Conformational and functional analysis of molecular dynamics trajectories by Self-Organising Maps

<p>Abstract</p> <p>Background</p> <p>Molecular dynamics (MD) simulations are powerful tools to investigate the conformational dynamics of proteins that is often a critical element of their function. Identification of functionally relevant conformations is generally done clustering the large ensemble of structures that are generated. Recently, Self-Organising Maps (SOMs) were reported performing more accurately and providing more consistent results than traditional clustering algorithms in various data mining problems. We present a novel strategy to analyse and compare conformational ensembles of protein domains using a two-level approach that combines SOMs and hierarchical clustering.</p> <p>Results</p> <p>The conformational dynamics of the α-spectrin SH3 protein domain and six single mutants were analysed by MD simulations. The Cα's Cartesian coordinates of conformations sampled in the essential space were used as input data vectors for SOM training, then complete linkage clustering was performed on the SOM prototype vectors. A specific protocol to optimize a SOM for structural ensembles was proposed: the optimal SOM was selected by means of a Taguchi experimental design plan applied to different data sets, and the optimal sampling rate of the MD trajectory was selected. The proposed two-level approach was applied to single trajectories of the SH3 domain independently as well as to groups of them at the same time. The results demonstrated the potential of this approach in the analysis of large ensembles of molecular structures: the possibility of producing a topological mapping of the conformational space in a simple 2D visualisation, as well as of effectively highlighting differences in the conformational dynamics directly related to biological functions.</p> <p>Conclusions</p> <p>The use of a two-level approach combining SOMs and hierarchical clustering for conformational analysis of structural ensembles of proteins was proposed. It can easily be extended to other study cases and to conformational ensembles from other sources.</p

Ginsenosides are novel naturally-occurring aryl hydrocarbon receptor ligands.

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates many of the biological and toxicological actions of structurally diverse chemicals. In this study, we examined the ability of a series of ginsenosides extracted from ginseng, a traditional Chinese medicine, to bind to and activate/inhibit the AHR and AHR signal transduction. Utilizing a combination of ligand and DNA binding assays, molecular docking and reporter gene analysis, we demonstrated the ability of selected ginsenosides to directly bind to and activate the guinea pig cytosolic AHR, and to stimulate/inhibit AHR-dependent luciferase gene expression in a recombinant guinea pig cell line. Comparative studies revealed significant species differences in the ability of ginsenosides to stimulate AHR-dependent gene expression in guinea pig, rat, mouse and human cell lines. Not only did selected ginsenosides preferentially activate the AHR from one species and not others, mouse cell line was also significantly less responsive to these chemicals than rat and guinea pig cell lines, but the endogenous gene CYP1A1 could still be inducted in mouse cell line. Overall, the ability of these compounds to stimulate AHR signal transduction demonstrated that these ginsenosides are a new class of naturally occurring AHR agonists

The Combination of a Hypertonic Saline Dressing and Negative Pressure Wound Therapy (NPWT) for Quick and Bloodless Debridement of Difficult Lesions in Complicated Patients

NPWT, also known as topical negative-pressure wound therapy, is widely used in managing and accelerating wound healing. However in wounds were slough is highly represented NPWT efficiency is low. In the patients included in this study clinical health conditions were precarious. We needed a rapid wound healing to not further compromise their health condition. So we added curity dressing to resolve the slough issue. In all the patients we observed slough reduction. This treatment provided beneficial for the patient, the surgeons and the National Health Service. Accelerating wound healing reduced hospitalization and thereby the patients achieved a reduction of risks of nosocomial infections and physical and psychological diseases

Percutaneous tibial nerve stimulation in patients with severe low anterior resection syndrome: randomized clinical trial

Treatment of low anterior resection syndrome (LARS) is challenging. Percutaneous tibial nerve stimulation (PTNS) can improve select bowel disorders. An RCT was conducted to assess the efficacy of PTNS compared with sham stimulation in patients with severe LARS

Prevention and therapy of acute and chronic wounds using NPWT devices during the COVID-19 pandemic, recommendation from The NPWT Working Group

Recent SARS-CoV-2 pandemic leading to a rapidly increasing number of hospitalizations enforced reevaluation of wound management strategies. The optimal treatment strategy for patients with chronic wounds and those recovering from emergency and urgent oncological surgery should aim to minimize the number of hospital admissions, as well as the number of surgical procedures and decrease the length of stay to disburden the hospital staff and to minimize viral infection risk. One of the potential solutions that could help to achieve these goals may be the extensive and early use of NPWT devices in the prevention of wound healing complications. Single-use NPWT devices are helpful in outpatient wound treatment and SSI prevention (ciNPWT) allowing to minimize in-person visits to the health care center while still providing the best possible wound-care. Stationary NPWT should be used in deep SSI and perioperative wound healing disorders as soon as possible. Patient’s education and telemedical support with visual wound healing monitoring and video conversations have the potential to minimize the number of unnecessary in-person visits in patients with wounds and therefore substantially increase the level of care

Arcobacter spp. in bovine milk: An emerging pathogen with potential zoonotic risk

The aim of the present study was to assess the prevalence and genetic characteristics of Arcobacter spp. in bovine bulk tank milk produced in Apulia Region (Italy). Samples collected from 396 dairy farms, after enrichment in a selective broth, were subjected to an Arcobacter genus - specific Real Time PCR. Positive broths, previously filtered, were seeded on Karmali, MCCD and Columbia Blood Agar plates; presumptive Arcobacter spp. colonies were identified using an amplification and sequencing method and then characterized by Multi-Locus Sequence Typing (MLST). Prevalence of Arcobacter spp. in bovine milk samples was 5% (20/396); A. butzleri was the only isolated species, in agreement with previous studies that reported A. butzleri as the most commonly recovered species in milk and dairy products. MLST analysis of the 20 A. butzleri strains identified 81 alleles and 16 STs. Consistent with previous studies, MLST revealed a high level of heterogeneity between the A. butzleri isolates and confirmed the high discriminatory power of this method and its suitability for epidemiological investigations. This study confirmed the importance of raw milk as a possible source of Arcobacter spp. for humans

Preoperative oral antibiotic prophylaxis reduces Pseudomonas aeruginosa surgical site infections after elective colorectal surgery: a multicenter prospective cohort study

BACKGROUND: Healthcare-associated infections caused by Pseudomonas aeruginosa are associated with poor outcomes. However, the role of P. aeruginosa in surgical site infections after colorectal surgery has not been evaluated. The aim of this study was to determine the predictive factors and outcomes of surgical site infections caused by P. aeruginosa after colorectal surgery, with special emphasis on the role of preoperative oral antibiotic prophylaxis. METHODS: We conducted an observational, multicenter, prospective cohort study of all patients undergoing elective colorectal surgery at 10 Spanish hospitals (2011-2014). A logistic regression model was used to identify predictive factors for P. aeruginosa surgical site infections. RESULTS: Out of 3701 patients, 669 (18.1%) developed surgical site infections, and 62 (9.3%) of these were due to P. aeruginosa. The following factors were found to differentiate between P. aeruginosa surgical site infections and those caused by other microorganisms: American Society of Anesthesiologists' score III-IV (67.7% vs 45.5%, p = 0.001, odds ratio (OR) 2.5, 95% confidence interval (95% CI) 1.44-4.39), National Nosocomial Infections Surveillance risk index 1-2 (74.2% vs 44.2%, p < 0.001, OR 3.6, 95% CI 2.01-6.56), duration of surgery ≥75thpercentile (61.3% vs 41.4%, p = 0.003, OR 2.2, 95% CI 1.31-3.83) and oral antibiotic prophylaxis (17.7% vs 33.6%, p = 0.01, OR 0.4, 95% CI 0.21-0.83). Patients with P. aeruginosa surgical site infections were administered antibiotic treatment for a longer duration (median 17 days [interquartile range (IQR) 10-24] vs 13d [IQR 8-20], p = 0.015, OR 1.1, 95% CI 1.00-1.12), had a higher treatment failure rate (30.6% vs 20.8%, p = 0.07, OR 1.7, 95% CI 0.96-2.99), and longer hospitalization (median 22 days [IQR 15-42] vs 19d [IQR 12-28], p = 0.02, OR 1.1, 95% CI 1.00-1.17) than those with surgical site infections due to other microorganisms. Independent predictive factors associated with P. aeruginosa surgical site infections were the National Nosocomial Infections Surveillance risk index 1-2 (OR 2.3, 95% CI 1.03-5.40) and the use of oral antibiotic prophylaxis (OR 0.4, 95% CI 0.23-0.90). CONCLUSIONS: We observed that surgical site infections due to P. aeruginosa are associated with a higher National Nosocomial Infections Surveillance risk index, poor outcomes, and lack of preoperative oral antibiotic prophylaxis. These findings can aid in establishing specific preventive measures and appropriate empirical antibiotic treatment