Regulation of cell proliferation and adhesion by means of a novel region of drosophila merlin interacting with Sip1

Background: The tumor suppressor protein merlin is thought to regulate cell proliferation and cell adhesion through interaction with protein partners. Loss of merlin is associated with Neurofibromatosis Type 2 (NF2) tumors. NHERF1 or EBP50 is a scaffolding protein that functions in apical organization of polarized cells. Merlin and NHERF1 have been shown to interact in vitro in vertebrates. We investigate how the Drosophila NHERF1 orthologue, Sip1, and Merlin function to regulate cell proliferation and adhesion. Results: We identify two conserved arginine residues (R325 and R335) in Merlin which, in addition to the FERM domain, are required for interaction with Sip1. Mutation of the arginine residues result in reduced Sip1 binding to Merlin and loss of Merlin growth suppressor function. Over‐expression of Merlin^R325A and/or Merlin^R335L in Drosophila wings result in increased proliferation in the adult wing (increase in size), which is rescued by co‐over‐expression of constitutively active Merlin protein. Reduced Sip1 binding to Merlin also produces defects in adhesion in follicle epithelial cells. Conclusions: Sip1 facilitates the activation of Merlin as a tumor suppressor protein. Thus, our work provides insight into how Merlin functions as a tumor suppressor and in adhesion and this provides insight into the mechanism of NF2 pathogenesis. Developmental Dynamics 243:1554–1570, 2014. © 2014 Wiley Periodicals, Inc.     

The Genome Clinic: A Multidisciplinary Approach to Assessing the Opportunities and Challenges of Integrating Genomic Analysis into Clinical Care

Our increasing knowledge of how genomic variants affect human health and the falling costs of whole‐genome sequencing are driving the development of individualized genetic medicine. This new clinical paradigm uses knowledge of an individual's genomic variants to guide health care decisions throughout life, to anticipate, diagnose, and manage disease. While individualized genetic medicine offers the promise of transformative change in health care, it forces us to reconsider existing ethical, scientific, and clinical paradigms. The potential benefits of presymptomatic identification of at risk individuals, improved diagnostics, individualized therapy, accurate prognosis, and avoidance of adverse drug reactions coexist with the potential risks of uninterpretable results, psychological harm, outmoded counseling models, and increased health care costs. Here, we review the challenges of integrating genomic analysis into clinical practice and describe a prototype for implementing genetic medicine. Our multidisciplinary team of bioinformaticians, health economists, ethicists, geneticists, genetic counselors, and clinicians has designed a “Genome Clinic” research project that addresses multiple challenges in genomic medicine—ranging from the development of bioinformatics tools for the clinical assessment of genomic variants and the discovery of disease genes to health policy inquiries, assessment of clinical care models, patient preference, and the ethics of consent.     

The planarian Schmidtea mediterranea as a model system for the discovery and characterization of cell‐penetrating peptides and bioportides

The general utility of the planarian Schmidtea mediterranea, an organism with remarkable regenerative capacity, was investigated as a convenient three‐dimensional model to analyse the import of cell‐penetrating peptides (CPPs) and bioportides (bioactive CPPs) into complex tissues. The unpigmented planarian blastema, 3 days post head amputation, is a robust platform to assess the penetration of red‐fluorescent CPPs into epithelial cells and deeper tissues. Three planarian proteins, Ovo, ZicA and Djeya, which collectively control head remodelling and eye regeneration following decapitation, are a convenient source of novel cationic CPP vectors. One example, Djeya1 (RKLAFRYRRIKELYNSYR), is a particularly efficient and seemingly inert CPP vector that could be further developed to assist the delivery of bioactive payloads across the plasma membrane of eukaryotic cells. Eye regeneration, following head amputation, was utilized in an effort to identify bioportides capable of influencing stem cell‐dependent morphogenesis. These investigations identified the tetradecapeptide mastoparan (INLKALAALAKKIL) as a bioportide able to influence the gross morphology of head development. We conclude that, compared with cellular monolayers, the S. mediterranea system provides many advantages and will support the identification of bioportides able to selectively modify the biology of totipotent neoblasts and, presumably, other mammalian stem cell types.     

Lymphatic filariasis and onchocerciasis prevention,treatment, and control costs across diverse settings: A systematic review

The control and eventual elimination of neglected tropical disease (NTD) requires the expansion of interventions such as mass drug administration (MDA), vector control, diagnostic testing, and effective treatment. The purpose of this paper is to present the evidence base for decision-makers on the cost and cost-effectiveness of lymphatic filariasis (LF) and onchocerciasis prevention, treatment, and control. A systematic review of the published literature was conducted. All studies that contained primary or secondary data on costs or cost-effectiveness of prevention and control were considered. A total of 52 papers were included for LF and 24 papers were included for onchocerciasis. Large research gaps exist on the synergies and cost of integrating NTD prevention and control programs, as well as research on the role of health information systems, human resource systems, service delivery, and essential medicines and technology for elimination. The literature available on costs and cost-effectiveness of interventions is also generally older, extremely focal geographically and of limited usefulness for developing estimates of the global economic burden of these diseases and prioritizing among various intervention options. Up to date information on the costs and cost-effectiveness of interventions for LF and onchocerciasis prevention are needed given the vastly expanded funding base for the control and elimination of these diseases.     

Community Health Workers and Stand-Alone or Integrated Case Management of Malaria: A Systematic Literature Review

A systematic literature review was conducted to assess the effectiveness of strategies to improve community case management (CCM) of malaria. Forty-three studies were included; most (38) reported indicators of community health worker (CHW) performance, 14 reported on malaria CCM integrated with other child health interventions, 16 reported on health system capacity, and 13 reported on referral. The CHWs are able to provide good quality malaria care, including performing procedures such as rapid diagnostic tests. Appropriate training, clear guidelines, and regular supportive supervision are important facilitating factors. Crucial to sustainable success of CHW programs is strengthening health system capacity to support commodity supply, supervision, and appropriate treatment of referred cases. The little evidence available on referral from community to health facility level suggests that this is an area that needs priority attention. The studies of integrated CCM suggest that additional tasks do not reduce the quality of malaria CCM provided sufficient training and supervision is maintained.