Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

Purpose: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. Methods: We performed exwct ome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. Results: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. Conclusion: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies

Predicting Bevirimat resistance of HIV-1 from genotype

<p>Abstract</p> <p>Background</p> <p>Maturation inhibitors are a new class of antiretroviral drugs. Bevirimat (BVM) was the first substance in this class of inhibitors entering clinical trials. While the inhibitory function of BVM is well established, the molecular mechanisms of action and resistance are not well understood. It is known that mutations in the regions CS p24/p2 and p2 can cause phenotypic resistance to BVM. We have investigated a set of p24/p2 sequences of HIV-1 of known phenotypic resistance to BVM to test whether BVM resistance can be predicted from sequence, and to identify possible molecular mechanisms of BVM resistance in HIV-1.</p> <p>Results</p> <p>We used artificial neural networks and random forests with different descriptors for the prediction of BVM resistance. Random forests with hydrophobicity as descriptor performed best and classified the sequences with an area under the Receiver Operating Characteristics (ROC) curve of 0.93 ± 0.001. For the collected data we find that p2 sequence positions 369 to 376 have the highest impact on resistance, with positions 370 and 372 being particularly important. These findings are in partial agreement with other recent studies. Apart from the complex machine learning models we derived a number of simple rules that predict BVM resistance from sequence with surprising accuracy. According to computational predictions based on the data set used, cleavage sites are usually not shifted by resistance mutations. However, we found that resistance mutations could shorten and weaken the <it>α</it>-helix in p2, which hints at a possible resistance mechanism.</p> <p>Conclusions</p> <p>We found that BVM resistance of HIV-1 can be predicted well from the sequence of the p2 peptide, which may prove useful for personalized therapy if maturation inhibitors reach clinical practice. Results of secondary structure analysis are compatible with a possible route to BVM resistance in which mutations weaken a six-helix bundle discovered in recent experiments, and thus ease Gag cleavage by the retroviral protease.</p

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies

Australian nurses in general practice, enabling the provision of cervical screening and well women's health care services: a qualitative study

Background\ud The role of Australian general practice nurses (PNs) has developed exponentially since the introduction of service based funding in 2005. In particular, their role has expanded to include cervical screening and well women’s health care services provided under the supervision of a general practitioner (GP). While previous research identifies barriers to the provision of these services, this study sought to investigate enablers for nurse led care in this area.\ud \ud Methods\ud A number of grounded theory methods including constantly comparing data, concurrent data collection and analysis and theoretical sampling are utilised in this qualitative, exploratory study. A purposive sample of PNs who completed the required program of education in order to provide cervical screening and well women’s health care services was recruited to the study. Data is presented in categories, however a limitation of the study is that a fully integrated grounded theory was unable to be produced due to sampling constraints.\ud \ud Results\ud Four enablers for the implementation of a change in the PN role to include cervical screening and well women’s health checks are identified in this study. These enablers are: GPs being willing to relinquish the role of cervical screener and well women’s health service provider; PNs being willing to expand their role to include cervical screening and well women’s health services; clients preferring a female practice nurse to meet their cervical screening and well women’s health needs; and the presence of a culture that fosters interprofessional teamwork. Seven strategies for successfully implementing change from the perspective of PNs are also constructed from the data. This study additionally highlights the lack of feedback on smear quality provided to PNs cervical screeners and well women’s health service providers.\ud \ud Conclusions\ud The influence of consumers on the landscape of primary care service delivery in Australia is of particular note in this study. Developing interprofessional teams \u