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Due to slow flow rates and inter-substance reactions in groundwater, remediation requires the addition of materials with sustained release properties. This research uses agricultural waste and zero-valent iron (Fe 0 ), coupling biology and chemistry, to research and develop a sustainable long-release carbon material with a synergistic physico-habitat, and to evaluate its performance, also taking into account the occurrence of nitrogen in groundwater. The material developed has a double-layer structure with an inner core and an outer shell. The core, consisting of agricultural waste, Fe 0 , and other raw materials, constitutes the repair layer. Agricultural waste provides a carbon source for microorganisms, and Fe 0 can quickly remove nitrate via chemical reactions and reduce DO to develop an anaerobic environment in water. The shell provides a solute permeation layer and consists of primary minerals and other components. This can slow the release of TOC from the core and adsorb secondary contaminants. Physical properties testing showed that the materials core was uniformly cross-linked, and its shell exhibited a clear uniform pore structure (SEM). Favorable mechanical compression was recorded for particle strengths of up to 80-105 N. With a density of 1.1 g·cm -3 , the material did not float in water. Experiments showed that the material had excellent sustained release. The amount[Max:21-25 mg·(g·L) -1 ] and rate[Max:0.185 mg·(g·L·d) -1 ] of TOC release exhibited a steady state trend, but fluctuated greatly in the case of agricultural wastes[(Max amount:53-75 mg·(g·L) -1 , Max rate:0.455 mg·(g·L·d) -1 ]. In terms of further functional gene abundance, materials leachate was found to be conducive to denitrifying bacteria. In early denitrification and oxygen trapping experiments, the Fe 0 chemical reaction was dominant for reduction of nitrogen and DO, facilitating denitrification. However, biological denitrification gradually dominated. Differences in denitrification rates between iron-free and iron-containing materials were smaller, as was the correlation between denitrification rate and iron content. These results indicate the formation of physico-habitat synergistic denitrification in the materials system.

A potent, noncytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This noncytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning from Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition, and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH-IMP-inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi-pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time-kill experiments in vitro suggest that sustained exposure to drug concentrations above the minimum inhibitory concentration (MIC) for 24 h were required for a cidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis-infected animals and patients revealed 0.5-2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate-dependent effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB.

Background: This study was to evaluate the subclinical left-ventricular (LV) systolic dysfunction with 2-dimensional speckle-tracking echocardiography in subjects with obstructive sleep apnea (OSA) with normal left ventricular ejection fraction and without any confounding disease that can cause myocardial dysfunction., Methods: Nineteen healthy individuals and 60 subjects with OSA were included in this study. According to the severity of disease, OSA subjects were examined in 3 groups: mild, moderate, and severe OSA. LV apical views (for longitudinal strain) and short-axis views (for circumferential strain) were acquired for evaluation. Three-layer longitudinal strain values and circumferential strain values were determined for each view, and averages of these were used in comparison with other groups., Results: Three-layer longitudinal strain values of the subjects with OSA were lower than those of the healthy individuals, and these values were decreased along with the OSA severity. The difference was significant between severe OSA and all other groups. Three-layer circumferential strain values of the OSA subjects were lower than those of the healthy individuals, and the difference was significant between the control group and all other groups. The apnea hypopnea index was found to be correlated with the 3-layer longitudinal strain (r = -0.74, P < .001; r = -0.72, P < .001; r = -0.69, P = <.001)., Conclusions: Three-layer longitudinal and circumferential LV systolic functions in OSA subjects with normal left ventricular ejection fraction are deteriorated in the subclinical stage. Two-dimensional speckle-tracking echocardiography can be used as an effective method in the determination of subclinical myocardial dysfunction in subjects with OSA., (Copyright © 2016 by Daedalus Enterprises.)

Objective: To investigate the effect of co-expression of bone morphogenetic protein 2 (BMP2) and Sox9 on chondrogenic differentiation of mesenchymal stem cells (MSCs) in vitro and provide experimental evidence for tissue engineering of cartilage., Methods: Mouse embryonic bone marrow MSC C3H10T1/2 cells were infected with recombinant adenovirus expressing BMP2, Sox9 and green fluorescent protein (GFP) for 3-14 days, with cells infected with the adenovirus carrying GFP gene as the control. The mRNA expression of the markers of chondrogenic differentiation, including collagen type II (Col2a1), aggrecan (ACAN), and collagen type X (Col10a1), were determined by real-time PCR. Alcian blue staining was used for quantitative analysis of sulfated glycosaminoglycan in the cellular matrix. The expression of Col2a1 protein was assayed by immunohistochemical staining and Western blot analysis., Results: Adenovirus-mediated BMP2 expression induced chondrogenic differentiation of C3H10T1/2 cells. Overexpression of Sox9 effectively enhanced BMP2-induced expression of the chondrogenic markers Col2a1, aggrecan and Col10a1 mRNAs, and promoted the synthesis of sulfated glycosaminoglycan and Col2a1 protein in C3H10T1/2 cells., Conclusion: Co-expression of BMP2 and Sox9 can promote chondrogenic differentiation of MSCs in vitro, which provides a new strategy for tissue engineering of cartilage.

Aim: To assess the efficacy and safety of combination therapy based on S-1, a novel oral fluoropyrimidine, vs S-1 monotherapy in advanced gastric cancer (AGC)., Methods: We searched PubMed, EMBASE and the Cochrane Library for eligible studies published before March 2013. Our analysis identified four randomized controlled trials involving 790 participants with AGC. The outcome measures were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and grade 3-4 adverse events., Results: Meta-analysis showed that S-1-based combination therapy significantly improved OS (HR = 0.77, 95%CI: 0.66-0.91, P = 0.002), PFS (HR = 0.58, 95%CI: 0.46-0.72, P = 0.000) and ORR (OR = 2.23, 95%CI: 1.54-3.21, P = 0.000). Sensitivity analysis further confirmed this association. Lower incidence of grade 3-4 leucopenia (OR = 4.06, 95%CI: 2.11-7.81), neutropenia (OR = 3.94, 95%CI: 2.1-7.81) and diarrhea (OR = 2.41, 95%CI: 1.31-4.44) was observed in patients with S-1 monotherapy., Conclusion: S-1-based combination therapy is superior to S-1 monotherapy in terms of OS, PFS and ORR. S-1 monotherapy is associated with less toxicity.

Landfills are usually located in unsaturated zones. Contaminant leaking can easily infiltrate groundwater through these porous media and contribute to groundwater pollution. The main objective of this work is to study the leachate migration in unsaturated porous media using X-ray computerized tomography (CT) and image-processing software. Silica sand and Yamazuna sand (collected from Japan) with different particle sizes are considered. Potassium iodide (KI) solution is used as a contaminant and injected into sand specimens at appropriate rates. The specimens are scanned at each cross section before and after contaminant injection by X-ray CT. Subsequently, all CT images are transformed into mean CT values by Image J software. VGStudio software is then used to reconstruct the subtracted images into three-dimensional images. The results indicate that vertical migration is dominant in uniform sand and horizontal migration is the main behavior in well-graded sand. Meanwhile, it is also confirmed that CT scanning is an effective technology to study contaminant migration in unsaturated porous media with different grain sizes.

Purpose: The purpose of this study is to investigate the effect of denture adhesive and oral wetting spray on the satisfaction of wearing complete denture in xerostomia patients., Methods: Ten edentulous patients who suffered from deficient residual alveolar ridge and xerostomia with poor retention and stability of complete dentures or mandibular complete dentures were employed to assess the differences of satisfaction after use of denture adhesive in their dry oral cavity for 1 week, and use of denture adhesive combined with oral wetting spray for 1 month, 3 months and 6 months by using satisfaction questionnaire. The statistical analysis was carried out with SPSS17.0 software package., Results: Six months after the use of denture adhesive combined with oral wetting spray, the satisfaction of complete denture was significantly improved in respects of general satisfaction, retention of mandible denture, comfort and mastication improvement than that before application (P<0.05). But 1 week after the use of denture adhesive alone, the satisfaction of comfort reduced than that before application (P<0.05)., Conclusions: Denture adhesive combined with oral wetting spray can be used to improve the satisfaction of xerostomia patients treated with complete denture who suffered from deficient residual alveolar ridge.

The EP(3) receptor on the platelet mediates prostaglandin E(2) potentiation of thrombogenic coagonists including collagen and adenosine diphosphate (ADP). A pharmacophore driven approach led to the identification of diverse peri-substituted heterocycles as potent and selective EP(3) receptor antagonists. A simultaneous chemical optimization and druglike assessment of prioritized molecules converged on a lead compound 50 (DG-041) that displayed favorable in vitro and functional activities as an inhibitor of human platelet aggregation. This agent is currently in human clinical trials for the treatment of atherothrombosis.

A series of potent and selective EP(3) receptor antagonists are described. Utilizing a pharmacophore model developed for the EP(3) receptor, a series of 3,4-disubstituted indoles were found to be efficient ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors. An optimized molecule 7c featured a sound profile and potency in the functional rat and human platelet aggregation assays.

Myocardial infarction and stroke are caused by blood clots forming over a ruptured or denuded atherosclerotic plaque (atherothrombosis). Production of prostaglandin E(2) (PGE(2)) by an inflamed plaque exacerbates atherothrombosis and may limit the effectiveness of current therapeutics. Platelets express multiple G-protein coupled receptors, including receptors for ADP and PGE(2). ADP can mobilize Ca(2+) and through the P(2)Y(12) receptor can inhibit cAMP production, causing platelet activation and aggregation. Clopidogrel (Plavix), a selective P(2)Y(12) antagonist, prevents platelets from clotting but thereby increases the risk of severe or fatal bleeding. The platelet EP(3) receptor for PGE(2), like the P(2)Y(12) receptor, also inhibits cAMP synthesis. However, unlike ADP, facilitation of platelet aggregation via the PGE(2)/EP(3) pathway is dependent on co-agonists that can mobilize Ca(2+). We used a ligand-based design strategy to develop peri-substituted bicylic acylsulfonamides as potent and selective EP(3) antagonists. We show that DG-041, a selective EP(3) antagonist, inhibits PGE(2) facilitation of platelet aggregation in vitro and ex vivo. PGE(2) can resensitize platelets to agonist even when the P(2)Y(12) receptor has been blocked by clopidogrel, and this can be inhibited by DG-041. Unlike clopidogrel, DG-041 does not affect bleeding time in rats, nor is bleeding time further increased when DG-041 is co-administered with clopidogrel. This indicates that EP(3) antagonists potentially have a superior safety profile compared to P(2)Y(12) antagonists and represent a novel class of antiplatelet agents.

A series of potent and selective EP(3) receptor antagonists are described. Utilizing a pharmacophore model developed for the EP(3) receptor, a series of 3,4-disubstituted indoles were shown to be high affinity ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors and are potent antagonists in functional assays.

A new class of inhibitors for cysteine proteases cathepsin B, L, K and S is described. These inhibitors are based on the beta-lactam ring designed to interact with the nucleophilic thiol of the cysteine in the active site of cysteine proteases. Some 3-acylamino-azetidin-2-one derivatives showed very potent inhibition activities for cathepsins L, K and S at the nanomolar or subnanomolar IC(50) values.

The synthesis of a new series of 6-acylamino penam derivatives and their inhibition of cysteine proteases cathepsins B, L, K, and S is described. The 6-acylamino-penam sulfone compounds showed excellent cathepsin L, K, and S inhibition activity with IC(50) values in the nanomolar and subnanomolar range.

A series of 6-substituted amino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one compounds was designed and synthesized as a new class of inhibitors for cysteine proteases cathepsins B, L, K, and S. One compound (5S,6S)-6-(N-benzyloxycarbonyl-L-phenylalanyl) amino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one showed excellent cathepsin L and K inhibition activity with IC(50) at a low nanomolar range.