HIV-1 protease inhibitor mutations affect the development of HIV-1 resistance to the maturation inhibitor bevirimat

<p>Abstract</p> <p>Background</p> <p>Maturation inhibitors are an experimental class of antiretrovirals that inhibit Human Immunodeficiency Virus (HIV) particle maturation, the structural rearrangement required to form infectious virus particles. This rearrangement is triggered by the ordered cleavage of the precursor Gag polyproteins into their functional counterparts by the viral enzyme protease. In contrast to protease inhibitors, maturation inhibitors impede particle maturation by targeting the substrate of protease (Gag) instead of the protease enzyme itself. Direct cross-resistance between protease and maturation inhibitors may seem unlikely, but the co-evolution of protease and its substrate, Gag, during protease inhibitor therapy, could potentially affect future maturation inhibitor therapy. Previous studies showed that there might also be an effect of protease inhibitor resistance mutations on the development of maturation inhibitor resistance, but the exact mechanism remains unclear. We used wild-type and protease inhibitor resistant viruses to determine the impact of protease inhibitor resistance mutations on the development of maturation inhibitor resistance.</p> <p>Results</p> <p>Our resistance selection studies demonstrated that the resistance profiles for the maturation inhibitor bevirimat are more diverse for viruses with a mutated protease compared to viruses with a wild-type protease. Viral replication did not appear to be a major factor during emergence of bevirimat resistance. In all <it>in vitro </it>selections, one of four mutations was selected: Gag V362I, A364V, S368N or V370A. The impact of these mutations on maturation inhibitor resistance and viral replication was analyzed in different protease backgrounds. The data suggest that the protease background affects development of HIV-1 resistance to bevirimat and the replication profiles of bevirimat-selected HIV-1. The protease-dependent bevirimat resistance and replication levels can be explained by differences in CA/p2 cleavage processing by the different proteases.</p> <p>Conclusions</p> <p>These findings highlight the complicated interactions between the viral protease and its substrate. By providing a better understanding of these interactions, we aim to help guide the development of second generation maturation inhibitors.</p

On the gauge boson's properties in a candidate technicolor theory

The technicolor scenario replaces the Higgs sector of the standard model with a strongly interacting sector. One candidate for a realization of such a sector is two-technicolor Yang-Mills theory coupled to two degenerate flavors of adjoint, massless techniquarks. Using lattice gauge theory the properties of the technigluons in this scenario are investigated as a function of the techniquark mass towards the massless limit. For that purpose the minimal Landau gauge two-point and three-point correlation functions are determined, including a detailed systematic error analysis. The results are, within the relatively large systematic uncertainties, compatible with a behavior very similar to QCD at finite techniquark mass. However, the limit of massless techniquarks exhibits features which could be compatible with a (quasi-)conformal behavior.Comment: 27 pages, 17 figures, 1 table; v2: persistent notational error corrected, some minor modification

The workability of Escherichia coli BL21 (DE3) and Pseudomonas putida KT2440 expression platforms with autodisplayed cellulases: a comparison

This article comparatively reports the workability of Escherichia coli BL21(DE3) and Pseudomonas putida KT2440 cell factories for the expression of three model autodisplayed cellulases (i.e., endoglucanase, BsCel5A; exoglucanase, CelK; β-glucosidase, BglA). The differentiation of the recombinant cells was restricted to their cell growth and enzyme expression/activity attributes. Comparatively, the recombinant E. coli showed higher cell growth rates but lower enzyme activities than the recombinant P. putida. However, the endo-, exoglucanase, and β-glucosidase on the surfaces of both cell factories showed activity over a broad range of pH (4-10) and temperature (30-100 °C). The pH and temperature optima were pH 6, 60 °C (BsCel5A); pH 6, 60-70 °C (CelK); and pH 6, 50 °C (BglA). Overall, the P. putida cell factory with autodisplayed enzymes demonstrated higher bioactivity and remarkable biochemical characteristics and thus was chosen for the saccharification of filter paper. A volumetric blend of the three cellulases with P. putida as the host yielded a ratio of 1:1:1.5 of endoglucanase, exoglucanase, and β-glucosidase, respectively, as the optimum blend composition for filter paper degradation. At an optical density (578 nm) of 50, the blend generated a maximum sugar yield of about 0.7 mg/ml (~ 0.08 U/g) from Whatman filter paper (Ø 6 mm, ~ 2.5 mg) within 24 h

Prader–Willi syndrome and autism spectrum disorders: an evolving story

Prader–Willi syndrome (PWS) is well-known for its genetic and phenotypic complexities. Caused by a lack of paternally derived imprinted material on chromosome 15q11–q13, individuals with PWS have mild to moderate intellectual disabilities, repetitive and compulsive behaviors, skin picking, tantrums, irritability, hyperphagia, and increased risks of obesity. Many individuals also have co-occurring autism spectrum disorders (ASDs), psychosis, and mood disorders. Although the PWS 15q11–q13 region confers risks for autism, relatively few studies have assessed autism symptoms in PWS or directly compared social, behavioral, and cognitive functioning across groups with autism or PWS. This article identifies areas of phenotypic overlap and difference between PWS and ASD in core autism symptoms and in such comorbidities as psychiatric disorders, and dysregulated sleep and eating. Though future studies are needed, PWS provides a promising alternative lens into specific symptoms and comorbidities of autism

The Teacher, the Physician and the Person: How Faculty's Teaching Performance Influences Their Role Modelling

OBJECTIVE: Previous studies identified different typologies of role models (as teacher/supervisor, physician and person) and explored which of faculty's characteristics could distinguish good role models. The aim of this study was to explore how and to which extent clinical faculty's teaching performance influences residents' evaluations of faculty's different role modelling statuses, especially across different specialties. METHODS: In a prospective multicenter multispecialty study of faculty's teaching performance, we used web-based questionnaires to gather empirical data from residents. The main outcome measures were the different typologies of role modelling. The predictors were faculty's overall teaching performance and faculty's teaching performance on specific domains of teaching. The data were analyzed using multilevel regression equations. RESULTS: In total 219 (69% response rate) residents filled out 2111 questionnaires about 423 (96% response rate) faculty. Faculty's overall teaching performance influenced all role model typologies (OR: from 8.0 to 166.2). For the specific domains of teaching, overall, all three role model typologies were strongly associated with "professional attitude towards residents" (OR: 3.28 for teacher/supervisor, 2.72 for physician and 7.20 for the person role). Further, the teacher/supervisor role was strongly associated with "feedback" and "learning climate" (OR: 3.23 and 2.70). However, the associations of the specific domains of teaching with faculty's role modelling varied widely across specialties. CONCLUSION: This study suggests that faculty can substantially enhance their role modelling by improving their teaching performance. The amount of influence that the specific domains of teaching have on role modelling differs across specialties

T-staging of rectal cancer: accuracy of 3.0 Tesla MRI compared with 1.5 Tesla

OBJECTIVES: Magnetic resonance imaging (MRI) is not accurate in discriminating T1-2 from borderline T3 rectal tumors. Higher resolution on 3 Tesla-(3T)-MRI could improve diagnostic performance for T-staging. The aim of this study was to determine whether 3T-MRI compared with 1.5 Tesla-(1.5T)-MRI improves the accuracy for the discrimination between T1-2 and borderline T3 rectal tumors and to evaluate reproducibility. METHODS: 13 patients with non-locally advanced rectal cancer underwent imaging with both 1.5T and 3T-MRI. Three readers with different expertise evaluated the images and predicted T-stage with a confidence level score. Receiver operator characteristics curves with areas under the curve (AUC) and diagnostic parameters were calculated. Inter- and intra-observer agreements were calculated with quadratic kappa-weighting. Histology was the reference standard. RESULTS: Seven patients had pT1-2 tumors and six had pT3 tumors. AUCs ranged from 0.66 to 0.87 at 1.5T vs. 0.52-0.82 at 3T. Mean overstaging rate was 43% at 1.5T and 57% at 3T (P = 0.23). Inter-observer agreement was kappa 0.50-0.71 at 1.5T vs. 0.15-0.68 at 3T. Intra-observer agreement was kappa 0.71 at 1.5T and 0.76 at 3T. CONCLUSIONS: This is the first study to compare 3T with 1.5T MRI for T-staging of rectal cancer within the same patients. Our results showed no difference between 3T and 1.5T-MRI for the distinction between T1-2 and borderline T3 tumors, regardless of expertise. The higher resolution at 3T-MRI did not aid in the distinction between desmoplasia in T1-2-tumors and tumor stranding in T3-tumors. Larger studies are needed to acknowledge these findings

Evaluation of a school-based HIV prevention intervention among Yemeni adolescents

<p>Abstract</p> <p>Background</p> <p>This article describes an evaluation of a school-based peer education intervention for HIV prevention among students in twenty seven high schools in Aden, Yemen. The intervention was developed after a survey among the same population in 2005, which revealed a high level of stigma towards people living with HIV (PLWH) and a low level of HIV knowledge.</p> <p>Methods</p> <p>In a quasi-experimental design students who received the peer education intervention (78.6%) were compared with students who did not receive the intervention (21.4%). No systematic procedure was applied in selecting students for the intervention condition. Data were collected using a self-administered questionnaire from a sample of 2510 students from all 27 high-schools in Aden governorate. To increase internal validity, students were also compared with a cohort control sample surveyed in 2005, which was a random sample of 2274 students from the same schools.</p> <p>Results</p> <p>Sixty eight percent of students targeted by peer education had good knowledge scores, compared with 43.3% of students not targeted by peer education (χ²= (df = 1) = 111.15, p < .01). Multi-level regression analysis revealed that, although there was a significant difference among schools, the intervention effect of peer education at the individual level was significant; students who received peer education had a statistically higher knowledge score(9.24 out of 12.0) compared with those not targeted (7.89 out of 12.0), OR = 2.11, 95% CI = 1.04-4.27, p < .05). Compared with the 2005 cohort control sample, students targeted by peer education had better knowledge on the modes of transmission and prevention and fewer misconceptions; and knowledge on the use of condoms increased from 49.4% to 67.8%. In addition, students who received the peer education interventions suggested significantly more actions to provide care and support for PLWH. Also, the levels of stigma and discrimination were much higher among the 2005 cohort control group, compared with those who received the peer education intervention.</p> <p>Conclusion</p> <p>The school-based peer education intervention has succeeded in improving levels of knowledge on modes of transmission and prevention, and in decreasing levels of stigma and discrimination in a culturally conservative setting.</p

Bid can mediate a pro-apoptotic response to etoposide and ionizing radiation without cleavage in its unstructured loop and in the absence of p53

BH3-only protein Bid is a key player in death receptor-induced apoptosis, because it provides the link with the mitochondrial route for caspase activation. In this pathway, Bid is activated upon cleavage by caspase-8. Its BH3 domain-containing carboxy-terminal fragment subsequently provokes mitochondrial outer membrane permeabilization by Bak/Bax activation. Bid has also been implicated in the apoptotic response to ionizing radiation (IR) and the topoisomerase inhibitor etoposide, anti-cancer regimens that cause double-strand (ds)DNA breaks. We confirm the existence of this pathway and show that it is p53-independent. However, the degree of Bid participation in the apoptotic response to dsDNA breaks depends on the nature of cell transformation. We used Bid-deficient mouse embryonic fibroblast (MEF) lines that were reconstituted with Bid to control the cellular background and demonstrated that the Bid-dependent apoptotic pathway induced by IR and etoposide operates in MEFs that are transformed by SV40, but is not evident in E1A/Ras-transformed MEFs. The Bid-dependent apoptotic response in p53-deficient SV40-transformed MEFs contributed to clonogenic execution of the cells, implying relevance for treatment outcome. In these cells, Bid acted in a conventional manner in that it required its BH3 domain to mediate apoptosis in response to IR and etoposide, and triggered apoptotic execution by indirect activation of Bak/Bax, mitochondrial permeabilization and caspase-9 activation. However, the mechanism of Bid activation was unconventional, because elimination of all known or suspected cleavage sites for caspases or other proteolytic enzymes and even complete elimination of its unstructured cleavage loop left Bid's pro-apoptotic role in the response to IR and etoposide unaffected

The Glasgow Outcome Scale -- 40 years of application and refinement

The Glasgow Outcome Scale (GOS) was first published in 1975 by Bryan Jennett and Michael Bond. With over 4,000 citations to the original paper, it is the most highly cited outcome measure in studies of brain injury and the second most-cited paper in clinical neurosurgery. The original GOS and the subsequently developed extended GOS (GOSE) are recommended by several national bodies as the outcome measure for major trauma and for head injury. The enduring appeal of the GOS is linked to its simplicity, short administration time, reliability and validity, stability, flexibility of administration (face-to-face, over the telephone and by post), cost-free availability and ease of access. These benefits apply to other derivatives of the scale, including the Glasgow Outcome at Discharge Scale (GODS) and the GOS paediatric revision. The GOS was devised to provide an overview of outcome and to focus on social recovery. Since the initial development of the GOS, there has been an increasing focus on the multidimensional nature of outcome after head injury. This Review charts the development of the GOS, its refinement and usage over the past 40 years, and considers its current and future roles in developing an understanding of brain injury