Gestational Insulin Resistance Is Mediated by the Gut Microbiome-Indoleamine 2,3-Dioxygenase Axis.

BACKGROUND & AIMS: Normal gestation involves a reprogramming of the maternal gut microbiome (GM) that contributes to maternal metabolic changes by unclear mechanisms. This study aimed to understand the mechanistic underpinnings of the GM-maternal metabolism interaction. METHODS: The GM and plasma metabolome of CD1, NIH-Swiss, and C57 mice were analyzed with the use of 16S rRNA sequencing and untargeted liquid chromatography-mass spectrometry throughout gestation. Pharmacologic and genetic knockout mouse models were used to identify the role of indoleamine 2,3-dioxygenase (IDO1) in pregnancy-associated insulin resistance (IR). Involvement of gestational GM was studied with the use of fecal microbial transplants (FMTs). RESULTS: Significant variation in GM alpha diversity occurred throughout pregnancy. Enrichment in gut bacterial taxa was mouse strain and pregnancy time point specific, with the species enriched at gestation day 15/19 (G15/19), a point of heightened IR, being distinct from those enriched before or after pregnancy. Metabolomics revealed elevated plasma kynurenine at G15/19 in all 3 mouse strains. IDO1, the rate-limiting enzyme for kynurenine production, had increased intestinal expression at G15, which was associated with mild systemic and gut inflammation. Pharmacologic and genetic inhibition of IDO1 inhibited kynurenine levels and reversed pregnancy-associated IR. FMT revealed that IDO1 induction and local kynurenine level effects on IR derive from the GM in both mouse and human pregnancy. CONCLUSIONS: GM changes accompanying pregnancy shift IDO1-dependent tryptophan metabolism toward kynurenine production, intestinal inflammation, and gestational IR, a phenotype reversed by genetic deletion or inhibition of IDO1. (Gestational Gut Microbiome-IDO1 Axis Mediates Pregnancy Insulin Resistance; EMBL-ENA ID: PRJEB45047. MetaboLights ID: MTBLS3598).

Immune Dysregulation in the Tonsillar Microenvironment of Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome.

Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome is an inflammatory disorder of childhood classically characterized by recurrent fevers, pharyngitis, stomatitis, cervical adenitis, and leukocytosis. While the mechanism is unclear, previous studies have shown that tonsillectomy can be a therapeutic option with improvement in quality of life in many patients with PFAPA, but the mechanisms behind surgical success remain unknown. In addition, long-term clinical follow-up is lacking. In our tertiary care center cohort, 62 patients with PFAPA syndrome had complete resolution of symptoms after surgery (95.3%). Flow cytometric evaluation demonstrates an inflammatory cell population, distinct from patients with infectious pharyngitis, with increased numbers of CD8+ T cells (5.9% vs. 3.8%, p < 0.01), CD19+ B cells (51% vs. 35%, p < 0.05), and CD19+CD20+CD27+CD38-memory B cells (14% vs. 7.7%, p < 0.01). Cells are primed at baseline with increased percentage of IL-1ß positive cells compared to control tonsil-derived cells, which require exogenous LPS stimulation. Gene expression analysis demonstrates a fivefold upregulation in IL1RN and TNF expression in whole tonsil compared to control tonsils, with persistent activation of the NF-κB signaling pathway, and differential microbial signatures, even in the afebrile period. Our data indicates that PFAPA patient tonsils have localized, persistent inflammation, in the absence of clinical symptoms, which may explain the success of tonsillectomy as an effective surgical treatment option. The differential expression of several genes and microbial signatures suggests the potential for a diagnostic biomarker for PFAPA syndrome.

Associations between fungal and bacterial microbiota of airways and asthma endotypes.

BACKGROUND: The relationship between asthma, atopy, and underlying type 2 (T2) airway inflammation is complex. Although the bacterial airway microbiota is known to differ in asthmatic patients, the fungal and bacterial markers that discriminate T2-high (eosinophilic) and T2-low (neutrophilic/mixed-inflammation) asthma and atopy are still incompletely identified. OBJECTIVES: The aim of this study was to demonstrate the fungal microbiota structure of airways in asthmatic patients associated with T2 inflammation, atopy, and key clinical parameters. METHODS: We collected endobronchial brush (EB) and bronchoalveolar lavage (BAL) samples from 39 asthmatic patients and 19 healthy subjects followed by 16S gene and internal transcribed spacer-based microbiota sequencing. The microbial sequences were classified into exact sequence variants. The T2 phenotype was defined by using a blood eosinophil count with a threshold of 300 cells/µL. RESULTS: Fungal diversity was significantly lower in EB samples from patients with T2-high compared with T2-low inflammation; key fungal genera enriched in patients with T2-high inflammation included Trichoderma species, whereas Penicillium species was enriched in patients with atopy. In BAL fluid samples the dominant genera were Cladosporium, Fusarium, Aspergillus, and Alternaria. Using generalized linear models, we identified significant associations between specific fungal exact sequence variants and FEV1, fraction of exhaled nitric oxide values, BAL fluid cell counts, and corticosteroid use. Investigation of interkingdom (bacterial-fungal) co-occurrence patterns revealed different topologies between asthmatic patients and healthy control subjects. Random forest models with fungal classifiers predicted asthma status with 75% accuracy for BAL fluid samples and 80% accuracy for EB samples. CONCLUSIONS: We demonstrate clear differences in bacterial and fungal microbiota in asthma-associated phenotypes. Our study provides additional support for considering microbial signatures in delineating asthma phenotypes.

Comparative metagenomic analyses of a high-altitude Himalayan geothermal spring revealed temperature-constrained habitat-specific microbial community and metabolic dynamics.

Metagenomic surveys across microbial mat (~ 55 °C) samples of high-altitude (1760 m above sea level) Himalayan geothermal springs have revealed specialized community enriched with niche-specific functions. In this study, we have performed metagenomic sequence-based analyses to get insights into taxonomic composition and functional potential of hyperthermophiles in water (~ 95 °C) and sediment samples (78-98 °C). Community analyses revealed predominance of thermophilic bacterial and archeal genera dwelling in water in contrast to microbial mats (55 °C), namely Methylophilus, Methyloversatilis, Emticicia, Caulobacter, Thermus, Enhydrobacter and Pyrobaculum. Sediment samples having surface temperature (~ 78 °C) were colonized by Pyrobaculum and Chloroflexus while genus Massilia was found to be inhabited in high-temperature sediments (~ 98 °C). Functional analyses of metagenomic sequences revealed genetic enrichment of genes such as type IV secretion system, flagellar assembly and two-component system in contrast to mats. Furthermore, inter-sample comparison of enriched microbial diversity among water, sediment and microbial mats revealed habitat-specific clustering of the samples within same environment highlighting the role of temperature dynamics in modulating community structure across different habitats in same niche. However, function-based analysis demonstrated site-specific clustering among sediment, microbial mat and water samples. Furthermore, a novel thermophilic genotype of the genus Emticicia (designated as strain MM) was reconstructed from metagenome data. This is a correlative study between three major habitats present in geothermal spring environment, i.e., water, sediment and microbial mats revealing greater phylogenetic and functional dispersion emphasizing changing habitat-specific dynamics with temperature.

Microbial taxonomy in the era of OMICS: application of DNA sequences, computational tools and techniques.

The current prokaryotic taxonomy classifies phenotypically and genotypically diverse microorganisms using a polyphasic approach. With advances in the next-generation sequencing technologies and computational tools for analysis of genomes, the traditional polyphasic method is complemented with genomic data to delineate and classify bacterial genera and species as an alternative to cumbersome and error-prone laboratory tests. This review discusses the applications of sequence-based tools and techniques for bacterial classification and provides a scheme for more robust and reproducible bacterial classification based on genomic data. The present review highlights promising tools and techniques such as ortho-Average Nucleotide Identity, Genome to Genome Distance Calculator and Multi Locus Sequence Analysis, which can be validly employed for characterizing novel microorganisms and assessing phylogenetic relationships. In addition, the review discusses the possibility of employing metagenomic data to assess the phylogenetic associations of uncultured microorganisms. Through this article, we present a review of genomic approaches that can be included in the scheme of taxonomy of bacteria and archaea based on computational and in silico advances to boost the credibility of taxonomic classification in this genomic era.

Survey of (Meta)genomic Approaches for Understanding Microbial Community Dynamics.

Advancement in the next generation sequencing technologies has led to evolution of the field of genomics and metagenomics in a slim duration with nominal cost at precipitous higher rate. While metagenomics and genomics can be separately used to reveal the culture-independent and culture-based microbial evolution, respectively, (meta)genomics together can be used to demonstrate results at population level revealing in-depth complex community interactions for specific ecotypes. The field of metagenomics which started with answering "who is out there?" based on 16S rRNA gene has evolved immensely with the precise organismal reconstruction at species/strain level from the deeply covered metagenome data outweighing the need to isolate bacteria of which 99% are de facto non-cultivable. In this review we have underlined the appeal of metagenomic-derived genomes in providing insights into the evolutionary patterns, growth dynamics, genome/gene-specific sweeps, and durability of environmental pressures. We have demonstrated the use of culture-based genomics and environmental shotgun metagenome data together to elucidate environment specific genome modulations via metagenomic recruitments in terms of gene loss/gain, accessory and core-genome extent. We further illustrated the benefit of (meta)genomics in the understanding of infectious diseases by deducing the relationship between human microbiota and clinical microbiology. This review summarizes the technological advances in the (meta)genomic strategies using the genome and metagenome datasets together to increase the resolution of microbial population studies.

Genome Mining and Predictive Functional Profiling of Acidophilic Rhizobacterium Pseudomonas fluorescens Pt14.

Pseudomonas fluorescens Pt14 is a non-pathogenic and acidophilic bacterium isolated from acidic soil (pH 4.65). Genome sequencing of strain Pt14 was performed using Single Molecule Real Time (SMRT) sequencing to get insights into unique existence of this strain in acidic environment. Complete genome sequence of this strain revealed a chromosome of 5,841,722 bp having 5354 CDSs and 88 RNAs. Phylogenomic reconstruction based on 16S rRNA gene, Average Nucleotide Identity (ANI) values and marker proteins revealed that strain Pt14 shared a common clade with P. fluorescens strain A506 and strain SS101. ANI value of strain Pt14 in relation to strain A506 was found 99.23% demonstrating a very close sub-species association at genome level. Further, orthology determination among these three phylogenetic neighbors revealed 4726 core proteins. Functional analysis elucidated significantly higher abundance of sulphur metabolism (>1×) which could be one of the reasons for the survival of strain Pt14 under acidic conditions (pH 4.65). Acidophilic bacteria have capability to oxidize sulphur into sulphuric acid which in turn can make the soil acidic and genome-wide analysis of P. fluorescens Pt14 demonstrated that this strain contributes towards making the soil acidic.

Response and resilience of soil microbial communities inhabiting in edible oil stress/contamination from industrial estates.

BACKGROUND: Gauging the microbial community structures and functions become imperative to understand the ecological processes. To understand the impact of long-term oil contamination on microbial community structure soil samples were taken from oil fields located in different industrial regions across Kadi, near Ahmedabad, India. Soil collected was hence used for metagenomic DNA extraction to study the capabilities of intrinsic microbial community in tolerating the oil perturbation. RESULTS: Taxonomic profiling was carried out by two different complementary approaches i.e. 16S rDNA and lowest common ancestor. The community profiling revealed the enrichment of phylum "Proteobacteria" and genus "Chromobacterium," respectively for polluted soil sample. Our results indicated that soil microbial diversity (Shannon diversity index) decreased significantly with contamination. Further, assignment of obtained metagenome reads to Clusters of Orthologous Groups (COG) of protein and Kyoto Encyclopedia of Genes and Genomes (KEGG) hits revealed metabolic potential of indigenous microbial community. Enzymes were mapped on fatty acid biosynthesis pathway to elucidate their roles in possible catalytic reactions. CONCLUSION: To the best of our knowledge this is first study for influence of edible oil on soil microbial communities via shotgun sequencing. The results indicated that long-term oil contamination significantly affects soil microbial community structure by acting as an environmental filter to decrease the regional differences distinguishing soil microbial communities.

Fictibacillus halophilus sp. nov., from a microbial mat of a hot spring atop the Himalayan Range.

A Gram-stain-positive staining, motile, endospore forming and moderately halophilic bacterium, designated as strain AS8T, was isolated from a microbial mat deposited at thermal discharges of Manikaran hot spring (with surface water temperature ~95 °C) located in Himachal Pradesh, India. 16S rRNA gene sequence based phylogenetic analysis revealed that strain AS8T belonged to the genus Fictibacillus with the highest sequence similarity to Fictibacillus nanhaiensis DSM 23009T (99.9 %) and Fictibacillus phosphorivorans Ca7T (99.9 %), followed by Fictibacillus barbaricus V2-BIII-A2T (99.1 %) and Fictibacillus arsenicus Con a/3T (97.4 %). The polar lipids fraction consisted of diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. The cell-wall peptidoglycan was of the type A1γ based on directly cross-linked meso-diaminopimelic acid. The DNA G+C content of strain AS8T was found to be 46.9 mol%. The quinone system of strain AS8T consisted of MK-7 predominantly, and the polyamine pattern primarily contained spermidine and spermine. The major cellular fatty acids in strain AS8T were iso-C15:0, anteiso-C15:0 and iso-C16:0. The strain showed DNA-DNA relatedness of 52.7 % with F. nanhaiensis DSM 23009T, 50.7 % with F. phosphorivorans Ca7T, 34.8 % with F. barbaricus V2-BIII-A2T and 38.0 % with F. arsenicus Con a/3T. In spite of the high 16S rRNA gene sequence similarities, the DNA-DNA hybridization and gyr B gene sequencing results (≤87 %) supported by physiological and biochemical tests demonstrated that strain AS8T is a representative of a novel species, for which the name Fictibacillus halophilus sp. nov. is proposed. The type strain is AS8T (=MCC 2765T=DSM 100124T=KCTC 33758T).

Algoriphagus roseus sp. nov., isolated from a hexachlorocyclohexane-contaminated dumpsite.

A Gram-staining negative, reddish-pink, non-motile, rod-shaped bacterial strain designated W29T, was isolated from a hexachlorocyclohexane-contaminated dumpsite located in the northern part of India at Ummari Village, Lucknow. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain W29T formed a lineage within the genus Algoriphagusand exhibited highest sequence similarity to Algoriphagus trabzonensis MS7T (98.8 %), followed by Algoriphagusalkaliphilus AC-74T (97.1 %). The 16S rRNA gene sequence similarity between strain W29T and other species of the genus Algoriphagusranged from 93.3-98.8 %. The DNA-DNA relatedness between strain W29T and A. trabzonensisMS7T was 47 % and with other related strains was found to be less than 45 %, confirming strain W29T represents a novel species. The DNA G+C content of strain W29T was 46.2 mol%. Strain W29T was oxidase- and catalase-positive. The major fatty acids (>10 %) of strain W29T were iso-C15 : 0, summed feature 9 (comprising 10-methyl C16 : 0 and/or iso-C17 : 1ω9c) and summed feature 3 (comprising C16 : 1ω6c and/or C16 : 1ω7c). The respiratory quinone was MK-7. The polar lipid profile consisted of phosphatidylethanolamine, diphosphatidylglycerol, two unidentified aminolipids, an unidentified aminophospholipid, an unidentified phospholipid and unidentified lipids. On the basis of the results obtained from DNA-DNA hybridization, and biochemical and physiological tests in this study, strain W29T represents a novel species of the genus Algoriphagus for which the name Algoriphagus roseus sp. nov. is proposed. The type strain is W29T (=KCTC 42940T=MCC 2876T=DSM 100160T).

Pontibacter virosus sp. nov., isolated from a hexachlorocyclohexane-contaminated dumpsite.

A Gram-staining-negative, red-pigmented, motile, rod-shaped bacterial strain, designated as W14T, was isolated from a hexachlorocyclohexane-contaminated dumpsite located in the northern part of India at Ummari Village, Lucknow. Phylogenetic analysis based on 16S rRNA gene sequence showed that the strain belongs to the genus Pontibacter with highest sequence similarity to Pontibacter lucknowensis DM9T (98.1 %). The 16S rRNA gene sequence similarity between strain W14T and members of other species of the genus Pontibacter ranged from 98.1 to 94.2 %. The DNA-DNA relatedness between strain W14T and P. lucknowensis DM9T was 33.7 % and with other closely related strains was found to be less than 20 %, confirming it to represent a novel species. The DNA G+C content of strain W14T was 51.3 mol%. Strain W14T was oxidase- and catalase-positive. The predominant cellular fatty acids were summed feature 4 (C17 : 1 iso I/anteiso B and C17 : 1 anteiso B/iso I), iso-C15 : 0 and iso-C17 : 0 3-OH. The polar lipid profile of strain W14T consisted of phosphatidylethanolamine, diphosphatidylglycerol, aminolipid and glycolipid. On the basis of the results obtained from DNA-DNA hybridization, biochemical and physiological tests in this study, strain W14T represents a novel species of the genus Pontibacter, for which the name Pontibacter virosus sp. nov. is proposed. The type strain is W14T (=MCC 2932T=DSM 100231T=KCTC 42941T).

Pan-genome dynamics of Pseudomonas gene complements enriched across hexachlorocyclohexane dumpsite.

BACKGROUND: Phylogenetic heterogeneity across Pseudomonas genus is complemented by its diverse genome architecture enriched by accessory genetic elements (plasmids, transposons, and integrons) conferring resistance across this genus. Here, we sequenced a stress tolerant genotype i.e. Pseudomonas sp. strain RL isolated from a hexachlorocyclohexane (HCH) contaminated pond (45 mg of total HCH g(-1) sediment) and further compared its gene repertoire with 17 reference ecotypes belonging to P. stutzeri, P. mendocina, P. aeruginosa, P. psychrotolerans and P. denitrificans, representing metabolically diverse ecosystems (i.e. marine, clinical, and soil/sludge). Metagenomic data from HCH contaminated pond sediment and similar HCH contaminated sites were further used to analyze the pan-genome dynamics of Pseudomonas genotypes enriched across increasing HCH gradient. RESULTS: Although strain RL demonstrated clear species demarcation (ANI ≤ 80.03%) from the rest of its phylogenetic relatives, it was found to be closest to P. stutzeri clade which was further complemented functionally. Comparative functional analysis elucidated strain specific enrichment of metabolic pathways like α-linoleic acid degradation and carbazole degradation in Pseudomonas sp. strain RL and P. stutzeri XLDN-R, respectively. Composition based methods (%codon bias and %G + C difference) further highlighted the significance of horizontal gene transfer (HGT) in evolution of nitrogen metabolism, two-component system (TCS) and methionine metabolism across the Pseudomonas genomes used in this study. An intact mobile class-I integron (3,552 bp) with a captured gene cassette encoding for dihydrofolate reductase (dhfra1) was detected in strain RL, distinctly demarcated from other integron harboring species (i.e. P. aeruginosa, P. stutzeri, and P. putida). Mobility of this integron was confirmed by its association with Tnp21-like transposon (95% identity) suggesting stress specific mobilization across HCH contaminated sites. Metagenomics data from pond sediment and recently surveyed HCH adulterated soils revealed the in situ enrichment of integron associated transposase gene (TnpA6100) across increasing HCH contamination (0.7 to 450 mg HCH g(-1) of soil). CONCLUSIONS: Unlocking the potential of comparative genomics supplemented with metagenomics, we have attempted to resolve the environment and strain specific demarcations across 18 Pseudomonas gene complements. Pan-genome analyses of these strains indicate at astoundingly diverse metabolic strategies and provide genetic basis for the cosmopolitan existence of this taxon.

Microbiome response in an urban river system is dominated by seasonality over wastewater treatment upgrades.

BACKGROUND: Microorganisms such as coliform-forming bacteria are commonly used to assess freshwater quality for drinking and recreational use. However, such organisms do not exist in isolation; they exist within the context of dynamic, interactive microbial communities which vary through space and time. Elucidating spatiotemporal microbial dynamics is imperative for discriminating robust community changes from ephemeral ecological trends, and for improving our overall understanding of the relationship between microbial communities and ecosystem health. We conducted a seven-year (2013-2019) microbial time-series investigation in the Chicago Area Waterways (CAWS): an urban river system which, in 2016, experienced substantial upgrades to disinfection processes at two wastewater reclamation plants (WRPs) that discharge into the CAWS and improved stormwater capture, to improve river water quality and reduce flooding. Using culture-independent and culture-dependent approaches, we compared CAWS microbial ecology before and after the intervention. RESULTS: Examinations of time-resolved beta distances between WRP-adjacent sites showed that community similarity measures were often consistent with the spatial orientation of site locations to one another and to the WRP outfalls. Fecal coliform results suggested that upgrades reduced coliform-associated bacteria in the effluent and the downstream river community. However, examinations of whole community changes through time suggest that the upgrades did little to affect overall riverine community dynamics, which instead were overwhelmingly driven by yearly patterns consistent with seasonality. CONCLUSIONS: This study presents a systematic effort to combine 16S rRNA gene amplicon sequencing with traditional culture-based methods to evaluate the influence of treatment innovations and systems upgrades on the microbiome of the Chicago Area Waterway System, representing the longest and most comprehensive characterization of the microbiome of an urban waterway yet attempted. We found that the systems upgrades were successful in improving specific water quality measures immediately downstream of wastewater outflows. Additionally, we found that the implementation of the water quality improvement measures to the river system did not disrupt the overall dynamics of the downstream microbial community, which remained heavily influenced by seasonal trends. Such results emphasize the dynamic nature of microbiomes in open environmental systems such as the CAWS, but also suggest that the seasonal oscillations remain consistent even when perturbed.

Impacts of COVID-19 on Glycemia and Risk of Diabetic Ketoacidosis.

Reports indicate that coronavirus disease 2019 (COVID-19) may impact pancreatic function and increase type 2 diabetes (T2D) risk, although real-world COVID-19 impacts on HbA1c and T2D are unknown. We tested whether COVID-19 increased HbA1c, risk of T2D, or diabetic ketoacidosis (DKA). We compared pre- and post-COVID-19 HbA1c and T2D risk in a large real-world clinical cohort of 8,755 COVID-19(+) patients and 11,998 COVID-19(-) matched control subjects. We investigated whether DKA risk was modified in COVID-19(+) patients with type 1 diabetes (T1D) (N = 701) or T2D (N = 21,830), or by race and sex. We observed a statistically significant, albeit clinically insignificant, HbA1c increase post-COVID-19 (all patients ΔHbA1c = 0.06%; with T2D ΔHbA1c = 0.1%) and no increase among COVID-19(-) patients. COVID-19(+) patients were 40% more likely to be diagnosed with T2D compared with COVID-19(-) patients and 28% more likely for the same HbA1c change as COVID-19(-) patients, indicating that COVID-19-attributed T2D risk may be due to increased recognition during COVID-19 management. DKA in COVID-19(+) patients with T1D was not increased. COVID-19(+) Black patients with T2D displayed disproportionately increased DKA risk (hazard ratio 2.46 [95% CI 1.48-6.09], P = 0.004) compared with White patients, suggesting a need for further clinical awareness and investigation.

Amelioration of the physio-biochemical responses to salinity stress and computing the primary germination index components in cauliflower on seed priming.

The significant horticultural crop, cauliflower (Brassica oleracea L. var. botrytis) is vulnerable to the excessive salt concentration in the soil, which contributes to its scaled-down growth and productivity, among other indices. The current study examines the efficacy of hydropriming, halopriming, and osmopriming on the physio-biochemical attributes and tolerance to salinity (100 mM NaCl) in cauliflower under controlled conditions. The results showed that the salinity (100 mM NaCl) has significant deleterious impacts on cauliflower seed germination, seedling growth, and photosynthetic attributes, and provoked the production of reactive oxygen species. In contrast, different priming approaches proved beneficial in mitigating the negative effects of salinity and boosted the germination, vigor indices, seedling growth, and physio-biochemical attributes like photosynthetic pigments, protein, and proline content while suppressing oxidative damage and MDA content in cauliflower seedlings in treatment- and dose-dependent manner. PCA revealed 61% (PC1) and 15% (PC2) of the total variance with substantial positive relationships and high loading conditions on all germination attributes on PC1 with greater PC1 scores for PEG treatments showing the increased germination indices in PEG-treated seeds among all the priming treatments tested. All 13 distinct priming treatments tried clustered into three groups as per Ward's approach of systematic categorization, clustering the third group showing relatively poor germination performances. Most germination traits exhibited statistically significant associations at the p < 0.01 level. Overall, the results established the usefulness of the different priming approaches facilitating better germination, survival, and resistance against salinity in the cauliflower to be used further before sowing in the salt-affected agro-ecosystems.

Genetic variations that influence paclitaxel pharmacokinetics and intracellular effects that may contribute to chemotherapy-induced neuropathy: A narrative review.

Taxanes, particularly paclitaxel and docetaxel, are chemotherapeutic agents commonly used to treat breast cancers. A frequent side effect is chemotherapy-induced peripheral neuropathy (CIPN) that occurs in up to 70% of all treated patients and impacts the quality of life during and after treatment. CIPN presents as glove and stocking sensory deficits and diminished motor and autonomic function. Nerves with longer axons are at higher risk of developing CIPN. The causes of CIPN are multifactorial and poorly understood, limiting treatment options. Pathophysiologic mechanisms can include: (i) disruptions of mitochondrial and intracellular microtubule functions, (ii) disruption of axon morphology, and (iii) activation of microglial and other immune cell responses, among others. Recent work has explored the contribution of genetic variation and selected epigenetic changes in response to taxanes for any insights into their relation to pathophysiologic mechanisms of CIPN20, with the hope of identifying predictive and targetable biomarkers. Although promising, many genetic studies of CIPN are inconsistent making it difficult to develop reliable biomarkers of CIPN. The aims of this narrative review are to benchmark available evidence and identify gaps in the understanding of the role genetic variation has in influencing paclitaxel's pharmacokinetics and cellular membrane transport potentially related to the development of CIPN.

Plasma metabolites with mechanistic and clinical links to the neurovascular disease cavernous angioma.

BACKGROUND: Cavernous angiomas (CAs) affect 0.5% of the population, predisposing to serious neurologic sequelae from brain bleeding. A leaky gut epithelium associated with a permissive gut microbiome, was identified in patients who develop CAs, favoring lipid polysaccharide producing bacterial species. Micro-ribonucleic acids along with plasma levels of proteins reflecting angiogenesis and inflammation were also previously correlated with CA and CA with symptomatic hemorrhage. METHODS: The plasma metabolome of CA patients and CA patients with symptomatic hemorrhage was assessed using liquid-chromatography mass spectrometry. Differential metabolites were identified using partial least squares-discriminant analysis (p < 0.05, FDR corrected). Interactions between these metabolites and the previously established CA transcriptome, microbiome, and differential proteins were queried for mechanistic relevance. Differential metabolites in CA patients with symptomatic hemorrhage were then validated in an independent, propensity matched cohort. A machine learning-implemented, Bayesian approach was used to integrate proteins, micro-RNAs and metabolites to develop a diagnostic model for CA patients with symptomatic hemorrhage. RESULTS: Here we identify plasma metabolites, including cholic acid and hypoxanthine distinguishing CA patients, while arachidonic and linoleic acids distinguish those with symptomatic hemorrhage. Plasma metabolites are linked to the permissive microbiome genes, and to previously implicated disease mechanisms. The metabolites distinguishing CA with symptomatic hemorrhage are validated in an independent propensity-matched cohort, and their integration, along with levels of circulating miRNAs, enhance the performance of plasma protein biomarkers (up to 85% sensitivity and 80% specificity). CONCLUSIONS: Plasma metabolites reflect CAs and their hemorrhagic activity. A model of their multiomic integration is applicable to other pathologies.

Cavernous angiomas (CAs) are clusters of abnormal blood vessels found in the brain or spinal cord. A blood test that could identify people with CAs that have recently bled would help determine who need surgery or closer medical monitoring. We looked at the blood of people with CAs to compare the levels of metabolites, a type of small molecule produced within the body, in those who had recently bled and those who had not. We found that some metabolites may contribute to CA and have an impact on CA symptoms. Monitoring the levels of these metabolites can determine whether there had been a recent bleed. In the future, drugs or other therapies could be developed that would block or change the levels of these molecules and possibly be used to treat CA disease.

A Multimodal Approach to Discover Biomarkers for Taxane-Induced Peripheral Neuropathy (TIPN): A Study Protocol.

Introduction: Taxanes are a class of chemotherapeutics commonly used to treat various solid tumors, including breast and ovarian cancers. Taxane-induced peripheral neuropathy (TIPN) occurs in up to 70% of patients, impacting quality of life both during and after treatment. TIPN typically manifests as tingling and numbness in the hands and feet and can cause irreversible loss of function of peripheral nerves. TIPN can be dose-limiting, potentially impacting clinical outcomes. The mechanisms underlying TIPN are poorly understood. As such, there are limited treatment options and no tools to provide early detection of those who will develop TIPN. Although some patients may have a genetic predisposition, genetic biomarkers have been inconsistent in predicting chemotherapy-induced peripheral neuropathy (CIPN). Moreover, other molecular markers (eg, metabolites, mRNA, miRNA, proteins) may be informative for predicting CIPN, but remain largely unexplored. We anticipate that combinations of multiple biomarkers will be required to consistently predict those who will develop TIPN. Methods: To address this clinical gap of identifying patients at risk of TIPN, we initiated the Genetics and Inflammatory Markers for CIPN (GENIE) study. This longitudinal multicenter observational study uses a novel, multimodal approach to evaluate genomic variation, metabolites, DNA methylation, gene expression, and circulating cytokines/chemokines prior to, during, and after taxane treatment in 400 patients with breast cancer. Molecular and patient reported data will be collected prior to, during, and after taxane therapy. Multi-modal data will be used to develop a set of comprehensive predictive biomarker signatures of TIPN. Conclusion: The goal of this study is to enable early detection of patients at risk of developing TIPN, provide a tool to modify taxane treatment to minimize morbidity from TIPN, and improved patient quality of life. Here we provide a brief review of the current state of research into CIPN and TIPN and introduce the GENIE study design.

Suppression of local type I interferon by gut microbiota-derived butyrate impairs antitumor effects of ionizing radiation.

The antitumor effects of ionizing radiation (IR) are mediated in part through activation of innate and adaptive immunity. Here we report that gut microbiota influences tumor control following IR. Vancomycin decreased the abundance of butyrate-producing gut bacteria and enhanced antitumor responses to IR. Oral administration of Lachnospiraceae, a family of vancomycin-sensitive bacteria, was associated with increased systemic and intratumoral butyric acid levels and impaired the efficacy of IR in germ-free (GF) mice. Local butyrate inhibited STING-activated type I IFN expression in dendritic cells (DCs) through blockade of TBK1 and IRF3 phosphorylation, which abrogated IR-induced tumor-specific cytotoxic T cell immune responses without directly protecting tumor cells from radiation. Our findings demonstrate that the selective targeting of butyrate-producing microbiota may provide a novel therapeutic option to enhance tumor radiation sensitivity.

COVID-19: Assessment of knowledge and awareness in Indian society.

COVID-19, which was initiated regionally at Wuhan of China, has become a global pandemic by infecting people of almost all the world. Human civilizations are facing threat for their survival and livelihood. No country are getting any substantial relief and solution from this pandemic rather to convince their citizens to make aware and taking precaution by changing their living style. In view of this, this study attempted to assess the awareness, threat, symptoms and its prevention among people of India about the COVID-19. A total of 522 responses from all over India were received. The respondents have adequate awareness for COVID-19 outbreak and its preventive measures, out of total, 98% (513) answered that the virus spreads from one person to another, 95% (494) answered that the disease is caused by a virus. Peoples understand the importance of social distancing and other preventive measures prescribed by the government with good attitude for coronavirus. Peoples are following trusted sources for corona information, having confidence to defeat disease but showed their concern for corona threat, are aware about the virus, its common symptoms and prevention, govt. testing and medical facilities. Principal component analysis was used to identify the latent dimensions regarding people's preventive measures and was found that they are majorly adopting three methods, that is, lockdown, naturopathy and social distancing. This study will help government and peoples to understand and handle this coronavirus pandemic effectively and in prevention of COVID-19, which is crucial for the awareness of society in coming time.