Signaling of Human Frizzled Receptors to the Mating Pathway in Yeast

Frizzled receptors have seven membrane-spanning helices and are considered as atypical G protein-coupled receptors (GPCRs). The mating response of the yeast Saccharomyces cerevisiae is mediated by a GPCR signaling system and this model organism has been used extensively in the past to study mammalian GPCR function. We show here that human Frizzled receptors (Fz1 and Fz2) can be properly targeted to the yeast plasma membrane, and that they stimulate the yeast mating pathway in the absence of added Wnt ligands, as evidenced by cell cycle arrest in G1 and reporter gene expression dependent on the mating pathway-activated FUS1 gene. Introducing intracellular portions of Frizzled receptors into the Ste2p backbone resulted in the generation of constitutively active receptor chimeras that retained mating factor responsiveness. Introducing intracellular portions of Ste2p into the Frizzled receptor backbone was found to strongly enhance mating pathway activation as compared to the native Frizzleds, likely by facilitating interaction with the yeast Gα protein Gpa1p. Furthermore, we show reversibility of the highly penetrant G1-phase arrests exerted by the receptor chimeras by deletion of the mating pathway effector FAR1. Our data demonstrate that Frizzled receptors can functionally replace mating factor receptors in yeast and offer an experimental system to study modulators of Frizzled receptors

Biology of human hair: Know your hair to control it

Hair can be engineered at different levels—its structure and surface—through modification of its constituent molecules, in particular proteins, but also the hair follicle (HF) can be genetically altered, in particular with the advent of siRNA-based applications. General aspects of hair biology are reviewed, as well as the most recent contributions to understanding hair pigmentation and the regulation of hair development. Focus will also be placed on the techniques developed specifically for delivering compounds of varying chemical nature to the HF, indicating methods for genetic/biochemical modulation of HF components for the treatment of hair diseases. Finally, hair fiber structure and chemical characteristics will be discussed as targets for keratin surface functionalization

Which Results to Return: Subjective Judgments in Selecting Medically Actionable Genes

Background: Advances in genomics have led to calls for returning information about medically actionable genes (MAGs) to patients, research subjects, biobank participants, and through screening programs, the general adult population. Which MAGs are returned affects the harms and benefits of every genetic testing endeavor. Despite published recommendations of selection criteria for MAGs to return, scant data exist regarding how decision makers actually apply such criteria. Methods: The process and criteria used by researchers when selecting MAGs for a preventive genomic sequencing program targeting the general adult population were examined. The authors observed and audio-recorded the gene selection meetings, and analyzed meeting transcripts, gene scoring sheets, and meeting handouts. Results: To select MAGs, the committee imported, from a preexisting project, “a semiquantitative metric” that scores genes on five criteria. Numerous subjective judgments and conceptual challenges in defining and applying the five criteria complicated the selection process. Criteria-related challenges also included the limited evidence available about facts fundamental to the scoring decisions and the emergence and application of criteria that were not part of the original metric. Conclusions: When identifying MAGs appropriate for screening and return, decision makers must expect and prepare to address such issues as the inevitability of subjective judgments, limited evidence about fundamental decision-making elements, the conceptual complexity of defining criteria, and the emergence of unplanned criteria during the gene selection process

Unexpected tissue and the biobank that closed: An exploration of value and the momentariness of bio-objectification processes

Unanticipated situations can arise in biobanking. This paper empirically documents unexpected situations at the anonymous biobank ‘Xbank’. Firstly, Xbank received an unexpected and significant quantity of tissue from the historical archive of a hospital network. Secondly, Xbank had its funding withdrawn before the designated end date for the grant, meaning the bank needed to either re-house or destroy its holdings. This paper articulates and uses the theoretical frameworks of bio-objectification and tissue economies to analyse the experiences of Xbank and draw out further implications of the potential precariousness of biobanking practice. The case study allows an inspection of how the value of tissue is configured and reconfigured as institutional contexts shift. We introduce the notion of momentariness as a way of grappling with the related temporariness and perpetualness of biobanking practice in both a theoretical and practical policy context.The UK’s Economic and Social Research Council (ESRC). This work is part of the research program of the ESRC Genomic Network at Cesagen (ESRC Centre for Economic and Social Aspects of Genomics RES-145-28-0003)

Is there evidence that we should screen the general population for Lynch syndrome with genetic testing? A systematic review

Anya E R Prince,1 R Jean Cadigan,1,2 Gail E Henderson,1,2 James P Evans,1,3–6 Michael Adams,1,3 Emmanuel Coker-Schwimmer,7 Dolly C Penn,2 Marcia Van Riper,1,8 Giselle Corbie-Smith,1,2,6 Daniel E Jonas1,6,7 1Center for Genomics and Society, 2Department of Social Medicine, 3Department of Genetics, 4Carolina Center for Genome Sciences, 5Lineberger Comprehensive Cancer Center, 6Department of Medicine, 7Cecil G. Sheps Center for Health Services Research, 8School of Nursing, The University of North Carolina-Chapel Hill, Chapel Hill, NC, USA Background: The emerging dual imperatives of personalized medicine and technologic advances make population screening for preventable conditions resulting from genetic alterations a realistic possibility. Lynch syndrome is a potential screening target due to its prevalence, penetrance, and the availability of well-established, preventive interventions. However, while population screening may lower incidence of preventable conditions, implementation without evidence may lead to unintentional harms. We examined the literature to determine whether evidence exists that screening for Lynch-associated mismatch repair (MMR) gene mutations leads to improved overall survival, cancer-specific survival, or quality of life. Documenting evidence and gaps is critical to implementing genomic approaches in public health and guiding future research.Materials and methods: Our 2014–2015 systematic review identified studies comparing screening with no screening in the general population, and controlled studies assessing analytic validity of targeted next-generation sequencing, and benefits or harms of interventions or screening. We conducted meta-analyses for the association between early or more frequent colonoscopies and health outcomes.Results: Twelve studies met our eligibility criteria. No adequate evidence directly addressed the main question or the harms of screening in the general population. Meta-analyses found relative reductions of 68% for colorectal cancer incidence (relative risk: 0.32, 95% confidence interval: 0.23–0.43, three cohort studies, 590 participants) and 78% for all-cause mortality (relative risk: 0.22, 95% confidence interval: 0.09–0.56, three cohort studies, 590 participants) for early or more frequent colonoscopies among family members of people with cancer who also had an associated MMR gene mutation.Conclusion: Inadequate evidence exists examining harms and benefits of population-based screening for Lynch syndrome. Lack of evidence highlights the need for data that directly compare benefits and harms. Keywords: Lynch syndrome, systematic review, targeted next-generation sequencing, genetic screening, general populatio

Neglected ethical issues in biobank management: Results from a U.S. study

The empirical literature on the ethical, legal, and social implications (ELSI) of biobanking has almost entirely relied on the perspectives of those outside of biobanks, such as the general public, researchers, and specimen contributors. Little attention has been paid to the perspectives and practices of those who operate biobanks. We conducted a study of U.S. biobanks consisting of six in-depth case studies and a large online survey (N = 456), which was developed from the case study results. The case studies included qualitative interviews with a total of 24 personnel. Both interview and survey questions focused on how biobanks operate, and what policies and practices govern their relationships with specimen contributors and the researchers who use the specimens. Analysis revealed unexpected ethical dilemmas embedded in those policies and practices that highlight a need for practical planning. In this paper, we review three issues seldom explored in the ELSI literature: 1. the discrepancy between biobankers’ hope that the bank will exist “permanently” and the fact that funding is limited; 2. the lack of planning for what will happen to the specimens if the bank closes; and 3. the concern that once collected, specimens may be underutilized. These dilemmas are missing from current public representations of biobanks, which instead focus on the intrinsic value in storing specimens as essential to the advancement of translational research. We argue that attention to these issues is important for biobanking, and that greater transparency of these policies and practices will contribute to promoting public trust in biobanks