Analogues of the frog skin peptide alyteserin‐2a with enhanced antimicrobial activities against Gram‐negative bacteria

The emergence of strains of multidrug‐resistant Gram‐negative bacteria mandates a search for new types of antimicrobial agents. Alyteserin‐2a (ILGKLLSTAAGLLSNL.NH₂) is a cationic, α‐helical peptide, first isolated from skin secretions of the midwife toad, Alytes obstetricans, which displays relatively weak antimicrobial and haemolytic activities. Increasing the cationicity of alyteserin‐2a while maintaining amphipathicity by the substitution Gly¹¹→ Lys enhanced the potency against both Gram‐negative and Gram‐positive bacteria by between fourfold and 16‐fold but concomitantly increased cytotoxic activity against human erythrocytes by sixfold (mean concentration of peptide producing 50% cell death; LC₅₀ = 24 µm ). Antimicrobial potency was increased further by the additional substitution Ser⁷→Lys, but the resulting analogue remained cytotoxic to erythrocytes (LC₅₀ = 38 µm ). However, the peptide containing d ‐lysine at positions 7 and 11 showed high potency against a range of Gram‐negative bacteria, including multidrug‐resistant strains of Acinetobacter baumannii and Stenotrophomonas maltophilia (minimum inhibitory concentration = 8 µm ) but appreciably lower haemolytic activity (LC₅₀ = 185 µm ) and cytotoxicity against A549 human alveolar basal epithelial cells (LC₅₀ = 65 µm ). The analogue shows potential for treatment of nosocomial pulmonary infections caused by bacteria that have developed resistance to commonly used antibiotics. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.     

MiRNA在TLR信号通路中的负性调控作用

TLR信号是生物体重要的病原体模式识别信号,在免疫识别和炎症反应中具有重要作用,其信号异常会导致许多免疫和炎症相关疾病的发生,因此探讨和明确TLR信号通路的调控机制具有非常重要的意义。近年来研究发现,作为重要的基因表达调控的小分子RNA,微RNA(microRNA,miRNA)能与TLR信号通路中众多靶基因mRNA的3’UTR区结合,从而抑制翻译过程或降解mRNA来发挥负性调控作用。本文就miRNA对TLR信号通路中的一些受体、信号分子、调节因子和细胞因子的负性调控作用方面进行阐述。     

临床分离凝固酶阴性葡萄球菌细菌谱

目的了解玉溪市人民医院临床分离凝固酶阴性葡萄球菌（CNS）的菌种构成和耐药特征。方法对该院近6年来临床分离的808株CNS作回顾性分析。结果808株CNS共有16种;表皮葡萄球菌、腐生葡萄球菌和溶血葡萄球菌占CNS的77.2%;甲氧西林耐药（MRCNS）和甲氧西林敏感（MSCNS）各占63.3%和36.7%;β-内酰胺酶阳性检出率为84.5%,且MRCNS显著高于MSCNS（χ^2=50.88,P〈0.01）;药敏结果：MRCNS除万古霉素、呋喃妥因和利福平外,青霉素、氨苄西林等12种临床常用抗菌药物的耐药率在50.6%-100%,显示了高度的耐药性和多重耐药。结论CNS在临床标本中的检出范围广、种类多,以表皮葡萄球菌、腐生葡萄球菌和溶血葡萄球菌为主,MRCNS的高度耐药和多重耐药形势严重,加强CNS的细菌学监测非常必要。     

ELISA法检测HBeAg假性结果原因分析

目的:探讨ELISA法检测HBeAg假性结果原因方法:用ELISA法检测乙肝血清标志物,对HBsAg阳性而HBeAg阴性的标本以及HBeAg阳性的标本用ELISA法和电化学发光法复查。结果:136例HBsAg阳性而HBeAg阴性的标本经稀释复查后检出10例HBeAg阳性标本。23例溶血标本引起HBeAg假阳性。结论:钩状效应和标本溶血是引起HBeAg假阴性和假阳性的重要原因。必要时应加以复查,以减少HBeAg的错检和漏检。     

False belief reasoning in the brain: An ERP study

Understanding others mind and interpersonal interaction are the cognitive basis of successful social interactions. People's mental states and behaviors rely on their holding beliefs for self and others. To investigate the neural substrates of false belief reasoning, the 32 channels event-related potentials (ERP) of 14 normal adults were measured while they understood false-belief and true belief used de-ceptive appearance task. After onset of the false-belief or true-belief questions, N100, P200 and late negative component (LNC) were elicited at centro-frontal sites. Compared with true belief, false belief reasoning elicited significant declined LNC in the time window from 400 to 800 ms. The source analysis of difference wave (False minus True) showed a dipole located in the middle cingulated cortex. These findings show that false belief reasoning probably included inhibitive process.     

Deficit schizophrenia: an update

The criteria for deficit schizophrenia were designed to define a group of patients with enduring, primary (or idiopathic) negative symptoms. In 2001, a review of the literature suggested that deficit schizophrenia constitutes a disease separate from nondeficit forms of schizophrenia. Here we provide a review of new studies, not included in that paper, in which patients with deficit schizophrenia and those with nondeficit schizophrenia were compared on dimensions typically used to distinguish diseases: signs and symptoms, course of illness, pathophysiological correlates, risk and etiological factors, and treatment response. Replicated findings and new evidence of double dissociation supporting the separate disease hypothesis are highlighted. Weaknesses in research and treatment options for these patients are also emphasized.     

CDK5 activator p35 downregulates E-cadherin precursor independently of CDK5

Dysfunction of E-cadherins often results in metastasis of cancerous cells. Here we show that p35, a critical regulator of cyclin-dependent kinase 5 (CDK5), specifically depletes the precursor form of E-cadherin, but not the mature form, by using a precursor-specific antibody. Most intriguingly, this downregulation of precursor E-cadherin by p35 is unequivocally independent of CDK5. Moreover, we found that p35 forms complexes with E-cadherin proteins. We also found that p35 co-expression can target E-cadherin to lysosomes and that p35-triggered disappearance of E-cadherin precursor can be blocked specifically by lysosomal protease inhibitors, indicating that p35 induces endocytosis and subsequent degradation of precursor E-cadherin.     

Complementary roles for histone deacetylases 1, 2, and 3 in differentiation of pluripotent stem cells

Abstract In eukaryotic cells, covalent modifications to core histones contribute to the establishment and maintenance of cellular phenotype via regulation of gene expression. Histone acetyltransferases (HATs) cooperate with histone deacetylases (HDACs) to establish and maintain specific patterns of histone acetylation. HDAC inhibitors can cause pluripotent stem cells to cease proliferating and enter terminal differentiation pathways in culture. To better define the roles of individual HDACs in stem cell differentiation, we have constructed "dominant-negative" stem cell lines expressing mutant, Flag-tagged HDACs with reduced enzymatic activity. Replacement of a single residue (His→Ala) in the catalytic center reduced the activity of HDACs 1 and 2 by 80%, and abolished HDAC3 activity; the mutant HDACs were expressed at similar levels and in the same multiprotein complexes as wild-type HDACs. Hexamethylene bisacetamide-induced MEL cell differentiation was potentiated by the individual mutant HDACs, but only to 2%, versus 60% for an HDAC inhibitor, sodium butyrate, suggesting that inhibition of multiple HDACs is required for full potentiation. Cultured E14.5 cortical stem cells differentiate to neurons, astrocytes, and oligodendrocytes upon withdrawal of basic fibroblast growth factor. Transduction of stem cells with mutant HDACs 1, 2, or 3 shifted cell fate choice toward oligodendrocytes. Mutant HDAC2 also increased differentiation to astrocytes, while mutant HDAC1 reduced differentiation to neurons by 50%. These results indicate that HDAC activity inhibits differentiation to oligodendrocytes, and that HDAC2 activity specifically inhibits differentiation to astrocytes, while HDAC1 activity is required for differentiation to neurons.