Optimization of reaction paths for enzymatic systems is a challenging problem because such systems have a very large number of degrees of freedom and many of these degrees are flexible. To meet this challenge, an efficient, robust and general approach is presented based on the well-known nudged elastic band reaction path optimization method with the following extensions: (1) soft spectator degrees of freedom are excluded from path definitions by using only inter-atomic distances corresponding to forming/breaking bonds in a reaction; (2) a general transformation of the distances is defined to treat multistep reactions without knowing the partitioning of steps in advance; (3) a multistage strategy, in which path optimizations are carried out for reference systems with gradually decreasing rigidity, is developed to maximize the opportunity of obtaining continuously changing environments along the path. We demonstrate the applicability of the approach using the acylation reaction of type A beta-lactamase as an example. The reaction mechanism investigated involves four elementary reaction steps, eight forming/breaking bonds. We obtained a continuous minimum energy path without any assumption on reaction coordinates, or on the possible sequence or the concertedness of chemical events. We expect our approach to have general applicability in the modeling of enzymatic reactions with quantum mechanical/molecular mechanical models.

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Fugitive road dust (FRD) particles emitted by traffic-generated turbulence are an important contributor to urban ambient fine particulate matter (PM2.5). Especially in urban areas of developing countries, FRD PM2.5 emissions are a serious environmental threat to air quality and public health. FRD PM2.5 emissions have been neglected or substantially underestimated in previous study, resulting in the underestimation of modeling PM concentrations and estimating their health impacts. This study constructed the FRD PM2.5 emissions inventory in a major inland city in China (Lanzhou) in 2017 at high-resolution (500 × 500 m2), investigated the spatiotemporal characteristics of the FRD emissions in different urban function zones, and quantified their health impacts. The FRD PM2.5 emission was approximately 1141 ± 71 kg d–1, accounting for 24.6% of total PM2.5 emission in urban Lanzhou. Spatially, high emissions exceeding 3 × 104 μg m–2 d–1 occurred over areas with smaller particle sizes, larger traffic intensities, and more frequent construction activities. The estimated premature mortality burden induced by FRD PM2.5 exposure was 234.5 deaths in Lanzhou in 2017. Reducing FRD emissions are an important step forward to protect public health in many developing urban regions.

Background:Despite proven benefits of upper extremity nerve decompression in diabetics, neurolysis for diabetic patients with lower extremity (LE) nerve compression remains controversial.Methods:A search of ClinicalTrials.gov and Cochrane clinical trials registries, CENTRAL (The Cochrane Library), MEDLINE, EMBASE, LILACS, CINAHL, SCOPUS, and Google Scholar from 1962 to 2012, yielded 1956 citations. Any potential randomized or quasi-randomized controlled trials and observational cohort studies of diabetics with neurolysis of the common peroneal nerve, deep peroneal nerve, or tibial nerve were assessed. We included articles in any language that 1) provided information about diabetic patients who had neurolysis for symptomatic nerve compression diagnosed by (+) Tinel sign or electrodiagnostic study, and 2) quantified outcomes for pain, sensibility, or ulcerations/amputations. Case reports, review articles, animal or cadaver studies, and studies with <10 patients were excluded. We assessed pain relief, recovery of sensibility, and postoperative incidence of ulcerations/amputations at follow-up >3 months. A meta-analysis of descriptive statistics was performed.Results:Ten clinical series with a mean clinical relevance score of 70% and a mean methodologic quality score of 50% met inclusion criteria. We included 875 diabetic patients and 1053 LEs. Pain relief >3 points on visual analog scale occurred in 91% of patients; sensibility improved in 69%. Postoperative ulceration/amputation incidence was significantly reduced compared to preoperative incidence (odds ratio = 0.066, 95% confidence interval = 0.026–0.164, P < 0.0001).Conclusions:Observational data suggest that neurolysis significantly improves outcomes for diabetic patients with compressed nerves of the LE. No randomized controlled trials have been published.

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We investigated the mechanisms by which CD8 T-cell trafficking in placenta contributes to perinatal brain injury by studying effects of maternal CD8 T-cell depletion (DEP) in a mouse model of intrauterine inflammation (IUI). Maternal CD8 T cells were depleted with anti-CD8 antibodies. IUI was induced with lipopolysaccharide (LPS). DEP was confirmed using flow cytometry. Preterm birth rate was evaluated. Offspring neurologic sequelae were assessed by Nissl staining, immune arrays, confirmatory individual TaqMan gene assays, and neurobehavioral tests. DEP did not significantly prevent LPS-induced preterm birth but improved neurobehavioral performance (P < .001) and increased cortical neuronal density (P < .05) in LPS-exposed pups compared to controls. These changes were associated with decreased CCL3 and CXCL10 and increased CCL5 in DEP LPS-exposed mice. We demonstrate that DEP reduces perinatal brain injury following IUI. This supports a role for maternal CD8 T-cell trafficking in placenta in mediating perinatal brain injury separate from preterm birth mechanisms.

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