the modern Central Asian Lineage 3, and expanding our understanding of Lineages 2 and 4. We assess sub-lineages using genomic sequences from 4939 pan-susceptible strains, and find 30 new genetically distinct clades that we validate in a dataset of 4645 independent isolates. We find a consistent geographically restricted or unrestricted pattern for 20 groups, including three groups of Lineage 1. The distribution of terminal branch lengths across the M. tuberculosis phylogeny supports the hypothesis of a higher transmissibility of Lineages 2 and 4, in comparison with Lineages 3 and 1, on a global scale. We define an expanded barcode of 95 single nucleotide substitutions that allows rapid identification of 69 M. tuberculosis sub-lineages and 26 additional internal groups. Our results paint a higher resolution picture of the M. tuberculosis phylogeny and biogeography.http://www.nature.com/naturecommunicationsam2022Medical Microbiolog

Auditory network connectivity in tinnitus patients: a resting-state fMRI study

Objective: Resting-state functional magnetic resonance imaging (fMRI) uncovers correlated activity between spatially distinct functionally related brain regions and offers clues about the integrity of functional brain circuits in people with chronic subjective tinnitus. We chose to investigate auditory network connectivity, adopting and extending previously used analyses methods to provide an independent evaluation of replicability. Design: Independent components analysis (ICA) was used to identify coherent patterns arising from spontaneous brain signals within the resting-state data. The auditory network component was extracted and evaluated. Bivariate and partial correlation analyses were performed on pre-defined regions of bilateral auditory cortex to assess functional connectivity. Study sample: Our design carefully matched participant groups for possible confounds, such as hearing status. Twelve patients (seven male, five female; mean age 66 years) all with chronic constant tinnitus and eleven controls (eight male, three female; mean age 68 years) took part. Results: No significant differences were found in auditory network connectivity between groups after correcting for multiple statistical comparisons in the analysis. This contradicts previous findings reporting reduced auditory network connectivity; albeit at a less stringent statistical threshold. Conclusions: Auditory network connectivity does not appear to be reliably altered by the experience of chronic subjective tinnitus

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

Acute kidney injury in patients treated with immune checkpoint inhibitors

BACKGROUND: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. METHODS: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. RESULTS: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. CONCLUSIONS: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery

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Not AvailableTo facilitate an easy, efficient, accurate and rapid retrieval of the information on germplasm accessions, an on-line Soybean Germplasm Information System (SGIS), using web technologies viz., Active Server Pages (ASP), Hyper Text Markup Language (HTML), JAVA script and COM components, was developed at Directorate of Soybean Research, Indore. A data management system for germplasm data has also been developed as a separate module using Visual Basic (6.0) to facilitate the digitization and updation of crop-specific germplasm data. The system provides the retrieval of the required information on 25 characters on more than 2000 germplasm accessions in the form of comparison tables, pie charts, bar/line graphs and reports in user-friendly manner. The paper discusses the functionality of the system and experiences gained during development phase along with its benefits for the end-user.Not Availabl

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Not AvailableLoss of seed quality in soybean is a serious problem in tropical and subtropical region. Foliar application of salicylic acid (SA), GA3 and acetyl salicylic acid (50 ppm) at seedling and pod filling stage, K2HPO4 (2%), -tocopherol (100 ppm) at flowering and pod filling stage was done on soybean varieties – NRC 7 and JS 335. Foliar application of SA showed positive effect on seed yield, seed health, germination and seed vigour during storage. Plant height was significantly improved by the GA3 spray in both the varieties. Significantly higher seed yield was obtained with foliar spray of alfa -tocopherol. Application of SA was found effective to protect plants from various diseases to get quality seed alfa -Tocopherol and K2HPO4 treatment significantly reduced MDA production in seeds. -Tocopherol application increased super oxide dismutase activity as a result the lipid peroxidation of seed during storage was significantly reduced. Application of alfa- tocopherol, K2HPO4 and salicylic acid improved the storage or keeping quality of soybean seed.Not Availabl

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Not AvailableBegomoviruses infecting legumes (family Geminiviridae) pose a serious threat to the productivity of grain legumes in general and soybean in particular. In this study, replication initiator protein gene (rep) of begomovirus causing yellow mosaic disease on soybean in Central Indian region is characterized. A total of 85 complete rep gene sequences of legume begomoviruses including sequence reported in this study were employed to delineate genetic diversity, population selection and evolutionary lineage. Nucleotide diversity analysis revealed that the major legume yellow mosaic viruses (LYMVs) viz., MYMV and MYMIV are less diverse than legume begomovirus population as a whole. Test of neutral evolution also reiterates the operation of purifying selection and population expansion of major legume begomoviruses. However interestingly, LYMVs as a whole, show decrease in population size and act of balancing or neutral selection. Recombinants have also been detected only among the isolates of MYMIV suggesting frequent genetic exchanges.Not Availabl

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SYNTHESIS OF SOME NEW PRODRUGS OF SULPHONAMIDES AND STUDIES ON THEIR ANTIMICROBIAL AND ANTI-INFLAMMATORY ACTION

Various amide-based prodrugs of sulphonamides have been synthesised by condensing appropriate sulphonamide moiety with different β-aroyl propionic acids. All the compounds have been evaluated for their antimicrobial and anti-inflammatory activities. Their structures were established on the basis of elemental analysis, 1H NMR and Mass spectral data. Some of these compounds were found to have significant activit