Propensity score matching comparisons of postoperative complications and morbidity between digestive tract reconstruction methods after gastrectomy in gastric cancer patients with visceral obesity.

Background: Few studies have compared the prognosis of different reconstruction methods after gastrectomy for gastric cancer (GC) patients with obesity. The aim of the present study was to compare postoperative complications and overall survival (OS) between the following reconstruction methods: Billroth I (B-I), Billroth II (B-II), and Roux-en-Y (R-Y) after gastrectomy for GC patients with visceral obesity (VO). Methods: We performed a double-institutional dataset study of 578 patients who underwent radical gastrectomy with B-I, B-II, and R-Y reconstructions between 2014 and 2016. VO was defined as a visceral fat area at the level of the umbilicus greater than 100 cm2. Propensity score-matching analysis was performed to balance the significant variables. Postoperative complications and OS were compared between the techniques. Results: VO was determined in 245 patients, of which 95, 36, and 114 underwent B-I, B-II, and R-Y reconstructions, respectively. B-II and R-Y were fused into the Non-B-I group due to the similar incidence of overall postoperative complications and OS. Therefore, 108 patients were enrolled after matching. The overall postoperative complications incidence and overall operative time in the B-I group were significantly lower than those in the non-B-I group. Further, multivariable analysis showed that B-I reconstruction was an independent protective factor for overall postoperative complications (odds ratio (OR) 0.366, P=0.017). However, no statistical difference in OS was found between the two groups (hazard ratio (HR) 0.644, P=0.216). Conclusions: B-I reconstruction was associated with decreased overall postoperative complications, rather than OS, in GC patients with VO who underwent gastrectomy.

Photo-Fenton Process over an Fe-Free 3%-CuO/Sr0.76Ce0.16WO4 Photocatalyst under Simulated Sunlight.

Photo-Fenton is a promising photocatalytic technology that utilizes sunlight. Herein, an Fe-free 3%-CuO/Sr0.76Ce0.16WO4 photocatalyst was synthesized to apply simulated wastewater degradation via a photo-Fenton process under simulated sunlight. The photodegradation efficiency of RhB solution over the 3%-CuO/Sr0.76Ce0.16WO4 photocatalyst is 93.2% in the first 3 h; its photocatalytic efficiency remains at 91.6% even after three cycle experiments. The kinetic constant of the 3%-CuO/Sr0.76Ce0.16WO4 photocatalyst is 0.0127 min-1, which is 2.8-fold that of an intrinsic Sr0.76Ce0.16WO4 sample. The experiment of radical quenching revealed that the photogenerated electrons and holes are transferred to CuO to form hydroxyl radicals. Besides, the photocatalyst was characterized by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), diffused reflectance spectroscopy (DRS), and X-ray photoelectron spectroscopy (XPS) measurements. It has some reference significance for the design of iron-free photocatalysts.

Novel Disassembly Mechanisms of Sigmoid Aß42 Protofibrils by Introduced Neutral and Charged Drug Molecules.

Alzheimer's disease (AD) is characterized by fibrillar deposits of amyloid-ß (Aß) peptides and neurofibrillary tangles of Tau proteins. Aß peptides are composed of 37-49 residues, among which the Aß42 isoform is particularly toxic and aggregation-prone and is enriched in the plaques of AD brains and thus considered central to the development of AD. Therefore, disaggregation and disruption provide potential therapeutic approaches to reduce, inhibit, and even reverse Aß aggregation. Here we capture the atomic-level details of the interactions between sigmoid Aß42 fibril 2MXU or 5KK3 and either natural tanshinone compounds TS1 or TS0 or negatively charged ER, proposing two unprecedented disassembly mechanisms. Natural TS1 or TS0 prefers to insert into the cavity together with part at the surface of the 2MXU to open up the mouth and twist the conformation, destroying the ordered growth of subsequent monomers along the fibril axis. For the more compact two-fold 5KK3 , attachment of TS1 or TS0 at the surface including some inserted in cavity results in the separation of the two folds. In the two sigmoid fibril systems, it is no longer applicable for the routine criteria to assess Aß42 fibril disassembly by introduction of these drugs, such as either reduced H-bond number, decreased ß-sheet contents, or both. ER, like-charged to Aß42 fibril, is especially exceptional, and departs utterly from the neutral ones to disassemble Aß42 fibril. Besides the inapplicable routine criteria, positive binding energy between ER and Aß42 fibril also deviates from the hypotheses of "ligands exhibiting greater affinity for the ß-amyloid peptide are effective at altering its aggregation and inhibiting cell toxicity" ( Cairo et al. , Biochemistry 2002 , 41 , 8620 - 8629 ) but results in stronger disassembly effect on the two kinds of sigmoid Aß42 fibrils than neutral TS0 or TS1. The disassembly power of charged ER molecules derives from its stronger deformation ability to the conformation of Aß42 fibril than the neutral ones, twisting the one-fold 2MXU into tapered-shape and separating two-fold 5KK3 in two parts further, which is in great agreement with experimental observations ( Irwin et al. Biomacromolecules 2013 , 14 ( 1 ), 264 - 274 ). The unusual disassembly mechanisms fill the gaps and offer an alternative direction in engineering new inhibitors to treat AD.

An Original Monomer Sampling from a Ready-Made Aß42 NMR Fibril Suggests a Turn-ß-Strand Synergetic Seeding Mechanism.

Aggregation of amyloid beta (Aß) is a central step of Alzheimer's disease. Aß42 monomers are building blocks in the formation of both "on pathway" intermediate structures and "off pathway" oligomers. How to sample an Aß monomer becomes a problem however due to the instinct of Aß high flexibility and diversity as well as aggregation propensity. Currently, (1) most samplings focus on either the ready-made helix-rich 1Z0Q/1IYT NMR structure, or the completely extended conformation, but (2) few on a ready-made Aß NMR fibril (i. e., 2BEG). Here we compare the simulation results from sampling in scheme (1) with that in scheme (2), and find that the coil and ß-sheet contents in the 1Z0Q-sampled system are comparable to the counterparts in the 2BEG-sampled system, but with a large difference in simulation time and dynamics character. 1Z0Q-sampled system not only takes several times longer than the 2BEG-sampled one, and only ß1-seeding dynamics characteristic is observed probably due to far insufficient conformation transition in the limited simulation time. Two dynamics characteristics of Aß42 folding observed experimentally, that either ß1 region or ß2 region aggregates first, reproduce in the present simulations for 2BEG-sampled system however, suggesting a preferential sampling in the future simulation. In addition, a turn-ß-strand synergetic seeding mechanism of aggregation is first proposed based on the trajectory analyses on the four regions of Aß42 chain.

Tautomerization Effect of Histidines on Oligomer Aggregation of ß-Amyloid(1-40/42) during the Early Stage: Tautomerism Hypothesis for Misfolding Protein Aggregation.

As the intrinsic origin of the hypothesis for ß-amyloid (Aß) from Alzheimer's disease, histidine behaviors were found to play a crucial role in Aß aggregation. To investigate the histidine behaviors during the early stage of aggregation, Aß40/42 pentamers with different histidine isomer states were simulated at the atomic level. Results show that five Aß40 (δδδ) and Aß42 (εδδ) monomers can rapidly decrease the aggregation threshold, promote stable pentamer formation, and increase pentamer contents by 51.8% and 56.7%, respectively, as compared with the values of their wild-type (εεε) counterparts. Additionally, pentamers of Aß40 (δδδ) and Aß42 (εδδ) have different aggregation pathways and disassembly species, Tr+D and Te+M, during the growth of the pentamer. This work discloses the significance of histidine tautomerization in Aß aggregation, implying a potential way to control Aß aggregation and develop the assembly inhibitors.

Positive effect of strong acidity on the twist of Aß42 fibrils and the counteraction of Aß42 N-terminus.

pH is a crucial factor in terms of affecting the aggregation and morphology of ß-Amyloid and hence a focus of study. In this study, structural and mechanical properties of a series of models (5, 6, …, 30 layer) of one-fold Aß42 fibrils at pH 1.5, 3.0 and 7.5, have been computed by using all-atom molecular dynamics simulations. 12, 14, and 15 layers are established to be the smallest realistic models for Aß42 fibrils at pH 1.5, 3.0 and 7.5, with twist angles of 0.40°, 0.34°, 0.31° respectively, disclosing the favorable effect of strong acidity on fibril twist. However, these angles are all lower than that (0.48°) determined for the truncated Aß17-42 fibril at pH 7.5, indicating that the disordered N-terminal depresses greatly the fibril twist and the lower pH disfavors the depression. Three commonly used indices to measure the fibril properties, namely number of H-bonds, interstrand distance and ß-sheet content have imperceptible changes with the pH alternation, therefore changes in fibril twist can be taken as a probe to monitor fibril properties. By contrast, N-terminus is determined not only to inhibit the U-shaped fibril twist by hampering the stagger between ß1 and ß2 strands, but also to play a vital carrier role in feeling solution (i.e., pH, salt) changes. These results can help design the nextgeneration of amyloid materials for state-of-the-art bio-nano-med applications by changing the solution pH or modifying chain length.

Toll-Like Receptor 4 Knockdown Attenuates Brain Damage and Neuroinflammation After Traumatic Brain Injury via Inhibiting Neuronal Autophagy and Astrocyte Activation.

Toll-like receptor 4 (TLR4) has been linked to various pathophysiological conditions, such as traumatic brain injury (TBI). It is reported that posttraumatic neuroinflammation is an essential event in the progression of brain injury after TBI. Recent evidences indicate that TLR4 mediates glial phagocytic activity and inflammatory cytokines production. Thus, TLR4 may be an important therapeutic target for neuroinflammatory injury post-TBI. This study was designed to explore potential effects and underlying mechanisms of TLR4 in rats suffered from TBI. TBI model was induced using a controlled cortical impact in rats, and application of TLR4 shRNA silenced TLR4 expression in brain prior to TBI induction. Elevated TLR4 was specifically observed in the hippocampal astrocytes and neurons posttrauma. Interestingly, TLR4 shRNA decreased the concentrations of interleukin (IL)-1ß, IL-6, and tissue necrosis factor-α; alleviated hippocampal neuronal damage; reduced brain edema formation; and improved neurological deficits after TBI. Meanwhile, to further explore underlying molecular mechanisms of this neuroprotective effects of TLR4 knockdown, our results showed that TLR4 knockdown significantly inhibited the upregulation of autophagy-associated proteins caused by TBI. More importantly, an autophagy inducer, rapamycin pretreated, could partially abolish neuroprotective effects of TLR4 knockdown on TBI rats. Furthermore, TLR4 silencing markedly suppressed GFAP upregulation and improved cell hypertrophy to attenuate TBI-induced astrocyte activation. Taken together, these findings suggested that TLR4 knockdown ameliorated neuroinflammatory response and brain injury after TBI through suppressing autophagy induction and astrocyte activation.