Collagen processing and cuticle formation is catalysed by the astacin metalloprotease DPY-31 in free-living and parasitic nematodes

The exoskeleton or cuticle performs many key roles in the development and survival of all nematodes. This structure is predominantly collagenous in nature and requires numerous enzymes to properly fold, modify, process and cross-link these essential structural proteins. The cuticle structure and its collagen components are conserved throughout the nematode phylum but differ from the collagenous matrices found in vertebrates. This structure, its formation and the enzymology of nematode cuticle collagen biogenesis have been elucidated in the free-living nematode Caenorhabditis elegans. The dpy-31 gene in C. elegans encodes a procollagen C-terminal processing enzyme of the astacin metalloprotease or bone morphogenetic protein class that, when mutated, results in a temperature-sensitive lethal phenotype associated with cuticle defects. In this study, orthologues of this essential gene have been identified in the phylogenetically diverse parasitic nematodes Haemonchus contortus and Brugia malayi. The DPY-31 protein is expressed in the gut and secretory system of C. elegans, a location also confirmed when a B. malayi transcriptional dpy-31 promoter-reporter gene fusion was expressed in C. elegans. Functional conservation between the nematode enzymes was supported by the fact that heterologous expression of the H. contortus dpy-31 orthologue in a C. elegans dpy-31 mutant resulted in the full rescue of the mutant body form. This interspecies conservation was further established when the recombinant nematode enzymes were found to have a similar range of inhibitable protease activities. In addition, the recombinant DPY-31 enzymes from both H. contortus and B. malayi were shown to efficiently process the C. elegans cuticle collagen SQT-3 at the correct C-terminal procollagen processing site

Analysis of the functional conservation of ethylene receptors between maize and Arabidopsis

Ethylene, a regulator of plant growth and development, is perceived by specific receptors that act as negative regulators of the ethylene response. Five ethylene receptors, i.e., ETR1, ERS1, EIN4, ETR2, and ERS2, are present in Arabidopsis and dominant negative mutants of each that confer ethylene insensitivity have been reported. In contrast, maize contains just two types of ethylene receptors: ZmERS1, encoded by ZmERS1a and ZmERS1b, and ZmETR2, encoded by ZmETR2a and ZmETR2b. In this study, we introduced a Cys to Tyr mutation in the transmembrane domain of ZmERS1b and ZmETR2b that is present in the etr1-1 dominant negative mutant and expressed each protein in Arabidopsis. Mutant Zmers1b and Zmetr2b receptors conferred ethylene insensitivity and Arabidopsis expressing Zmers1b or Zmetr2b were larger and exhibited a delay in leaf senescence characteristic of ethylene insensitive Arabidopsis mutants. Zmers1b and Zmetr2b were dominant and functioned equally well in a hemizygous or homozygous state. Expression of the Zmers1b N-terminal transmembrane domain was sufficient to exert dominance over endogenous Arabidopsis ethylene receptors whereas the Zmetr2b N-terminal domain failed to do so. Neither Zmers1b nor Zmetr2b functioned in the absence of subfamily 1 ethylene receptors, i.e., ETR1 and ERS1. These results suggest that Cys65 in maize ZmERS1b and ZmETR2b plays the same role that it does in Arabidopsis receptors. Moreover, the results demonstrate that the mutant maize ethylene receptors are functionally dependent on subfamily 1 ethylene receptors in Arabidopsis, indicating substantial functional conservation between maize and Arabidopsis ethylene receptors despite their sequence divergence

Intestinal Perforations in Behçet’s Disease

Behçet’s disease accompanied by intestinal involvement is called intestinal Behçet’s disease. The intestinal ulcers of Behçet’s disease are usually multiple and scattered and tend to perforate easily, so that many patients require emergency operation. The aim of this study is to determine the extent of surgical resection necessary to prevent reperforation and to point out the findings of concurrent oral and genital ulcers and multiple intestinal perforations in all patients of our series. During a 25-year study period, information of 125 Behçet’s disease cases was gathered. Among the 82 patients who were diagnosed with intestinal Behçet’s disease, 22 cases had intestinal perforations needing emergency laparotomy. We investigated and analyzed these cases according to the patients’ demographic characteristics, clinical presentations, laboratory data, and surgical outcome. There were 14 men and 8 women ranging from 22 to 65 years of age. Nine cases were diagnosed preoperatively, and the diagnoses were confirmed in all 22 cases during the surgical intervention. Surgical resection was performed in every patient, with right hemicolectomy and ileocecal resection in 11 cases, partial ileum resection in 8 cases with two reperforations, and ileocecal resection in 3 cases with one reperforation

Regional differences in awareness and attitudes regarding genetic testing for disease risk and ancestry

Little is known about the lay public’s awareness and attitudes concerning genetic testing and what factors influence their perspectives. The existing literature focuses mainly on ethnic and socioeconomic differences; however, here we focus on how awareness and attitudes regarding genetic testing differ by geographical regions in the US. We compared awareness and attitudes concerning genetic testing for disease risk and ancestry among 452 adults (41% Black and 67% female) in four major US cities, Norman, OK; Cincinnati, OH; Harlem, NY; and Washington, DC; prior to their participation in genetic ancestry testing. The OK participants reported more detail about their personal ancestries (p = 0.02) and valued ancestry testing over disease testing more than all other sites (p < 0.01). The NY participants were more likely than other sites to seek genetic testing for disease (p = 0.01) and to see benefit in finding out more about one’s ancestry (p = 0.02), while the DC participants reported reading and hearing more about genetic testing for African ancestry than all other sites (p < 0.01). These site differences were not better accounted for by sex, age, education, self-reported ethnicity, religion, or previous experience with genetic testing/counseling. Regional differences in awareness and attitudes transcend traditional demographic predictors, such as ethnicity, age and education. Local sociocultural factors, more than ethnicity and socioeconomic status, may influence the public’s awareness and belief systems, particularly with respect to genetics

Dysregulated apoptosis and NFκB expression in COPD subjects

<p>Abstract</p> <p>Background</p> <p>The abnormal regulation of neutrophil apoptosis may contribute to the ineffective resolution of inflammation in chronic lung diseases. Multiple signalling pathways are implicated in regulating granulocyte apoptosis, in particular, NFκB (nuclear factor-kappa B) signalling which delays constitutive neutrophil apoptosis. Although some studies have suggested a dysregulation in the apoptosis of airway cells in chronic obstructive pulmonary disease (COPD), no studies to date have directly investigated if NFκB is associated with apoptosis of airway neutrophils from COPD patients. The objectives of this study were to examine spontaneous neutrophil apoptosis in stable COPD subjects (n = 13), healthy smoking controls (n = 9) and non-smoking controls (n = 9) and to investigate whether the neutrophil apoptotic process in inflammatory conditions is associated with NFκB activation.</p> <p>Methods</p> <p>Analysis of apoptosis in induced sputum was carried out by 3 methods; light microscopy, Annexin V/Propidium iodide and the terminal transferase-mediated dUTP nick end-labeling (TUNEL) method. Activation of NFκB was assessed using a flow cytometric method and the phosphorylation state of IκBα was carried out using the Bio-Rad Bio-Plex phosphoprotein IκBα assay.</p> <p>Results</p> <p>Flow cytometric analysis showed a significant reduction in the percentage of sputum neutrophils undergoing spontaneous apoptosis in healthy smokers and subjects with COPD compared to non-smokers (p < 0.001). Similar findings were demonstrated using the Tunel assay and in the morphological identification of apoptotic neutrophils. A significant increase was observed in the expression of both the p50 (p = 0.006) and p65 (p = 0.006) subunits of NFκB in neutrophils from COPD subjects compared to non-smokers.</p> <p>Conclusion</p> <p>These results demonstrate that apoptosis is reduced in the sputum of COPD subjects and in healthy control smokers and may be regulated by an associated activation of NFκB.</p

Enhancement of the activity of phenoxodiol by cisplatin in prostate cancer cells

Phenoxodiol is a novel isoflav-3-ene, currently undergoing clinical trials, that has a broad in vitro activity against a number of human cancer cell lines. Phenoxodiol alone inhibited DU145 and PC3 in a dose- and time-dependent manner with IC50 values of 8±1 and 38±9 μM, respectively. The combination of phenoxodiol and cisplatin was synergistic in DU145, and additive in PC3, as assessed by the Chou–Talalay method. Carboplatin was also synergistic in combination with phenoxodiol in DU145 cells. The activity of the phenoxodiol and cisplatin combination was confirmed in vivo using a DU145 xenograft model in nude mice. Pharmacokinetic data from these mice suggest that the mechanism of synergy may occur through a pharmacodynamic mechanism. An intracellular cisplatin accumulation assay showed a 35% (P<0.05) increase in the uptake of cisplatin when it was combined in a ratio of 1 μM: 5 μM phenoxodiol, resulting in a 300% (P<0.05) increase in DNA adducts. Taken together, our results suggest that phenoxodiol has interesting properties that make combination therapy with cisplatin or carboplatin appealing

Angiopoietin-1 promotes functional neovascularization that relieves ischemia by improving regional reperfusion in a swine chronic myocardial ischemia model

10.1007/s11373-006-9082-xJournal of Biomedical Science134579-59

Effects of workplace-based dietary and/or physical activity interventions for weight management targeting healthcare professionals : a systematic review of randomised controlled trials

BACKGROUND: The prevalence of overweight and obesity is high amongst healthcare professionals and there is growing interest in delivering weight loss interventions in the workplace. We conducted a systematic review to (i) examine the effectiveness of workplace-based diet and/or physical activity interventions aimed at healthcare professionals and to (ii) identify and describe key components of effective interventions. Seven electronic databases were systematically searched. RESULTS: Thirteen randomised controlled trials met the inclusion criteria, of which seven had data available for meta-analysis. Where meta-analysis was possible, studies were grouped according to length of follow-up (<12 months and ≥12 months) and behavioural target (diet only, physical activity only or diet and physical activity), with outcome data pooled using a weighted random effects model. Nine studies reported statistically significant (between-group) differences. Four studies reported being informed by a behaviour change theory. Meta-analysis of all trials reporting weight data demonstrated healthcare professionals allocated to dietary and physical activity interventions lost significantly more body weight (-3.95 Kg, [95% CI -4.96 to- 2.95 Kg]) than controls up to 12 months follow up. CONCLUSIONS: Workplace diet and/or physical activity interventions targeting healthcare professionals are limited in number and are heterogeneous. To improve the evidence base, we recommend additional evaluations of theory-based interventions and adequate reporting of intervention content.Peer reviewedFinal Published versio

Host Cell Factors in HIV Replication: Meta-Analysis of Genome-Wide Studies

We have analyzed host cell genes linked to HIV replication that were identified in nine genome-wide studies, including three independent siRNA screens. Overlaps among the siRNA screens were very modest (<7% for any pairwise combination), and similarly, only modest overlaps were seen in pairwise comparisons with other types of genome-wide studies. Combining all genes from the genome-wide studies together with genes reported in the literature to affect HIV yields 2,410 protein-coding genes, or fully 9.5% of all human genes (though of course some of these are false positive calls). Here we report an “encyclopedia” of all overlaps between studies (available at http://www.hostpathogen.org), which yielded a more extensively corroborated set of host factors assisting HIV replication. We used these genes to calculate refined networks that specify cellular subsystems recruited by HIV to assist in replication, and present additional analysis specifying host cell genes that are attractive as potential therapeutic targets

Understanding How University Students Use Perceptions of Consent, Wantedness, and Pleasure in Labeling Rape.

While the lack of consent is the only determining factor in considering whether a situation is rape or not, there is sufficient evidence that participants conflate wantedness with consent and pleasurableness with wantedness. Understanding how people appraise sexual scenarios may form the basis to develop appropriate educational packages. We conducted two large-scale qualitative studies in two UK universities in which participants read vignettes describing sexual encounters that were consensual or not, wanted or unwanted and pleasurable or not pleasurable. Participants provided free-text responses as to whether they perceived the scenarios to be rape or not and why they made these judgments. The second study replicated the results of the first and included a condition where participants imagined themselves as either the subject or initiator of the sexual encounter. The results indicate that a significant portion of our participants held attitudes reflecting rape myths and tended to blame the victim. Participants used distancing language when imagining themselves in the initiator condition. Participants indicated that they felt there were degrees of how much a scenario reflected rape rather than it simply being a dichotomy (rape or not). Such results indicate a lack of understanding of consent and rape and highlight avenues of potential educational materials for schools, universities or jurors