Synthesis and study of antibiofilm and antivirulence properties of flavonol analogues generated by palladium catalyzed ligand free Suzuki-Miyaura coupling against Pseudomonas aeruginosa PAO1.

The Suzuki-Miyaura coupling is one of the ubiquitous method for the carbon-carbon bond-forming reactions in organic chemistry. Its popularity is due to its ability to undergo extensive coupling reactions to generate a broad range of biaryl motifs in a straightforward manner displaying a high level of functional group tolerance. A convenient and efficient synthetic route to arylate different substituted flavonols through the Suzuki-Miyaura cross-coupling reaction has been explained in this study. The arylated products were acquired by the coupling of a variety of aryl boronic acids with flavonols under Pd(OAc)2 catalyzed reaction conditions in a ligand-free reaction strategy. Subsequently, the antibiofilm and antivirulence properties of the arylated flavonols against Pseudomonas aeruginosa PAO1 were studied thoroughly. The best ligands for quorum sensing proteins LasR, RhlR, and PqsR were identified using molecular docking study. These best fitting ligands were then studied for their impact on gene expression level of P. aeruginosa by RT-PCR towards quorum sensing genes lasB, rhlA, and pqsE. The downregulation in the gene expression with the effect of synthesized flavonols endorse the antibiofilm efficiency of the compounds.

Comparing storm resolving models and climates via unsupervised machine learning.

Global storm-resolving models (GSRMs) have gained widespread interest because of the unprecedented detail with which they resolve the global climate. However, it remains difficult to quantify objective differences in how GSRMs resolve complex atmospheric formations. This lack of comprehensive tools for comparing model similarities is a problem in many disparate fields that involve simulation tools for complex data. To address this challenge we develop methods to estimate distributional distances based on both nonlinear dimensionality reduction and vector quantization. Our approach automatically learns physically meaningful notions of similarity from low-dimensional latent data representations that the different models produce. This enables an intercomparison of nine GSRMs based on their high-dimensional simulation data (2D vertical velocity snapshots) and reveals that only six are similar in their representation of atmospheric dynamics. Furthermore, we uncover signatures of the convective response to global warming in a fully unsupervised way. Our study provides a path toward evaluating future high-resolution simulation data more objectively.

Diffusion Probabilistic Modeling for Video Generation.

Denoising diffusion probabilistic models are a promising new class of generative models that mark a milestone in high-quality image generation. This paper showcases their ability to sequentially generate video, surpassing prior methods in perceptual and probabilistic forecasting metrics. We propose an autoregressive, end-to-end optimized video diffusion model inspired by recent advances in neural video compression. The model successively generates future frames by correcting a deterministic next-frame prediction using a stochastic residual generated by an inverse diffusion process. We compare this approach against six baselines on four datasets involving natural and simulation-based videos. We find significant improvements in terms of perceptual quality and probabilistic frame forecasting ability for all datasets.

Trends of syphilis seroprevalence at a tertiary care center in New Delhi, India: A 10-year analysis.

Objectives: Syphilis has been called the great mimicker or the great imitator due to its myriad of clinical presentations. Despite strenuous concerted efforts toward the elimination of syphilis, it still remains a goal to be achieved. During recent years, many different trends of syphilis have been reported from around the globe. Methods: A retrospective observational clinico-investigative study was carried out to analyze the 10-year trends of syphilis at one of the largest public sector hospitals in India. Results and Conclusion: Both venereal disease research laboratory and Treponema pallidum Hemagglutination assay positivity rates showed a significant declining trend from 2007 to 2016, reflecting the success of the National Sexually Transmitted Infection Prevention and Control Program.

Membrane Vesicles Derived from Gut Microbiota and Probiotics: Cutting-Edge Therapeutic Approaches for Multidrug-Resistant Superbugs Linked to Neurological Anomalies.

Multidrug-resistant (MDR) superbugs can breach the blood-brain barrier (BBB), leading to a continuous barrage of pro-inflammatory modulators and induction of severe infection-related pathologies, including meningitis and brain abscess. Both broad-spectrum or species-specific antibiotics (ß-lactamase inhibitors, polymyxins, vancomycin, meropenem, plazomicin, and sarecycline) and biocompatible poly (lactic-co-glycolic acid) (PLGA) nanoparticles have been used to treat these infections. However, new therapeutic platforms with a broad impact that do not exert off-target deleterious effects are needed. Membrane vesicles or extracellular vesicles (EVs) are lipid bilayer-enclosed particles with therapeutic potential owing to their ability to circumvent BBB constraints. Bacteria-derived EVs (bEVs) from gut microbiota are efficient transporters that can penetrate the central nervous system. In fact, bEVs can be remodeled via surface modification and CRISPR/Cas editing and, thus, represent a novel platform for conferring protection against infections breaching the BBB. Here, we discuss the latest scientific research related to gut microbiota- and probiotic-derived bEVs, and their therapeutic modifications, in terms of regulating neurotransmitters and inhibiting quorum sensing, for the treatment of neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases. We also emphasize the benefits of probiotic-derived bEVs to human health and propose a novel direction for the development of innovative heterologous expression systems to combat BBB-crossing pathogens.

A Review of Immunomodulatory Reprogramming by Probiotics in Combating Chronic and Acute Diabetic Foot Ulcers (DFUs).

Diabetic foot ulcers (DFUs) are characterized by a lack of angiogenesis and distal limb diabetic neuropathy. This makes it possible for opportunistic pathogens to protect the biofilm-encased micro-communities, causing a delay in wound healing. The acute and chronic phases of DFU-associated infections are distinguished by the differential expression of innate proinflammatory cytokines and tumor necrosis factors (TNF-α and -ß). Efforts are being made to reduce the microbial bioburden of wounds by using therapies such as debridement, hyperbaric oxygen therapy, shock wave therapy, and empirical antibiotic treatment. However, the constant evolution of pathogens limits the effectiveness of these therapies. In the wound-healing process, continuous homeostasis and remodeling processes by commensal microbes undoubtedly provide a protective barrier against diverse pathogens. Among commensal microbes, probiotics are beneficial microbes that should be administered orally or topically to regulate gut-skin interaction and to activate inflammation and proinflammatory cytokine production. The goal of this review is to bridge the gap between the role of probiotics in managing the innate immune response and the function of proinflammatory mediators in diabetic wound healing. We also highlight probiotic encapsulation or nanoformulations with prebiotics and extracellular vesicles (EVs) as innovative ways to tackle target DFUs.

Efficacy of sub-MIC level of meropenem and ciprofloxacin against extensive drug-resistant (XDR) Pseudomonas aeruginosa isolates of diabetic foot ulcer patients.

The increasing emergence of extensive drug-resistant bacteria (XDR) among chronic diabetic foot ulcer patients (DFU) possess serious threat which leads to foot amputation. The ideal measurement estimations of the presently accessible medications are getting insufficient against extensive drug-resistant strains. For quite a long-time piperacillin monotherapy, Piperacillin-tazobactam, ceftazidime, Carbapenem class of anti-toxin, ceftalozane-Tazobactam, and so on, has been the suggested therapy towards persistent instances of diabetic foot ulcer but because of the resistance mechanism of the potent pathogens the potency and usage of the antibiotic concentration regime is under the radar. Based on this hypothesis two isolates namely VIT PC 7 &VIT PC 9 were found to be resistant to all five classes of antibiotics exhibiting extensive drug resistance (XDR). The whole-genome sequence of Pseudomonas aeruginosa VIT PC 7 and VIT PC 9 data showed the presence of various RND efflux related genes and antibiotic resistance genes. The broth microdilution assay showed minimum inhibitory concentration (MIC) for ciprofloxacin and meropenem, Synergistic test was performed through checkerboard analysis and sub-MIC concentration of ciprofloxacin/meropenem was deduced using ∑ FICI, Time kills analysis was done for varying time interval to check the maximum reduction in CFU/ml of the bacterial cells, sub-MIC level of meropenem and ciprofloxacin showed inhibitory activity at lower concentration respectively. In vitro time-kill analysis showed the decrease in the number of cells, suggesting that the synergistic antimicrobial combinations are effective in decreasing the MIC level, and combinational test involving sub-MIC level of antibiotics also showed maximum reduction in biofilm forming cells, portraying the effectiveness of both the drugs. Accordingly, an expansion in the antimicrobial spectrum can be accomplished by utilizing the ideal measurements of ciprofloxacin/meropenem in persistent condition like diabetic foot ulcer, sub-MIC level of ciprofloxacin/meropenem could be a promising choice for anticipation against the ongoing drug-resistant crisis.

Comparative data analsysis of two multi-drug resistant homoserine lactone and rhamnolipid producing Pseudomonas aeruginosa from diabetic foot infected patient.

Pseudomonas aeruginosa generally forms strong biofilm during chronic condition of wound. The whole mechanism of biofilm formation works in tandem with quorum sensing circuit of the organism in order to produce virulence. Here we report the draft genome sequence of two diabetic foot ulcer Pseudomonas aeruginosa isolates (VIT PC 7 and VIT PC 9) displaying homoserine lactone, rhamnolipid producing, biofilm phenotype and antibiotic resistance genes related to carbapenem, aminoglycoside, beta- lactamase and tetracycline resistance. The whole genome sequencing library was prepared according to the Oxford Nanopore's SQK-LSK108 kit protocol on Oxford Nanopore's Minion platform. The 7.1 Mb and 6.3-Mb draft genome sequence with GC content of 65.8% and 66.4% respectively provides insight into their resistance mechanism and virulence factors.

Cardiopulmonary resuscitation discussions with patients admitted to acute oncology wards: A national audit of current practice.

OBJECTIVES: To map current practice regarding discussions around resuscitation across England and Scotland in patients with cancer admitted acutely to hospital and to demonstrate the value of medical students in rapidly collecting national audit data. METHODS: Collaborators from the Macmillan medical student network collected data from 251 patient encounters across eight hospitals in England and Scotland. Data were collected to identify whether discussion regarding resuscitation was documented as having taken place during inpatient admission to acute oncology. As an audit standard, it was expected that all patients should be invited to discuss resuscitation within 24 hr of admission. RESULTS: Resuscitation discussions were had in 43.1% of admissions and of these 64.0% were within 24 hr; 27.6% of all admissions. 6.5% of patients had a "do not attempt resuscitation" order prior to admission with a difference noted between patients receiving palliative and curative treatment (8.5% and 0.39%, respectively, p < .05). Discussions regarding escalation of care took place in only 29.3% of admissions. CONCLUSIONS: These data highlight deficiencies in the number of discussions regarding resuscitation that are being conducted with cancer patients that become acutely unwell. It also demonstrates the value of medical student collaboration in rapidly collecting national audit data.