Clearing amyloid through the blood-brain barrier

According to the amyloid hypothesis, accumulation of amyloid beta-peptide (A beta) in the brain is the primary pathogenic event in Alzheimer's disease (AD). Recent evidence indicates that A beta within the intravascular space is linked to A beta deposited in the brain suggesting that transport of A beta between the brain, blood and cerebrospinal fluid, and across the blood-brain barrier, regulates brain A beta. Thus, understanding A beta exchanges between brain and blood, and vice versa, and developing transport-based systemic A beta-lowering strategies may provide new important insights into pathogenesis and therapeutic control of AD.     

Ecotoxicological impacts of exposure to copper oxide nanoparticles on the gill of the Swan mussel,Anodonta cygnea (Linnaeus, 1758)

This study was conducted to investigate the ecotoxicological effects of exposure to copper oxide nanoparticles (CuO NPs) on the gill of the swan mussel Anodonta cygnea using several approaches including qualitative and quantitative histopathology, ultra-morphology (scanning electron microscopy [SEM]) and measures of clearance rate (CR) and bioaccumulation of CuO NPs. Histological alterations in mussels exposed to 0.25 (T1), 2.5 (T2) and 25.0?µg L^?1 (T3) CuO NPs for 12 days include changes in the length and form of gill lamellae, changes in inter-lamellar spaces, epithelial hyperplasia, atrophy and tissue rupture. Ultra-morphological changes following CuO NP exposure included epithelial hyperplasia and hypertrophy, epithelial lifting, tissue rupture (water channel fusion) and extensive necrosis of the gill surfaces. I_Gill (gill damage severity) index values for both histopathological and ultra-morphological data were significantly (P?0.05) higher in T3. The CR of mussels was significantly (P??1 g^?1 dry weight]) in comparison to controls (CR?=?108?±?47.14 [L min^?1 g^?1 dry weight]). CuO NPs accumulated in exposed mussels at all exposure concentrations until day 4, but there was no further change in accumulation levels by the end of the exposure period. The accumulated content of CuO NPs was significantly (P??1 exposure concentration. Based on these results, significant accumulation of CuO NPs in the gills of swan mussel could affect histological and ultra-structural characteristics of this organ and consequently have deleterious impacts on its filtration activity.     

SHA.LIN评分和S.T.O.N.E评分对经皮肾镜取石术结石清除率的预测价值比较

目的:比较SHA.LIN评分和S.T.O.N.E评分对经皮肾镜取石术结石清除率的预测价值。方法:选择我院于2016年1月-2017年12月期间行经皮肾镜取石术患者67例为研究对象,在术前对所有患者进行SHA.LIN评分和S.T.O.N.E评分。根据手术结果将患者分为结石清除组(n=49)和结石残留组(n=18),对两组患者的一般资料、SHA.LIN评分、S.T.O.N.E评分进行统计对比。采用多因素Logistic回归分析方法分析患者术后结石残留的影响因素。采用绘制ROC曲线的方法分析SHA.LIN评分和S.T.O.N.E评分对结石清除率的预测结果的敏感性和特异性。结果:67例患者术后结石清除者49例、结石残留者18例,结石清除率为73.13%。结石残留组患者手术时间、术中失血量、住院时间、结石最大截面积、最大累积截面积、结石解剖分布肾盂的发生率、受累肾盏数均高于结石清除组,穿刺通道长度低于结石清除组(P0.05)。结石清除组患者的SHA.LIN评分、S.T.O.N.E评分均低于结石残留组(P0.05)。经多因素Logistic回归分析显示,手术时间、术中失血量、SHA.LIN评分、S.T.O.N.E评分、受累肾盏数是结石残留的影响因素(P0.05)。通过绘制ROC曲线可知,SHA.LIN评分的敏感性为91.25%、特异性为89.12%、曲线下面积(AUC)为0.912(95%CI 0.869~0.948);S.T.O.N.E评分的敏感性为78.75%、特异性为84.24%、AUC为0.782(95%CI 0.690~0.871)。结论:经皮肾镜取石术患者结石清除率与SHA.LIN评分、S.T.O.N.E评分明显相关,两种评分系统均能预测患者的结石清除率,但SHA.LIN评分的敏感性、特异性高于S.T.O.N.E评分。     

Discovery of 1-(4-((3-(4-methylpiperazin-1-yl)propyl)amino)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one,an orally active multi-target agent for the treatment of diabetic nephropathy

Oxidative stress, inflammation and fibrosis can cause irreversible damage on cell structure and function of kidney and are key pathological factors in Diabetic Nephropathy (DN). Therefore, multi-target agents are urgently need for the clinical treatment of DN. Using Pirfenidone as a lead compound and based on the previous research, two novel series (5-trifluoromethyl)-2(1H)-pyridone analogs were designed and synthesized. SAR of (5-trifluoromethyl)-2(1H)-pyridone derivatives containing nitrogen heterocyclic ring have been established for in vitro potency. In addition, compound 8, a novel agent that act on multiple targets of anti-DN with IC₅₀ of 90 μM in NIH3T3 cell lines, t_1/2 of 4.89 ± 1.33 h in male rats and LD₅₀ > 2000 mg/kg in mice, has been advanced to preclinical studies as an oral treatment for DN.     

Establishing in vitro in vivo correlations to screen monoclonal antibodies for physicochemical properties related to favorable human pharmacokinetics

Implementation of in vitro assays that correlate with in vivo human pharmacokinetics (PK) would provide desirable preclinical tools for the early selection of therapeutic monoclonal antibody (mAb) candidates with minimal non-target-related PK risk. Use of these tools minimizes the likelihood that mAbs with unfavorable PK would be advanced into costly preclinical and clinical development. In total, 42 mAbs varying in isotype and soluble versus membrane targets were tested in in vitro and in vivo studies. MAb physicochemical properties were assessed by measuring non-specific interactions (DNA- and insulin-binding ELISA), self-association (affinity-capture self-interaction nanoparticle spectroscopy) and binding to matrix-immobilized human FcRn (surface plasmon resonance and column chromatography). The range of scores obtained from each in vitro assay trended well with in vivo clearance (CL) using both human FcRn transgenic (Tg32) mouse allometrically projected human CL and observed human CL, where mAbs with high in vitro scores resulted in rapid CL in vivo. Establishing a threshold value for mAb CL in human of 0.32 mL/hr/kg enabled refinement of thresholds for each in vitro assay parameter, and using a combinatorial triage approach enabled the successful differentiation of mAbs at high risk for rapid CL (unfavorable PK) from those with low risk (favorable PK), which allowed mAbs requiring further characterization to be identified. Correlating in vitro parameters with in vivo human CL resulted in a set of in vitro tools for use in early testing that would enable selection of mAbs with the greatest likelihood of success in the clinic, allowing costly late-stage failures related to an inadequate exposure profile, toxicity or lack of efficacy to be avoided.     

Defining the mechanistic binding of viral particles to a multi‐modal anion exchange resin

A multi‐tiered approach to determine the binding mechanism of viral clearance utilizing a multi‐modal anion exchange resin was applied to a panel of four viral species that are typically used in validating viral clearance studies (i.e., X‐MuLV, MVM, REO3, and PrV). First, virus spiked buffer‐only experiments were conducted to evaluate the virus's affinity for single mode and multi‐modal chromatography resins under different buffer conditions in a chromatography column setting. From these results we hypothesize that the mechanisms of binding of the viruses involve binding to both the hydrophobic and anionic functional groups. This mechanistic view agreed with the general surface characteristics of the different virus species in terms of isoelectric point and relative hydrophobicity values. This hypothesized mechanistic binding was then tested with commercially relevant, in‐process materials, in which competitive binding occurred between the load components (e.g., viruses, target product, and impurities) and the resin. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1019–1026, 2018     

不同林地清理方式对杉木人工林生态系统的影响

在杉木中心产区福建尤溪建立径流场,进行不同林地清理方式对杉木人工生态系统影响的６ａ定位研究结果表明：炼山清理迹地导致林地严重的水土流失,炼山后的６ａ中要地的水、土、肥人分别达８７６７．３２ｍ＾３／ｈｍ＾２、３８．００ｔ／ｈｍ＾２、５２３．１６ｋｇ／ｈｍ＾２,分别是不炼山林地的３．１０、１９．７０、６．１０倍。两种清理方式林地流失量差异随时间推移逐年缩小,于第６年趋于一致,炼山具有短期激效效应,经雨     

Contribution of serum protein association to discrepancy between the in vivo and in vitro UDS results for 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-d]pyrimidine (U-89843)

U-89843 has been shown to undergo biotransformation, both in vitro and in vivo, to form U-97924 as a major primary metabolite. U-89843 was found to be positive in an in vitro UDS mutagenesis screen conducted with primary rat hepatocytes in serum-free media. In contrast to in vitro results, no evidence of genetic toxicity of U-89843 was observed in rats in the in vivo/in vitro version of the UDS test with single oral doses up to 1400 mg/kg. The negative results may be related to more robust in vivo detoxification mechanisms or relatively lower exposure to reactive metabolites formed by bioactivation of U-89843 as compared to that observed in the serum-free in vitro hepatocyte test system. Further studies showed rat serum suppressed the in vitro metabolism of U-89843 as well as the formation of the corresponding hydroxylated metabolite, U-97924, the putative precursor of proposed reactive electrophilic metabolite. The measured in vivo systemic clearance of U-89843 (0.53 l/h/kg) in rats was about 1000-fold slower than the in vitro intrinsic clearance (606 l/h/kg) estimated by measuring the formation of U-97924 in rat liver microsomal incubations. Since U-89843 is extensively associated with serum proteins a poor extraction ratio into the liver may account for the slower biotransformation of U-89843 in vivo as compared to that exhibited in in vitro serum-free hepatocyte incubations. Addition of bovine serum albumin (1–40 mg/ml) to the in vitro UDS assay medium decreased the UDS mean net grains per nucleus response of U-89843. These results suggest that the effect of serum protein should be considered when comparing serum-free in vitro UDS and in vivo UDS results for highly serum protein bound compounds.     

按(一级并行)米氏过程消除药物的稳态性质分析的数值解法

本文讨论消除符合（一级并行）米氏过程药物的多剂量周期性血管外或血管内给药稳态性质分析的数值解法。