云南省2006～2010年非脊灰肠道病毒分子流行病学特征分析

为了解云南省非脊髓灰质炎(脊灰)肠道病毒(NPEV)的基因型分布及分子进化特征,对2006～2010年间从急性迟缓性麻痹(AFP)病例中分离到的105株NPEVs进行VP1区部分核苷酸扩增和序列测定。所获得的云南地方株基因序列与各基因型原型株进行核苷酸与氨基酸同源性比较,并与GenBank中选取的代表株构建基因进化关系树。结果分析显示:105株NPEVs分别属于HEV-A、HEV-B、HEV-C,其中HEV-A 18株(7个血清型)所占比例为17.1%;HEV-B 77株(22个血清型)所占比例为73.3%,表明云南省AFP病例中流行的NPEV还是以HEV-B为主;HEV-C 10株(4个血清型)所占比例为9.5%;没有分离到HEV-D组肠道病毒;基因进化树中各种血清型病毒与对应原型株及代表株聚集一起,除CA2、EV90和EV76外,云南地方株与原型株位于不同分支。相同型别的毒株在5年的流行过程中变异程度亦不同,亲缘关系远近不一,表明这些病毒在云南省存在不同的传播链。     

Cationic membrane peptides: atomic-level insight of structure–activity relationships from solid-state NMR

Many membrane-active peptides, such as cationic cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs), conduct their biological functions by interacting with the cell membrane. The interactions of charged residues with lipids and water facilitate membrane insertion, translocation or disruption of these highly hydrophobic species. In this review, we will summarize high-resolution structural and dynamic findings towards the understanding of the structure–activity relationship of lipid membrane-bound CPPs and AMPs, as examples of the current development of solid-state NMR (SSNMR) techniques for studying membrane peptides. We will present the most recent atomic-resolution structure of the guanidinium-phosphate complex, as constrained from experimentally measured site-specific distances. These SSNMR results will be valuable specifically for understanding the intracellular translocation pathway of CPPs and antimicrobial mechanism of AMPs, and more generally broaden our insight into how cationic macromolecules interact with and cross the lipid membrane.     

Proteomic analysis of kidney and protective effects of grape seed procyanidin B2 in db/db mice indicate MFG-E8 as a key molecule in the development of diabetic nephropathy

Diabetic nephropathy, as a severe microvascular complication of diabetic mellitus, has become the leading cause of end-stage renal diseases. However, no effective therapeutic strategy has been developed to prevent renal damage progression to end stage renal disease. Hence, the present study evaluated the protective effects of grape seed procyanidin B2 (GSPB2) and explored its molecular targets underlying diabetic nephropathy by a comprehensive quantitative proteomic analysis in db/db mice. Here, we found that oral administration of GSPB2 significantly attenuated the renal dysfunction and pathological changes in db/db mice. Proteome analysis by isobaric tags for relative and absolute quantification (iTRAQ) identified 53 down-regulated and 60 up-regulated proteins after treatment with GSPB2 in db/db mice. Western blot analysis confirmed that milk fat globule EGF-8 (MFG-E8) was significantly up-regulated in diabetic kidney. MFG-E8 silencing by transfection of MFG-E8 shRNA improved renal histological lesions by inhibiting phosphorylation of extracellular signal-regulated kinase1/2 (ERK1?2), Akt and glycogen synthase kinase-3beta (GSK-3β) in kidneys of db/db mice. In contrast, over-expression of MFG-E8 by injection of recombinant MFG-E8 resulted in the opposite effects. GSPB2 treatment significantly decreased protein levels of MFG-E8, phospho-ERK1/2, phospho-Akt, and phospho-GSK-3β in the kidneys of db/db mice. These findings yield insights into the pathogenesis of diabetic nephropathy, revealing MFG-E8 as a new therapeutic target and indicating GSPB2 as a prospective therapy by down-regulation of MFG-E8, along with ERK1/2, Akt and GSK-3β signaling pathway.     

AEBP1 upregulation confers acquired resistance to BRAF (V600E) inhibition in melanoma

An activating BRAF (V600E) kinase mutation occurs in approximately half of melanomas. Recent clinical studies have demonstrated that vemurafenib (PLX4032) and dabrafenib, potent and selective inhibitors of mutant v-raf murine sarcoma viral oncogene homolog B1 (BRAF), exhibit remarkable activities in patients with V600 BRAF mutant melanomas. However, acquired drug resistance invariably develops after the initial treatment. Identification of acquired resistance mechanisms may inform the development of new therapies that elicit long-term responses of melanomas to BRAF inhibitors. Here we report that increased expression of AEBP1 (adipocyte enhancer-binding protein 1) confers acquired resistance to BRAF inhibition in melanoma. AEBP1 is shown to be highly upregulated in PLX4032-resistant melanoma cells because of the hyperactivation of the PI3K/Akt-cAMP response element-binding protein (CREB) signaling pathway. This upregulates AEBP1 expression and thus leads to the activation of NF-κB via accelerating IκBa degradation. In addition, inhibition of the PI3K/Akt-CREB-AEBP1-NF-κB pathway greatly reverses the PLX4032-resistant phenotype of melanoma cells. Furthermore, increased expression of AEBP1 is validated in post-treatment tumors in patients with acquired resistance to BRAF inhibitor. Therefore, these results reveal a novel PI3K/Akt-CREB-AEBP1-NF-κB pathway whose activation contributes to acquired resistance to BRAF inhibition, and suggest that this pathway, particularly AEBP1, may represent a novel therapeutic target for treating BRAF inhibitor-resistant melanoma.     

Comparative phylogeography of two sympatric beeches in subtropical China: Species‐specific geographic mosaic of lineages

In subtropical China, large‐scale phylogeographic comparisons among multiple sympatric plants with similar ecological preferences are scarce, making generalizations about common response to historical events necessarily tentative. A phylogeographic comparison of two sympatric Chinese beeches (Fagus lucida and F. longipetiolata, 21 and 28 populations, respectively) was conducted to test whether they have responded to historical events in a concerted fashion and to determine whether their phylogeographic structure is exclusively due to Quaternary events or it is also associated with pre‐Quaternary events. Twenty‐three haplotypes were recovered for F. lucida and F. longipetiolata (14 each one and five shared). Both species exhibited a species‐specific mosaic distribution of haplotypes, with many of them being range‐restricted and even private to populations. The two beeches had comparable total haplotype diversity but F. lucida had much higher within‐population diversity than F. longipetiolata. Molecular dating showed that the time to most recent common ancestor of all haplotypes was 6.36 Ma, with most haplotypes differentiating during the Quaternary. [Correction added on 14 October 2013, after first online publication: the time unit has been corrected to ‘6.36’.] Our results support a late Miocene origin and southwards colonization of Chinese beeches when the aridity in Central Asia intensified and the monsoon climate began to dominate the East Asia. During the Quaternary, long‐term isolation in subtropical mountains of China coupled with limited gene flow would have lead to the current species‐specific mosaic distribution of lineages.     

血液科感染患者致病菌的临床资料分析

目的：探讨血液病患者的感染特点,为临床治疗提供病原学依据。方法：回顾性分析北京友谊医院2008年7月至2011年7月血液科住院患者临床分离出病原菌的情况。结果：原发病以血液系统恶性肿瘤为主。共培养出致病菌357株,包括革兰阴性杆菌（40.8%）;革兰阳性球菌（24.1%）;真菌（35.1%）。引起感染最常见的革兰阴性杆菌为铜绿假单胞菌,最常见的革兰阳性球菌为粪肠球菌,最常见的真菌为白色假丝酵母菌。革兰阴性杆菌来源为血29.4%,痰46.6%,尿10.3%;革兰阳性球菌来源为血14%,痰47.7%,尿10.4%;真菌来源为血8%,痰60.8%,尿4%。66.4%真菌感染患者中性粒细胞〈1.5×109/L。结论：血液病感染的致病菌以革兰阴性杆菌为主,呼吸道是主要感染部位。对于中性粒细胞减少的血液病感染患者,真菌感染的几率明显增加,经验性抗真菌治疗具有一定的意义。     

Molecular Subtypes in Head and Neck Cancer Exhibit Distinct Patterns of Chromosomal Gain and Loss of Canonical Cancer Genes

Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal heterogeneous disease. Beyond the role of human papilloma virus (HPV), no validated molecular characterization of the disease has been established. Using an integrated genomic analysis and validation methodology we confirm four molecular classes of HNSCC (basal, mesenchymal, atypical, and classical) consistent with signatures established for squamous carcinoma of the lung, including deregulation of the KEAP1/NFE2L2 oxidative stress pathway, differential utilization of the lineage markers SOX2 and TP63, and preference for the oncogenes PIK3CA and EGFR. For potential clinical use the signatures are complimentary to classification by HPV infection status as well as the putative high risk marker CCND1 copy number gain. A molecular etiology for the subtypes is suggested by statistically significant chromosomal gains and losses and differential cell of origin expression patterns. Model systems representative of each of the four subtypes are also presented.     

Vasorelaxin: A Novel Arterial Smooth Muscle-Relaxing Eicosapeptide from the Skin Secretion of the Chinese Piebald Odorous Frog (Odorrana schmackeri)

The defensive skin secretions of amphibians are a rich resource for the discovery of novel, bioactive peptides. Here we report the identification of a novel vascular smooth muscle-relaxing peptide, named vasorelaxin, from the skin secretion of the Chinese piebald odorous frog, Odorrana schmackeri. Vasorelaxin consists of 20 amino acid residues, SRVVKCSGFRPGSPDSREFC, with a disulfide-bridge between Cys-6 and Cys-20. The structure of its biosynthetic precursor was deduced from cloned skin cDNA and consists of 67 amino acid residues encoding a single copy of vasorelaxin (vasorelaxin, accession number: {"type":"entrez-nucleotide","attrs":{"text":"HE860494","term_id":"429534177","term_text":"HE860494"}}HE860494). Synthetic vasorelaxin caused a profound relaxation of rat arterial smooth muscle with an EC₅₀ of 6.76 nM.