Multi-omics analysis identifies potential microbial and metabolite diagnostic biomarkers of bacterial vaginosis.

BACKGROUND: Bacterial vaginosis (BV) is a common clinical manifestation of a perturbed vaginal ecology associated with adverse sexual and reproductive health outcomes if left untreated. The existing diagnostic modalities are either cumbersome or require skilled expertise, warranting alternate tests. Application of machine-learning tools to heterogeneous and high-dimensional multi-omics datasets finds promising potential in data integration and may aid biomarker discovery. OBJECTIVES: The present study aimed to evaluate the potential of the microbiome and metabolome-derived biomarkers in BV diagnosis. Interpretable machine-learning algorithms were used to evaluate the utility of an integrated-omics-derived classification model. METHODS: Vaginal samples obtained from reproductive-age group women with (n = 40) and without BV (n = 40) were subjected to 16S rRNA amplicon sequencing and LC-MS-based metabolomics. The vaginal microbiome and metabolome were characterized, and machine-learning analysis was performed to build a classification model using biomarkers with the highest diagnostic accuracy. RESULTS: Microbiome-based diagnostic model exhibited a ROC-AUC (10-fold CV) of 0.84 ± 0.21 and accuracy of 0.79 ± 0.18, and important features were Aerococcus spp., Mycoplasma hominis, Sneathia spp., Lactobacillus spp., Prevotella spp., Gardnerella spp. and Fannyhessea vaginae. The metabolome-derived model displayed superior performance with a ROC-AUC of 0.97 ± 0.07 and an accuracy of 0.92 ± 0.08. Beta-leucine, methylimidazole acetaldehyde, dimethylethanolamine, L-arginine and beta cortol were among key predictive metabolites for BV. A predictive model combining both microbial and metabolite features exhibited a high ROC-AUC of 0.97 ± 0.07 and accuracy of 0.94 ± 0.08 with diagnostic performance only slightly superior to the metabolite-based model. CONCLUSION: Application of machine-learning tools to multi-omics datasets aid biomarker discovery with high predictive performance. Metabolome-derived classification models were observed to have superior diagnostic performance in predicting BV than microbiome-based biomarkers.

Digital Gangrene is a Rare Presentation of Takayasu's Arteritis.

Takayasu's arteritis is a chronic large vessel vasculitis that mainly affects the aorta and its major branches such as brachiocephalic, carotid, subclavian, vertebral, renal, coronary and pulmonary arteries. It most commonly occurs in female at child bearing age and female to male ratio is 8:2. Initial presentations of Takayasu's arteritis may be nonspecific like fever, malaise, weakness, fatigue, arthralgia, myalgia and weight loss but in advanced stage there may be features of vascular inflammation like segmental stenosis, occlusion, dilatation and/or aneurysm. It is a sub acute process over months to years and usually with good collateral formation. So, critical limb ischemia due to acute onset of vascular stenosis is very rare. Here we are reporting a case of a 50-year- old male patient who presented with digital gangrene due to critical limb ischemia. Though the age of onset was at 50 years and the patient lacks clinical features like constitutional symptoms, bruit, claudication, asymmetrical blood pressure, the patient was diagnosed as a case of Takayasus's arteritis. The patient dramatically improved with oral glucocorticoid treatment. Although rare, takayasu's arteritis can presents only with digital gangrene without having other clinical features. The physicians should be aware of this unusual but limb threatening presentation and more studies are needed to find out the exact mechanism of this presentation.

Differential gene expression analysis under salinity stress in the selected turmeric (Curcuma longa L.) cultivars for curcuminoid biosynthesis.

BACKGROUND: Curcuminoids are the phenolic compounds found exclusively in turmeric. Their presence is known to increase immunity and resistance against certain cancers and neurological disorders in humans also, protecting the plant itself against salinity stress. METHODS: In this experiment, we studied the expression levels of MAPK1 and DCS genes, their curcuminoid biosynthesis under salinity stress conditions so that the impact of individual genes can be understood using semi- quantitative PCR. RESULTS: The expressions of the genes with respect to curcuminoid biosynthesis showed fluctuations in their band intensity values due to the production of curcuminoids, which is initiated first in the leaves followed by the rhizomes. Not all the genes responsible for the curcuminoid biosynthesis show positive regulation under salt stress conditions which is observed in response to the severity of the stress imposed on the cultivars. CONCLUSIONS: In our findings, both the genes MAPK1 and DCS were down-regulated for curcuminoid biosynthesis compared to their controls in both the cultivars Vallabh Sharad and Selection 1.

Design, synthesis, biological evaluation and molecular dynamics of some novel 3-phenylpyrazolo[1,5-a]pyrimidine-2,7(1H,4H)-dione based compounds as anti-tubercular agents.

Decaprenylphosphoryl-ß-d-ribose-2'-epimerase (DprE1) is a druggable target which is being exploited for the development of new anti-TB agents. In the present work, we report developing a pharmacophore model and performing virtual screening of Asinex database using the developed pharmacophore model to get eight hits as potential DprE1 inhibitors. The hits were used as leads to design new 3-phenylpyrazolo[1,5-a]pyrimidine-2,7(1H,4H)-dione based potential anti-TB agents. On the basis of the identified lead molecules, a total of 18 compounds were synthesized and evaluated for their anti-TB activity by using MABA. ADMET predictions for all the compounds revealed that these compounds have drug-like and lead-like properties. One of the final compounds was found to exhibit potent anti-TB activity against Mycobacterium bovis.Communicated by Ramaswamy H. Sarma.

Ligand-free Pd-catalyzed double Heck reaction of N-(o-bromoaryl)acrylamides with α-F/CF3-acrylates.

Herein, we have demonstrated an operationally simple Pd-catalyzed double-Heck reaction between N-(o-bromoaryl)acrylamide derivatives and α-fluoro/trifluoromethyl acrylates to enable monofluoro/trifluoromethyl alkene tethered 3,3-disubstituted oxindoles in a stereoselective manner. Remarkably, the reaction proceeds well without any external ligand in an open-air atmosphere. Control experiments and spectroscopic analysis are performed to understand the reaction mechanism.

Cu(I)/N,N-Imine Ligand Catalyzed C(sp3)-C(sp) Coupling of Alkyl Bromides with Alkynes: Scope and Mechanistic Investigation.

We have developed an efficient Cu/N,N-bidentate imine ligand catalytic system for C(sp3)-C(sp) coupling to obtain internal alkynes, di/trisubstituted allenes and strained bridged cyclic lactams in moderate to excellent yields from readily available alkyl(benzyl) bromides in one-pot transformation. Density Functional Theory (DFT) assisted mechanistic study along with control experiments support the involvement of bialkynylated copper species which undergo single electron transfer (SET) with alkyl halides to generate radical intermediate in the reaction. The N,N-bidentate imine ligand plays a vital role in stabilization of intermediate copper complex and facilitates the product formation.

Photoinduced Alkyl/Aryl Radical Cascade for the Synthesis of Quaternary CF3-Containing Oxindoles and Indoline Alkaloids.

Metal- and additive-free, photoinduced decarboxylative radical alkylation-cyclization of CF3-acrylamides with alkyl redox-active esters provided the corresponding quaternary CF3-oxindole derivatives in good yields. Notably, diaryliodonium salts also efficiently participated in the arylation-cyclization of CF3-acrylamides in environmentally benign H2O as a solvent. The present approach has been extended for the concise synthesis of CF3-attached indoline alkaloid analogues, i.e., CF3-(±)-desoxyeseroline, CF3-(±)-esermethole, and CF3-(±) progesterone receptor antagonists. The preliminary mechanistic studies revealed that the reaction is likely to proceed through initial photoexcitation of redox-active ester/diaryliodonium salts followed by the SET process with acrylamide.

Cu(II)-Catalyzed Unsymmetrical Dioxidation of gem-Difluoroalkenes to Generate α,α-Difluorinated-α-phenoxyketones.

A Cu-based catalyst system convergently couples gem-difluoroalkenes with phenols under aerobic conditions to deliver α,α-difluorinated-α-phenoxyketones, an unstudied hybrid fluorinated functional group. Composed of α,α-difluorinated ketone and α,α-difluorinated ether moieties, these compounds have rarely been reported as a synthetic intermediate. Computational predictions and later experimental corroboration suggest that the phenoxy-substituted fluorinated ketone's sp3-hybridized hydrate form is energetically favored relative to the respective nonether variant and that perturbation of the electronic character of the ketone can further encourage the formation of the hydrate. The more facile conversion between ketone and hydrate forms suggests that analogues should readily covalently inhibit proteases and other enzymes. Further functionalization of the ketone group enables access to other useful fluorinated functional groups.

Synchronous uterine serous carcinoma and ovarian sex cord stromal tumor (thecoma)-A rare first case report.

Synchronous endometrial and ovarian carcinoma is a rare instance and it accounts for 50 to 70% of all synchronous female genital tract tumors. However, it is very rare to find synchronous endometrial carcinoma and ovarian sex cord-stromal tumor (thecoma). The present case is a 75-year-old woman with a complaint of post-menopausal vaginal bleeding. Radiologically, the magnetic resonance imaging (MRI) pelvis revealed altered signal intensity mass in the uterus. Frozen section and routine histopathological examination were done on radical hysterectomy. Microscopically, serous carcinoma involving uterine corpus and left Fallopian tube was identified along with the unusual finding of contralateral ovarian sex cord-stromal tumor (thecoma), which was confirmed on immunohistochemical examination. It is a very rare association and is first reported in the present study after a thorough search of the published literature. Their relationship based on a high level of estrogen produced by the hyperactive ovary is controversial as serous carcinomas are less hormone-dependent.

Plantaricin LD1 purified from Lactobacillus plantarum LD1 inhibits biofilm formation of Enterococcus faecalis ATCC 29212 in tooth model.

Plantaricin LD1 was purified to homogeneity using activity-guided chromatography. Enterococcus faecalis ATCC 29212 was found to be sensitive to plantaricin LD1 showing 13 ± 0·21 mm zone of growth inhibition. The minimum inhibitory concentration (MIC) was found to be 50 µg ml-1 against Ent. faecalis ATCC 29212. The in vitro biofilm formation by Ent. faecalis ATCC 29212 was observed, which was completely inhibited in the presence of bacteriocin. Similarly, biofilm formation was also observed on the teeth surface showing purple colour, whereas treated-teeth were clean and indicated no biofilm formation. Further, untreated cells of Ent. faecalis ATCC 29212 were found normal and plantaricin LD1-treated cells were ruptured when seen under light microscope, suggesting killing of target cells. These findings have proven the initial leads for antimicrobial and anti-biofilm activity of plantaricin LD1 against Ent. faecalis and its possible application for the treatment of endodontic diseases.

A systematic review and meta-analysis of otorhinolaryngological manifestations of coronavirus disease 2019 in paediatric patients.

BACKGROUND: This meta-analysis provides a quantitative measure of the otorhinolaryngological manifestations of coronavirus disease 2019 in children. METHODS: A structured literature review was carried out using PubMed, Embase and Cochrane Central, employing pertinent search terms. The statistical analysis was performed using Stata version 14.2 software, and the analysed data were expressed as the pooled prevalence of the symptoms with 95 per cent confidence intervals. RESULTS: The commonest symptoms noted were cough (38 per cent (95 per cent confidence interval = 33-42; I2 = 97.5 per cent)), sore throat (12 per cent (95 per cent confidence interval =10-14; I2 = 93.7 per cent)), and nasal discharge (15 per cent (95 per cent confidence interval = 12-19; I2 = 96.9 per cent)). Anosmia and taste disturbances showed a pooled prevalence of 8 per cent each. Hearing loss, vertigo and hoarseness were rarely reported. CONCLUSION: Cough, sore throat and nasal discharge were the commonest otorhinolaryngological symptoms in paediatric patients with coronavirus disease 2019. Compared with adults, anosmia and taste disturbances were infrequently reported in children.

Design, synthesis, and computational studies of phenylacetamides as antidepressant agents.

In the present work, a hit molecule obtained from zinc 'clean drug-like database' by systematically performed computational studies was modified chemically to obtain different derivatives (VS1-VS25). Structures of synthesized derivatives were confirmed by IR, 1H-NMR, 13C-NMR, 13C-DEPT, MS, and elemental analysis. All the synthesized compounds were biologically evaluated for their antidepressant activity by using tail suspension test and forced swimming test in albino mice. All these derivatives showed moderate to good antidepressant activity. The most potent compound (VS25) among the synthesized compounds showed better antidepressant potential than the standard drugs moclobemide, imipramine, and fluoxetine. To understand the time-dependent interactions of this most active compound with MAO-A molecular dynamics was carried out and reported here. Additionally, acute oral toxicity was performed for the most active compound as per OECD guidelines.

Design and synthesis of novel N-[3-(benzimidazol-2-ylamino)phenyl]amine and N-[3-(benzoxazol-2-ylamino)phenyl]amine derivatives as potential anticancer agents.

In this contribution, we report the design, synthesis and cytotoxicity studies of a series of N-[3-(benzimidazol-2-yl-amino)phenyl]amine and N-[3-(benzoxazol-2-ylamino)phenyl]amine derivatives. In vitro cytotoxicity assay of 26 selected compounds was carried out at National Cancer Institute (NCI), USA. Out of them, compounds 10e (NSC D-762842/1) and 11s (NSC D-764942/1) have shown remarkable cytotoxicity with GI50 values ranging between "0.589-14.3 µM" and "0.276-12.3 µM," respectively, in the representative nine subpanels of human tumor cell lines. Further, flow cytometry analysis demonstrated that compound 10e exerted cell cycle arrest at G2/M phase and showed dose-dependent enhancement in apoptosis in K-562 leukemia cancer cells.

Assessing the effects of common topical exposures on skin bacteria associated with atopic dermatitis.

BACKGROUND: While patients and families struggling with atopic dermatitis (AD) have documented concerns for a contributory role of skin care products in AD pathology, nearly all the skin microbiome studies to date have asked participants to avoid topical products (such as soaps or select medications) for the preceding days to weeks prior to sample collection. Thus, given the established role of the microbiome in AD, the interactions between topical exposures, dysbiosis and AD remains underrepresented in the academic literature. OBJECTIVES: To address this knowledge gap, we expanded our previous evaluations to test the toxicological effects of a broader range of common chemicals, AD treatment lotions, creams and ointments using both health- and AD-associated strains of Roseomonas mucosa and Staphylococcus spp. METHODS: Use of in vitro culture techniques and mouse models were deployed to identify chemicals with dysbiotic or pre-biotic potential. A proof-of-concept study was subsequently performed in healthy volunteers to assess global microbiome shifts after exposure to select chemicals using dermatologic patch testing. RESULTS: Numerous chemicals possessed antibiotic properties, including many not marketed as anti-microbials. Through targeted combination of potentially beneficial chemicals, we identified combinations which promoted the growth of health-associated isolates over disease-associated strains in bacterial culture and enhanced microbe-specific outcomes in an established mouse model of AD; the most promising of which was the combination of citral and colophonium (often sold as lemon myrtle oil and pine tar). Additional studies would likely further optimize the combination of ingredients use. Similar results were seen in the proof-of-concept human studies. CONCLUSIONS: Our results could offer a systematic, multiplex approach to identify which products carry dysbiotic potential and thus may guide formulation of new topicals to benefit patients with AD.

Recent developments in decarboxylative C(aryl)-X bond formation from (hetero)aryl carboxylic acids.

Decarboxylative coupling reactions using readily available (hetero)aryl carboxylic acids are a highly efficient approach for the formation of new C-C and C-X bonds. These decarboxylative coupling reactions eliminate CO2 as a by-product, resulting in a greener and environmentally more benign approach than conventional coupling reactions. In this review, we summarize the recent developments in ipso-decarboxylative C-X (X = O/N/halo/S/Se/P/CN) bond formations using (hetero)aryl carboxylic acids. Furthermore, we highlight the current limitations and future research opportunities of aryl-decarboxylative coupling reactions.

Morpho-molecular and mating-type locus diversity of Ustilaginoidea virens: an incitant of false smut of rice from Southern parts of India.

AIMS: To characterize the geo-distinct isolates of Ustilaginoidea virens for morpho-molecular and mating-type locus diversity. METHODS AND RESULTS: Sixty-one isolates of U. virens collected from Southern India exhibited significant diversity in mycelial width (3·45-5·50 µm), colony colour (yellow, pale yellow, and white), and growth pattern (thick leather mat, raised-fluffy, flat-fluffy, and raised). Field-borne chlamydospores of each isolate were significantly smaller in size (3·34-5·26 µm2 ) compared to those formed on culture media (18·6-100·89 µm2 ). The phylogenetic study based on internal transcribed sequences revealed two clusters; however, most isolates (n = 54) were grouped in cluster-I, indicating common ancestral origin. We also identified 42 haplotypes; among them, Hap_3 has the highest number of isolates (n = 19). Mating-type locus (MAT1) analysis revealed all sixty-one isolates as heterothallic, wherein 37 and 24 isolates belonging to MAT1-1-1 and MAT1-2-1 heterothallic mating types, respectively. The microsynteny analysis of MAT1 loci of one of the Indian strain (Uv-Gvt) along with Uv-8b (China) strain revealed synteny conservation at MAT1 locus, which is flanked by conserved genes SLA2 and a hypothetical protein in the upstream and APN2, COX12 and APC5 in the downstream of the locus. CONCLUSIONS: Morpho-molecular study revealed the significant diversity among geo-distinct isolates, and MAT1 loci analysis indicated the distribution of heterothallic mating types in south Indian paddy fields. And also, complete synteny conservation between Indian and Chinese strain was observed at the MAT1 locus. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report describing the sexuality of Indian strains of the U. virens, which would help better understand the genetic diversity of the U. virens prevailing in Southern India and aid in developing resistant rice cultivars against this pathogen population.

Overview of the rules of the microbial engagement in the gut microbiome: a step towards microbiome therapeutics.

Human gut microbiome is a diversified, resilient, immuno-stabilized, metabolically active and physiologically essential component of the human body. Scientific explorations have been made to seek in-depth information about human gut microbiome establishment, microbiome functioning, microbiome succession, factors influencing microbial community dynamics and the role of gut microbiome in health and diseases. Extensive investigations have proposed the microbiome therapeutics as a futuristic medicine for various physiological and metabolic disorders. A comprehensive outlook of microbial colonization, host-microbe interactions, microbial adaptation, commensal selection and immuno-survivability is still required to catalogue the essential genetic and physiological features for the commensal engagement. Evolution of a structured human gut microbiome relies on the microbial flexibility towards genetic, immunological and physiological adaptation in the human gut. Key features for commensalism could be utilized in developing tailor-made microbiome-based therapy to overcome various physiological and metabolic disorders. This review describes the key genetics and physiological traits required for host-microbe interaction and successful commensalism to institute a human gut microbiome.

Comparative Assessment of Revascularization Versus Drug Management in Coronary Artery Disease (CAD) Associated with Left Ventricular Dysfunction (EF < 40%) - A 12 Month Study with FDG PET and SPECT MPI Analyses.

AIM OF THE STUDY: Left Ventricular (LV) function and myocardial viability is the key predictor of prognosis after myocardial infarction. Management of ischemic cardiomyopathy (revascularization and or drugs alone) is the objective of this study. METHODOLOGY: 72 patients were assigned to revascularization and medical management group based on the inclusion criteria Follow up was done upto 12 months with advanced imaging techniques (FDG PET and SPECT MPI analyses). RESULTS: Subjects with significant viable myocardium, revascularization resulted in significant improvement in heart failure symptoms. The mean NYHA functional class improved from 2.9 ± 0.3 to 2.3 ± 0.5(mean ± SD) after 6 months of revascularization (p < 0.01). This improvement in functional class was maintained after 12 months of revascularization (2.0 ± 0.4 (mean ± SD). Subjects on medical management with a baseline NYHA functional class 2.7 ± 0.5, at 6 months of follow, there was no significant change in functional class (2.8 ± 0.3) (p<0.24). However at 12 months follow up functional class had dropped to 3.0 + 0.3, which was significant as compared to baseline (p <0.03). CONCLUSION: coronary revascularization has a protective effect on patients with ischemic coronary who have viable myocardium and reversible myocardial ischemia as assessed by 18F-FDG PET and SPECT MPI Imaging.

Late onset systemic sclerosis with seronegativity: a rare presentation of an uncommon disease.

Systemic sclerosis (SSc) is an uncommon connective tissue disorder characterized by multisystem involvement with fibrosis of skin and internal organs. Antibody formation is one of the hallmarks of SSc. Antinuclear antibodies (ANA) are positive in 97% of patients with SSc. We report a rare case where the patient was negative for ANA, Anti-topoisomerase I, Anti-centromere and Anti-RNA polymerase III antibodies.