Tyrosine kinase 2 is not limiting human antiviral type III interferon responses

Tyrosine kinase 2 (TYK2) associates with interferon (IFN) alpha receptor, IL‐10 receptor (IL‐10R) beta and other cytokine receptor subunits for signal transduction, in response to various cytokines, including type‐I and type‐III IFNs, IL‐6, IL‐10, IL‐12 and IL‐23. Data on TYK2 dependence on cytokine responses and in vivo consequences of TYK2 deficiency are inconsistent. We investigated a TYK2 deficient patient, presenting with eczema, skin abscesses, respiratory infections and IgE levels >1000 U/mL, without viral or mycobacterial infections and a corresponding cellular model to analyze the role of TYK2 in type‐III IFN mediated responses and NK‐cell function. We established a novel simple diagnostic monocyte assay to show that the mutation completely abolishes the IFN‐α mediated antiviral response. It also partly reduces IL‐10 but not IL‐6 mediated signaling associated with reduced IL‐10Rβ expression. However, we found almost normal type‐III IFN signaling associated with minimal impairment of virus control in a TYK2 deficient human cell line. Contrary to observations in TYK2 deficient mice, NK‐cell phenotype and function, including IL‐12/IL‐18 mediated responses, were normal in the patient. Thus, preserved type‐III IFN responses and normal NK‐cell function may contribute to antiviral protection in TYK2 deficiency leading to a surprisingly mild human phenotype.     

Dual-targeting delivery system for bone cancer: synthesis and preliminary biological evaluation

Chemotherapy in treatment of malignant tumors has many side effects due to the poor physiochemical properties and the toxicity to normal tissues. The dual-targeting drug delivery system combining two high-affinity ligands can target anticancer drug primary to the diseased tissue, then to the tumor, which provides both greater efficacy of treatment and less harm to normal tissues. In this paper, a novel dual-targeting moiety RGD₇ (R-G-D-D-D-D-D-D-D; Nonapeptide for bone cancer combining D₆ peptide as bone target moiety and RGD peptide as tumors target moiety was contracted. A series of bone and/or tumor targeting conjugates have been synthesized in a convergent approach and well characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS) techniques. The hydroxyapatite (HAP) binding, water solubility, the drug release and the distribution in vivo were evaluated. All the conjugates were water-soluble and able to release the parent drugs in vitro. The bone-targeting property of the dual-targeting delivery system was enhanced from the results of the HAP binding and the distribution in vivo. The experiment for verifying tumor targeting property was underway. These results provided an effective entry to the development of a new dual-targeting delivery system for bone cancer.     

Emerging themes in GABAergic synapse development

Glutamatergic synapse development has been rigorously investigated for the past two decades at both the molecular and cell biological level yet a comparable intensity of investigation into the cellular and molecular mechanisms of GABAergic synapse development has been lacking until relatively recently. This review will provide a detailed overview of the current understanding of GABAergic synapse development with a particular emphasis on assembly of synaptic components, molecular mechanisms of synaptic development, and a subset of human disorders which manifest when GABAergic synapse development is disrupted. An unexpected and emerging theme from these studies is that glutamatergic and GABAergic synapse development share a number of overlapping molecular and cell biological mechanisms that will be emphasized in this review.     

Piecing together the puzzle of acetaldehyde as a neuroactive agent

Mainly known for its more famous parent compound, ethanol, acetaldehyde was first studied in the 1940s, but then research interest in this compound waned. However, in the last two decades, research on acetaldehyde has seen a revitalized and uninterrupted interest. Acetaldehyde, per se, and as a product of ethanol metabolism, is responsible for many pharmacological effects which are not clearly distinguishable from those of its parent compound, ethanol. Consequently, the most recent advances in acetaldehyde's psychopharmacology have been inspired by the experimental approach to test the hypothesis that some of the effects of ethanol are mediated by acetaldehyde and, in this regard, the characterization of metabolic pathways for ethanol and the localization within discrete brain regions of these effects have revitalized the interest on the role of acetaldehyde in ethanol's central effects. Here we present and discuss a wealth of experimental evidence that converges to suggest that acetaldehyde is an intrinsically active compound, is metabolically generated in the brain and, finally, mediates many of the psychopharmacological properties of ethanol.     

左氧氟沙星注射液两种给药方法治疗老年院内获得性肺炎的临床分析

目的比较左氧氟沙星注射液两种给药方法治疗老年病区院内获得性肺炎（HAP）的有效性与安全性。方法56例老年HAP患者随机分为2组，治疗组（n=28）用左氧氟沙星注射液0．5e,／次，1次／d；对照组（n=28）用注射用左氧氟沙星注射液0．3g，2次／d，疗程均为7。14d。结果治疗组和对照组的临床总有效率分剐为85．7％和82．1％，细菌清除率分别为80．8％和80．0％，两组不良反应发生率分别为14．3％和17．9％。结论左氧氟沙星注射液两种给药方法治疗老年HAP疗效确切、不良反应少而轻微，可作为治疗老年患者院内获得性肺炎的一线用药。     

纳米羟基磷灰石悬浮液稳定性能的研究

为了得到稳定分散的纳米羟基磷灰石水悬浮液,以羧甲基纤维素钠（CMCNa）作分散剂,采用吸光率实验考察了羧甲基纤维素钠的用量及超声分散时间对纳米羟基磷灰石水悬浮液稳定性的影响,并对其分散机理进行了初步的探讨。结果表明：CMCNa作分散剂时,能有效地分散纳米羟基磷灰石粒子,得到均匀、稳定的纳米羟基磷灰石水悬浮液体系;当CMCNa用量为0.35wt%、超声时间为150s时分散效果最佳;CMCNa分散后,体系的Zeta电位的绝对值提高了69.82mV;CMCNa对纳米HAP悬浮液的稳定分散作用主要是通过粒子间的静电作用和空间位阻来实现的。由此可见,CMCNa对HAP纳米粒子具有较好的分散效果,是制备高分散稳定HAP的理想分散剂。     

La chaîne alimentaire vecteur de Polluants Organiques Persistants

Human activities produce polluting compounds such as the Persistent Organic Pollutants group (POPs) which may interact with agriculture. These molecules raised concern about risk of transfer through the food chain via the animal product. The POPs are characterised by a strong persistence in the environment, a high volatility and a lipophilicity which lead to their accumulation in fat tissues. These compounds are enlisted in international conventions to organise the information about their potential toxicity for humans and the environment. The aim of this paper is to study transfer in the food chain of three groups of POPs: the dioxins-furans (PCDD/F), the polychlorobiphenyls (PCB) and the Polycyclic Aromatic Hydrocarbons (PAH). The results show that the contamination of fodder by these compounds is observed when they are exposed to emission sources compared to remote areas. They also show that a differential transfer of the molecules is detected towards biological matrices (milk).     

In vitro demineralization of tooth enamel subjected to two whitening regimens

BackgroundThe resistance of bleached enamel to demineralization has not been elucidated fully. In this study, the authors aimed to examine the level of in vitro demineralization of human tooth enamel after bleaching by using two common bleaching regimens: home bleaching (HB) and office bleaching (OB) with photoirradiation.MethodsThe authors bleached teeth to equivalent levels by means of the two bleaching regimens. They used fluorescence spectroscopy to measure the reduction in enamel density and the release of calcium into solution after storing the treated teeth in a demineralizing solution for two weeks. They also visualized and quantified mineral distribution in demineralized bleached enamel over time by using a desktop microcomputed-tomographic analyzer.ResultsEnamel subjected to HB or to photoirradiation without bleaching showed increased demineralization. In contrast, enamel treated with OB was more resistant to demineralization. This resistance to demineralization in teeth treated with OB presumably is due to peroxide's permeating to deeper layers of enamel before being activated by photoirradiation, which enhances mineralization.ConclusionsThe mineral distribution pattern of enamel after treatment plays a critical role in providing resistance to demineralization in whitened teeth.Practical ImplicationsOB confers to enamel significant resistance to in vitro demineralization. Dentists should supervise the nightguard HB process.     

Design,synthesis, and evaluation of novel heteroaryldihydropyrimidine derivatives as non‐nucleoside hepatitis B virus inhibitors by exploring the solvent‐exposed region

In continuation of our efforts toward the discovery of potent non‐nucleoside hepatitis B virus (HBV) inhibitors with novel structures, we have explored the solvent‐exposed protein region of heteroaryldihydropyrimidine derivatives. Herein, the morpholine ring of GLS4 was replaced with substituted sulfonamides and triazoles to generate novel non‐nucleoside HBV inhibitors with desirable potency. In in vitro biological evaluation, several derivatives showed good anti‐HBV DNA replication activity compared to lamivudine. In particular, compound II‐1 displayed the most potent activity against HBV DNA replication (IC₅₀ = 0.35 ± 0.04 μM). The preliminary structure–activity relationships of the new compounds were summarized, which may help in discovering more potent anti‐HBV agents via rational drug design.