Quantum-instanton evaluation of the kinetic isotope effects

A general quantum-mechanical method for computing kinetic isotope effects is presented. The method is based on the quantum instanton approximation for the rate constant and on the path integral Metropolis Monte-Carlo evaluation of the Boltzmann operator matrix elements. It computes the kinetic isotope effect directly, using a thermodynamic integration with respect to the mass of the isotope, thus avoiding the more computationally expensive process of computing the individual rate constants. The method is more accurate than variational transition-state theories or the semiclassical instanton method since it does not assume a single reaction path and does not use a semiclassical approximation of the Boltzmann operator. While the general Monte-Carlo implementation makes the method accessible to systems with a large number of atoms, we present numerical results for the Eckart barrier and for the collinear and full three-dimensional isotope variants of the hydrogen exchange reaction H+H{sub 2} {yields} H{sub 2}+H. In all seven test cases, for temperatures between 250 K and 600 K, the error of the quantum instanton approximation for the kinetic isotope effects is less than {approx}10%

Membrane Cholesterol Regulates Lysosome-Plasma Membrane Fusion Events and Modulates Trypanosoma cruzi Invasion of Host Cells

Trypanosoma cruzi, is the etiological agent of a neglected tropical malady known as Chagas' disease, which affects about 8 million people in Latin America. 30–40% of affected individuals develop a symptomatic chronic infection, with cardiomyopathy being the most prevalent condition. T. cruzi utilizes an interesting strategy for entering cells: T. cruzi enhances intracellular calcium levels, which in turn trigger the exocytosis of lysosomal contents. Lysosomes then donate their membrane for the formation of the parasitophorous vacuole. Membrane rafts, cholesterol-enriched microdomains in the host cell plasma membrane, have also been implicated in T. cruzi invasion process. Since both plasma membrane and lysosomes collaborate in parasite invasion, we decided to study the importance of these membrane domains for lysosomal recruitment and fusion during T. cruzi invasion into host cells. Our results show that drug dependent depletion of plasma membrane cholesterol changes raft organization and induces excessive lysosome exocytosis in the earlier stages of treatment, leading to a depletion of lysosomes near the cell cortex, which in turn compromises T. cruzi invasion. Based on these results, we propose that cholesterol depletion leads to unregulated exocytic events of pre-docked lysosomes, reducing lysosome availability at the cell cortex and consequently compromising T. cruzi infection

Massively parallel simulations for disordered systems

Simulations of systems with quenched disorder are extremely demanding, suffering from the combined effect of slow relaxation and the need of performing the disorder average. As a consequence, new algorithms, improved implementations, and alternative and even purpose-built hardware are often instrumental for conducting meaningful studies of such systems. The ensuing demands regarding hardware availability and code complexity are substantial and sometimes prohibitive. We demonstrate how with a moderate coding effort leaving the overall structure of the simulation code unaltered as compared to a CPU implementation, very significant speed-ups can be achieved from a parallel code on GPU by mainly exploiting the trivial parallelism of the disorder samples and the near-trivial parallelism of the parallel tempering replicas. A combination of this massively parallel implementation with a careful choice of the temperature protocol for parallel tempering as well as efficient cluster updates allows us to equilibrate comparatively large systems with moderate computational resources.Comment: accepted for publication in EPJB, Topical issue - Recent advances in the theory of disordered system

Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation

Background: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. Main body: We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. Conclusions: As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.Frances Corrigan, Kimberley A. Mander, Anna V. Leonard and Robert Vin

Postoperative outcomes in oesophagectomy with trainee involvement

BACKGROUND: The complexity of oesophageal surgery and the significant risk of morbidity necessitates that oesophagectomy is predominantly performed by a consultant surgeon, or a senior trainee under their supervision. The aim of this study was to determine the impact of trainee involvement in oesophagectomy on postoperative outcomes in an international multicentre setting. METHODS: Data from the multicentre Oesophago-Gastric Anastomosis Study Group (OGAA) cohort study were analysed, which comprised prospectively collected data from patients undergoing oesophagectomy for oesophageal cancer between April 2018 and December 2018. Procedures were grouped by the level of trainee involvement, and univariable and multivariable analyses were performed to compare patient outcomes across groups. RESULTS: Of 2232 oesophagectomies from 137 centres in 41 countries, trainees were involved in 29.1 per cent of them (n = 650), performing only the abdominal phase in 230, only the chest and/or neck phases in 130, and all phases in 315 procedures. For procedures with a chest anastomosis, those with trainee involvement had similar 90-day mortality, complication and reoperation rates to consultant-performed oesophagectomies (P = 0.451, P = 0.318, and P = 0.382, respectively), while anastomotic leak rates were significantly lower in the trainee groups (P = 0.030). Procedures with a neck anastomosis had equivalent complication, anastomotic leak, and reoperation rates (P = 0.150, P = 0.430, and P = 0.632, respectively) in trainee-involved versus consultant-performed oesophagectomies, with significantly lower 90-day mortality in the trainee groups (P = 0.005). CONCLUSION: Trainee involvement was not found to be associated with significantly inferior postoperative outcomes for selected patients undergoing oesophagectomy. The results support continued supervised trainee involvement in oesophageal cancer surgery

Objective assessment of clinical, oncological and cosmetic outcomes following volume replacement in patients undergoing oncoplastic breast-conserving surgery: protocol for a systematic review

Introduction Oncoplastic breast surgery allows the excision of larger tumours without compromising cosmetic outcome and can be broadly divided into volume displacement and volume replacement techniques. Although oncoplastic surgery has rapidly gained acceptance and is now widely practised, evidence is still lacking especially in patients who underwent volume replacement techniques. As it is a relatively new technique that has been described in the literature in the recent years, a summary of evidence from this literature can help clinicians to understand the clinical, oncologicalandcosmetic outcomes of such procedures. Methods and analysis All original studies including randomised controlled trials, cohort studies, case–control studies and case series involving more than 10 women undergoing partial breast reconstruction using a volume replacement technique will be included. The primary objective is to evaluate the clinical, oncological and cosmetic outcomes following volume replacement in patients undergoing oncoplastic breast-conserving surgery. The secondary objective is to review the patient-reported outcomes (PROMs) associated with oncoplastic breast surgery to help identify any unmet needs and to consider refining the existing PROMs to suit women undergoing volume replacement surgery. A comprehensive literature search, eligibility assessment and extraction of data will be conducted by two trained teams acting independently. Data will be extracted and stored in a database with standardised extraction fields to facilitate easy and consistent data entry. Heterogeneity will be assessed using the Cochrane tests. Ethics and dissemination This systematic review requires no ethical approval. It will be published in a peer-reviewed journal, and it will also be presented at nationalandinternational conferences.</p