A novel method of multiple alignment of biopolymer sequences

A novel algorithm for multiple alignment of biological sequences is suggested. At the first step the DotHelix procedure is employed for construction of motifs, i.e. continuous fragments of local similarity of various “thickness” and strength, and then these motifs are concatenated into chains consistent with the order of letters in the sequences. The algorithm is implemented in the MA-Tools program of the GeneBee package. An example illustrating the effectivity of the algorithm is presented.     

PET-CT在非完全实性肺结节中的应用价值

肺癌在中国恶性肿瘤的发病率位居第一,随着低剂量薄层CT在肺癌筛查中的广泛应用,临床发现更多表现为非完全实性结节的肺腺癌,目前众多研究使CT影像学特征和肺腺癌病理的关系得到更进一步的认知,虽然CT能对部分非完全实性结节做出定性和定位诊断,但仍有部分非完全实性结节诊断困难,PET-CT结合了病灶的代谢信息和精确的定位信息,从而提高对肺部结节诊断的敏感性、特异性、准确性,综合多个文献PET-CT在非完全实性结节中的诊断分期价值较CT无明显提升,却在评估预后和制定合适手术方案上可以起到一定的作用,本文就PET-CT在SSN中的应用价值进行阐述。     

Somatoform disorders among patients attending walk-in clinics in Trinidad: prevalence and association with depression and anxiety

Objectives Somatoform disorders are common in international primary care settings, but have been little studied in the developing world. The objective of this study was to determine the prevalence of severe undifferentiated somatoform disorder, and its relationship to depression and anxiety, among patients attending walk-in clinics in Trinidad.Methods The study participants, who were all aged 18 years or older and attending walk-in clinics at 16 randomly selected health centres, were surveyed between May and August 2007 using the PRIME-MD questionnaire.Results There were 594 participants (the response rate was 92%), of whom 72.7% were female. Their ages ranged from 18 to 93 years, and 54.5% were over 50 years of age. In total, 37.2% were married and 25.9% were single. Indo-Trinidadians represented 43.1% and Afro-Trinidadians represented 36% of the study sample; 56.5% of the participants reported that their income was less than US$ 400 per month, and 65.7% were unemployed. At walk-in clinics in Trinidad, the estimated prevalence of severe undifferentiated somatoform disorder was 10.3% (95% CI: 7.86–12.74), that of hypochondriasis was 28.5% (95% CI: 24.9–32.1), and that of body dysmorphic disorder was 15.8% (95% CI: 11.9–18.7). Severe undifferentiated somatoform disorder was statistically significantly associated with gender and ethnicity but not with age, level of education, employment status or income. Chi-square testing found significant associations between the presence of severe undifferentiated somatoform disorder and both depression and anxiety (P < 0.05), between hypochondriasis and both anxiety and depression (P < 0.05), and between body dysmorphic disorder and depression (P < 0.05) but not anxiety. Regression analysis suggested that the demographic features that predicted severe undifferentiated somatoform disorder were being female or Indo-Trinidadian.Conclusions Walk-in clinics in Trinidad that serve older patients on a lower income have a high proportion of patients with somatoform disorders as measured by the PRIME-MD scale. These patients exhibit many features of anxiety and depression. These findings have implications for medical training and service delivery.     

Neurons of the human basal ganglia (striatum and basolateral amygdala) expressing the enzyme NADPH-d

In human striatum and basolateral amygdala NADPH-d+ neurons were revealed (after Vincent et al., 1983); and in striatum strio-cortical neurons were also revealed using DiI marker (after Dahtstrom and Belichenko, 1995). The NADPH-d+ neurons were numerous in both formations. Staining of NADPH-d+ neurons with their processes, and our previous study of striatal and amygdalar human neurons by Golgi method made it possible to identify the species of neurons with their assessment as sparsely or densely branched. The main efferent neurons of striatum and basolateral amygdala (densely branched medium spiny and bushy spiny, respectively) and their densely branched interneurons were not marked. Efferent NADPH-d+ neurons included the most numerous ones in both formations. A projection of reticular striatal neurons to cortex was also shown. The NADPH-d+ interneurons belonged to sparsely branched forms. In striatum they included slender-dendritic and long-dendritic bipolars (numerous), ordinary bipolars, twisted and large poor-dendritic cells; in amygdala--the same bipolars and radial cells. Thus, the NADPH-d positive cells in the formations under study were represented by more "ancient" or less structurally complex cell forms.     

Pyrazole compound BPR1P0034 with potent and selective anti-influenza virus activity

Background

Influenza viruses are a major cause of morbidity and mortality around the world. More recently, a swine-origin influenza A (H1N1) virus that is spreading via human-to-human transmission has become a serious public concern. Although vaccination is the primary strategy for preventing infections, influenza antiviral drugs play an important role in a comprehensive approach to controlling illness and transmission. In addition, a search for influenza-inhibiting drugs is particularly important in the face of high rate of emergence of influenza strains resistant to several existing influenza antivirals.

Methods

We searched for novel anti-influenza inhibitors using a cell-based neutralization (inhibition of virus-induced cytopathic effect) assay. After screening 20,800 randomly selected compounds from a library from ChemDiv, Inc., we found that BPR1P0034 has sub-micromolar antiviral activity. The compound was resynthesized in five steps by conventional chemical techniques. Lead optimization and a structure-activity analysis were used to improve potency. Time-of-addition assay was performed to target an event in the virus life cycle.

Results

The 50% effective inhibitory concentration (IC₅₀) of BPR1P0034 was 0.42 ± 0.11 μM, when measured with a plaque reduction assay. Viral protein and RNA synthesis of A/WSN/33 (H1N1) was inhibited by BPR1P0034 and the virus-induced cytopathic effects were thus significantly reduced. BPR1P0034 exhibited broad inhibition spectrum for influenza viruses but showed no antiviral effect for enteroviruses and echovirus 9. In a time-of-addition assay, in which the compound was added at different stages along the viral replication cycle (such as at adsorption or after adsorption), its antiviral activity was more efficient in cells treated with the test compound between 0 and 2 h, right after viral infection, implying that an early step of viral replication might be the target of the compound. These results suggest that BPR1P0034 targets the virus during viral uncoating or viral RNA importation into the nucleus.

Conclusions

To the best of our knowledge, BPR1P0034 is the first pyrazole-based anti-influenza compound ever identified and characterized from high throughput screening to show potent (sub-μM) antiviral activity. We conclude that BPR1P0034 has potential antiviral activity, which offers an opportunity for the development of a new anti-influenza virus agent.     

KUD773, a phenylthiazole derivative,displays anticancer activity in human hormone-refractory prostate cancers through inhibition of tubulin polymerization and anti-Aurora A activity

Background

Hormone-refractory prostate cancer (HRPC), which is resistant to hormone therapy, is a major obstacle in clinical treatment. An approach to inhibit HRPC growth and ultimately to kill cancers is highly demanded.

Results

KUD773 induced the anti-proliferative effect and subsequent apoptosis in PC-3 and DU-145 (two HRPC cell lines); whereas, it showed less active in normal prostate cells. Further examination showed that KUD773 inhibited tubulin polymerization and induced an increase of mitotic phosphoproteins and polo-like kinase 1 (PLK1) phosphorylation, indicating a mitotic arrest of the cell cycle through an anti-tubulin action. The kinase assay demonstrated that KUD773 inhibited Aurora A activity. KUD773 induced an increase of Cdk1 phosphorylation at Thr¹⁶¹ (a stimulatory phosphorylation site) and a decrease of phosphorylation at Tyr¹⁵ (an inhibitory phosphorylation site), suggesting the activation of Cdk1. The data were substantiated by an up-regulation of cyclin B1 (a Cdk1 partner). Furthermore, KUD773 induced the phosphorylation and subsequent down-regulation of Bcl-2 and activation of caspase cascades.

Conclusions

The data suggest that KUD773 induces apoptotic signaling in a sequential manner. It inhibits tubulin polymerization associated with an anti-Aurora A activity, leading to Cdk1 activation and mitotic arrest of the cell cycle that in turn induces Bcl-2 degradation and a subsequent caspase activation in HRPCs.