Tarynn M. Witten

Shortest-Path Network Analysis Is a Useful Approach toward Identifying Genetic Determinants of Longevity

Background Identification of genes that modulate longevity is a major focus of aging-related research and an area of intense public interest. In addition to facilitating an improved understanding of the basic mechanisms of aging, such genes represent potential targets for therapeutic intervention in multiple age-associated diseases, including cancer, heart disease, diabetes, and neurodegenerative disorders. To date, however, targeted efforts at identifying longevity-associated genes have been limited by a lack of predictive power, and useful algorithms for candidate gene-identification have also been lacking. Methodology/Principal Findings We have utilized a shortest-path network analysis to identify novel genes that modulate longevity in Saccharomyces cerevisiae. Based on a set of previously reported genes associated with increased life span, we applied a shortest-path network algorithm to a pre-existing protein–protein interaction dataset in order to construct a shortest-path longevity network. To validate this network, the replicative aging potential of 88 single-gene deletion strains corresponding to predicted components of the shortest-path longevity network was determined. Here we report that the single-gene deletion strains identified by our shortest-path longevity analysis are significantly enriched for mutations conferring either increased or decreased replicative life span, relative to a randomly selected set of 564 single-gene deletion strains or to the current data set available for the entire haploid deletion collection. Further, we report the identification of previously unknown longevity genes, several of which function in a conserved longevity pathway believed to mediate life span extension in response to dietary restriction. Conclusions/Significance This work demonstrates that shortest-path network analysis is a useful approach toward identifying genetic determinants of longevity and represents the first application of network analysis of aging to be extensively validated in a biological system. The novel longevity genes identified in this study are likely to yield further insight into the molecular mechanisms of aging and age-associated disease.

Validation of a computational platform for the analysis of the physiologic mechanisms of a human experimental model of hemorrhage

Computational models of integrative physiology may serve as a framework for understanding the complex adaptive responses essential for homeostasis in critical illness and resuscitation and may provide insights for design of diagnostics and therapeutics. In this study a computer model of human physiology was compared to results obtained from experiments using Lower Body Negative Pressure (LBNP) analog model of human hemorrhage. LBNP has been demonstrated to produce physiologic changes in humans consistent with hemorrhage. The computer model contains over 4000 parameters that describe the detailed integration of physiology based upon basic physical principles and established biologic interactions. The LBNP protocol consisted of a 5min rest period (0mmHg) followed by 5min of chamber decompression of the lower body to -15, -30, -45, and -60mmHg and additional increments of -10mmHg every 5min until the onset of hemodynamic decompensation (n=20). Physiologic parameters recorded include mean arterial pressure (MAP), cardiac output (CO), and venous oxygen saturation (SVO(2); from peripheral venous blood), during the last 30s at each LBNP level. The computer model analytic procedure recreates the investigational protocol for a virtual individual in an In Silico environment. After baseline normalization, the model predicted measurements for MAP, CO, and SVO(2) were compared to those observed through the entire range of LBNP. Differences were evaluated using standard statistical performance error measurements (median performance error (PE) <5%). The simulation results closely tracked the average changes observed during LBNP. The predicted MAP fell outside the standard error measurement for the experimental data at only LBNP -30mmHg while CO was more variable. The predicted SVO(2) fell outside the standard error measurement for the experimental data only during the post-LBNP recovery point. However, the statistical median PE measurement was found to be within the 5% objective error measure (1.3% for MAP, -3.5% for CO, and 3.95% for SVO(2)). The computer model was found to accurately predict the experimental results observed using LBNP. The model should be explored as a platform for studying concepts and physiologic mechanisms of hemorrhage including its diagnosis and treatment.

Graceful Exits: Intersection of Aging, Transgender Identities, and the Family/Community

In a previous series of papers, this author investigated many of the challenges of growing old within the transgender population. Challenges with respect to violence, abuse, and hate crimes were examined as they related to institutional organizations such as the health care system, religious organizations, the military, and the legal system. Medical and general health care needs of transgender-identified elders were also addressed. However, within all of these articles, the central discussion has been around the needs of the transgender-identified elder. In this paper, I revisit the challenges of being an elder trans-person from the perspective of family members and community. I explore how they intersect with constructs of family as well as family relationships. I take on some of the normative aging processes discussed in these earlier papers and examine the overlap of transgender and aging with family/community. Examples are drawn from the authors field studies and surveys.

Religious Affiliation and Successful Aging Among Transgender Older Adults: Findings From the Trans MetLife Survey

Religion may enhance successful aging by reducing stress, improving well-being, and augmenting social engagement. However, there is a paucity of research specific to religious affiliation in the elusive transgender-identified population. This exploratory study describes the demographic profile and religious affiliation of 289 transgender adults age 51 and older. Results indicate that the majority of transgender older adults (73.4%) are aging successfully, even though many are disabled or chronically ill. Transgender older adults affiliate with a wide range of religious and spiritual practices with a greater participation in lesbian, gay, bisexual, transgender-affirming religions than the normative sex and gender population.

A biomechanical model of wound contraction and scar formation

We propose a biomechanical model for investigating wound contraction mechanism and resulting scarring. Extracellular matrix is modeled as fiber-reinforced anisotropic soft tissue, with its elastic properties dynamically changing with the density and orientation of collagen fibers. Collagen fibers are deposited by fibroblasts infiltrating the wound space, and are dynamically aligned with both migrating fibroblasts and tissue residing tension field. Our new 2D hybrid agent-based model provides a comprehensive platform for examining the mechanobiology in wound contraction and scar formation. Simulation results are consistent with experimental observations and are able to reveal the effects of wound morphology and mechanical environment on contraction patterns. Our model results support the hypothesis that scar formation is the product of collagen fiber synthesis and alignment in the presence of the tensile stress field generated by a wound contraction process.

Providing Competent and Affirming Services for Transgender and Gender Nonconforming Older Adults

ABSTRACT Despite the growing visibility and acceptance of transgender and gender nonconforming (TGNC) individuals, TGNC older adults experience many barriers in accessing competent and affirming health and social services due to anti-TGNC prejudice, discrimination, and lack of competent healthcare training on the part of healthcare workers. Clinical gerontologists and geriatricians will likely encounter TGNC adults in their practice given population aging and greater numbers of TGNC people who are living in their affirmed gender identities. The American Psychological Association recently published its Guidelines for Psychological Practice with Transgender and Gender Nonconforming People, which document the unique needs of TGNC individuals and outlines approaches for competent and affirming service provision (APA, 2015). We interpret these Guidelines using a gerontological lens to elucidate specific issues faced by the TGNC older adult along with the practice and policy implications for this population.

Elder transgender lesbians: exploring the intersection of age, lesbian sexual identity, and transgender identity.

This study is the first to examine the experiences and needs of an international sample of current, English-speaking, lesbian, transgender-identified (trans-lesbian) adults around a number of later life and end-of-life perceptions, preparations, and concerns. I analyzed a subset (n = 276) of the cross-sectional data collected from the online Trans MetLife Survey on Later-Life Preparedness and Perceptions in Transgender-Identified Individuals (N = 1,963). I assessed perceptions and fears around aging, preparation for later life, and end-of-life as well as numerous demographic and psycho-social variables. Despite the overall feeling that they have aged successfully, the respondent trans-lesbian population harbors significant fears about later life. I found that this population, while better-prepared than the overall respondent trans-identified population, is still ill-prepared for the major legalities and events that occur in the later to end-of-life time periods.

Resilience and Multiple Stigmatized Identities: Lessons from Transgender Persons’ Reflections on Aging

This chapter describes the qualitative analysis of responses given by 122 transgender persons aged 61 and older who answered nine questions in an online survey about hopes and fears about aging, strategies for successful aging, and wisdom to convey to younger transgender individuals. More than 70 % stated they believe they are aging successfully. We identified six components of the resilience repertoires that enabled them to say they are aging successfully despite the stigma associated with their gender-variant identities and sexual minority status. Queer theory and the idea of intersectionality contributed to our interpretation of the resilience repertoires.

An in silico approach to the analysis of acute wound healing

The complex interactions that characterize acute wound healing have stymied the development of effective therapeutic modalities. The use of computational models holds the promise to improve our basic approach to understanding the process. By modifying an existing ordinary differential equation model of systemic inflammation to simulate local wound healing, we expect to improve the understanding of the underlying complexities of wound healing and thus allow for the development of novel, targeted therapeutic strategies. The modifications in this local acute wound healing model include: evolution from a systemic model to a local model, the incorporation of fibroblast activity, and the effects of tissue oxygenation. Using these modifications we are able to simulate impaired wound healing in hypoxic wounds with varying levels of contamination. Possible therapeutic targets, such as fibroblast death rate and rate of fibroblast recruitment, have been identified by computational analysis. This model is a step toward constructing an integrative systems biology model of human wound healing.

Transgender bodies, identities, and healthcare: Effects of perceived and actual violence and abuse

“Disparity” implies the existence of a “markedly distinct in quality or character,” difference between one group and another. Some groups, due to elevated stigma associated with group membership, are invisible as a disparate minority and therefore, while there may be a great inequity in healthcare between that group and the normative population, the invisible minority is ignored. This chapter addresses the issue of healthcare for the transgender-identified population. We address how the normative viewpoint of mental illness and unacceptable religious status, along with lifelong perceived and actual abuse and violence, creates a socially sanctioned inequality in healthcare for this population.