Identification and evaluation of bioactive natural products as potential inhibitors of human microtubule affinity-regulating kinase 4 (MARK4)

Microtubule affinity-regulating kinase 4 (MARK4) has recently been identified as a potential drug target for several complex diseases including cancer, diabetes and neurodegenerative disorders. Inhibition of MARK4 activity is an appealing therapeutic option to treat such diseases. Here, we have performed structure-based virtual high-throughput screening of 100,000 naturally occurring compounds from ZINC database against MARK4 to find its potential inhibitors. The resulted hits were selected, based on the binding affinities, docking scores and selectivity. Further, binding energy calculation, Lipinski filtration and ADMET prediction were carried out to find safe and better hits against MARK4. Best 10 compounds bearing high specificity and binding efficiency were selected, and their binding pattern to MARK4 was analyzed in detail. Finally, 100 ns molecular dynamics simulation was performed to evaluate; the dynamics stability of MARK4-compound complex. In conclusion, these selected natural compounds from ZINC database might be potential leads against MARK4, and can further be exploited in drug design and development for associated diseases.     

Reporting of Quantitative Protein Electrophoresis in Australia and New Zealand: a Call for Standardisation

Background

The lack of guidelines on reporting standards for protein electrophoresis may have led to significant differences in reports from different laboratories.

Objective

To determine the extent of variation in reporting of protein electrophoresis results in Australia and New Zealand.

Method

Questionnaires were distributed to laboratories throughout Australia and New Zealand asking about protein electrophoresis practices and reporting.

Results

Extensive variation was found in the following reporting practices: (a) units for urine Bence Jones protein (BJP); (b) reporting absence of a paraprotein rather than a normal pattern; (c) numerical reporting of all protein fractions or only the paraprotein; (d) warning of possible inaccuracy in the serum immunoglobulin result of the paraprotein type; (e) co-migration of a paraprotein with a normal serum protein; (f) use of a confirmatory test when a known paraprotein is no longer detectable.

Conclusions

A working party should be established to make recommendations on the reporting of protein electrophoresis. Implementation of such recommendations should reduce both report variation between laboratories and the risk of misinterpretation of reports.     

Diet-induced obesity in rats leads to a decrease in sperm motility

Background  

Obesity is rapidly becoming a worldwide epidemic that affects children and adults. Some studies have shown a relationship between obesity and infertility, but until now it remains controversial. Thus, the aim of the present study was to investigate the effect of high-fat diet-induced obesity on male reproductive parameters.     

长爪沙鼠ATPase8,ATPase6,COX3基因的克隆及序列分析

目的对长爪沙鼠线粒体ATPase8,ATPase6,COX3基因全序列进行测定,并对其进行鉴定及进化分析。方法根据长爪沙鼠已知基因序列设计引物,采用PCR产物测序法,对目的片段进行测序鉴定。结合已公布啮齿类动物ATPase8,ATPase6,COX3基因序列,分析其碱基组成、遗传距离、并基于最小进化法和UPGMA法构建系统进化树。结果获得长爪沙鼠线粒体ATPase8,ATPase6,COX3基因全序列,其与家鼠、小家鼠和仓鼠均具有较高的同源性（76～98%）;进化分析结果显示,长爪沙鼠与家鼠、黑家鼠和仓鼠遗传距离较近;碱基G的含量分别为6.9%,10.7%,15.2%,符合mtDNA的特点;A＋T含量分别为68.2%,64.1%,59.2%,明显低于G＋C含量,符合哺乳动物的特点。结论本研究为首次获得长爪沙鼠ATPase8,ATPase6,COX3基因全序列,长爪沙鼠与家鼠、黑家鼠和仓鼠具有较近遗传距离,本研究为长爪沙鼠进化研究、线粒体的结构和功能研究奠定基础。     

Dkk1 Stabilizes Wnt Co-Receptor LRP6: Implication for Wnt Ligand-Induced LRP6 Down-Regulation

Background

The low density lipoprotein receptor-related protein-6 (LRP6) is an essential co-receptor for canonical Wnt signaling. Dickkopf 1 (Dkk1), a major secreted Wnt signaling antagonist, binds to LRP6 with high affinity and prevents the Frizzled-Wnt-LRP6 complex formation in response to Wnts. Previous studies have demonstrated that Dkk1 promotes LRP6 internalization and degradation when it forms a ternary complex with the cell surface receptor Kremen.

Methodology/Principal Findings

In the present study, we found that transfected Dkk1 induces LRP6 accumulation while inhibiting Wnt/LRP6 signaling. Treatment with Dkk1-conditioned medium or recombinant Dkk1 protein stabilized LRP6 with a prolonged half-life and induces LRP6 accumulation both at the cell surface and in endosomes. We also demonstrated that Kremen2 co-expression abrogated the effect of Dkk1 on LRP6 accumulation, indicating that the effect of Kremen2 is dominant over Dkk1 regulation of LRP6. Furthermore, we found that Wnt3A treatment induces LRP6 down-regulation, an effect paralleled with a Wnt/LRP6 signaling decay, and that Dkk1 treatment blocked Wnt3A-induced LRP6 down-regulation. Finally, we found that LRP6 turnover was blocked by an inhibitor of caveolae-mediated endocytosis.

Conclusions/Significance

Our results reveal a novel role for Dkk1 in preventing Wnt ligand-induced LRP6 down-regulation and contribute significantly to our understanding of Dkk1 function in Wnt/LRP6 signaling.     

黑线毛足鼠年龄和种群密度与肝毛细线虫感染率的关系

2004—2005年,在内蒙古锡林郭勒盟阿巴嘎旗和东乌珠穆沁旗研究了肝毛细线虫病对黑线毛足鼠种群感染情况,分析肝毛细线虫对黑线毛足鼠的感染率与鼠体年龄以及种群密度的关系。结果表明,黑线毛足鼠达到一定的年龄(或体质量)才可感染肝毛细线虫病,最低感染个体体质量为14.6g。肝毛细线虫对低龄鼠的感染检出率比较低,而对成体鼠感染检出率较高,其感染率和感染度均随着个体年龄的增长而增高(感染率与年龄:r=0.97,P<0.05;感染度与年龄:r=0.93,P<0.05)。此外,黑线毛足鼠体质量与肝毛细线虫感染率和感染度也存在显著的相关关系(感染率与体质量:r=0.99,P<0.05;感染度与体质量:r=0.95,P<0.05),黑线毛足鼠的种群密度则对肝毛细线虫的感染率(r=0.27,P>0.05)和平均感染度(r=0.41,P>0.05)没有明显的影响,其感染率可能与地区不同有关。     

Process development for the synthesis of 5'-O-(4,4'-dimethoxytrityl)-N2-isobutyryl-2'-O-(2-methoxyethyl)-guanosine--a potential precursor for the second generation antisense oligonucleotides: an improved process for the preparation of 2'-O-alkyl-2,6-diaminopurine riboside

An efficient four step process for the preparation of 5'-O-(4,4'-dimethoxytrityl)-N2-isobutyryl-2'-O-(2-methoxyethyl)-guanosine 1 was developed. Direct 2'-O-alkylation of 2,6-diaminopurine riboside 2 was accomplished via inexpensive and commercially available reagents such as KOH, DMSO and alkyl halides at room temperature in 4-6 hrs. Pure 2'-O-(2-methoxyethyl)-DAPR 3 was isolated by crystallization from methanol. Enzymatic deamination of 3 followed by selective N2-isobutyrylation and 5'-O-dimethoxytritylation furnished desired 1 in high yield and purity. Fully optimized four step synthetic process has been scaled up to the pilot plant level.     

内蒙古大兴安岭森林可燃物燃烧释放PM2.5中水溶性离子排放特性

研究森林可燃物燃烧释放的细颗粒物(PM2.5)的排放因子对于揭示森林火灾对大气和生态系统的影响至关重要,而水溶性离子是细颗粒物的重要化学成分,对颗粒物的形成具有重要意义.利用自主设计的生物质燃烧系统,模拟内蒙古大兴安岭5种典型乔木(蒙古栎、白桦、兴安落叶松、黑桦、山杨)的3种组成部分(树干、树枝、树皮)及其地表死可燃物...