An efficient algorithm to compute marginal posterior genotype probabilities for every member of a pedigree with loops

<p>Abstract</p> <p>Background</p> <p>Marginal posterior genotype probabilities need to be computed for genetic analyses such as geneticcounseling in humans and selective breeding in animal and plant species.</p> <p>Methods</p> <p>In this paper, we describe a peeling based, deterministic, exact algorithm to compute efficiently genotype probabilities for every member of a pedigree with loops without recourse to junction-tree methods from graph theory. The efficiency in computing the likelihood by peeling comes from storing intermediate results in multidimensional tables called cutsets. Computing marginal genotype probabilities for individual <it>i </it>requires recomputing the likelihood for each of the possible genotypes of individual <it>i</it>. This can be done efficiently by storing intermediate results in two types of cutsets called anterior and posterior cutsets and reusing these intermediate results to compute the likelihood.</p> <p>Examples</p> <p>A small example is used to illustrate the theoretical concepts discussed in this paper, and marginal genotype probabilities are computed at a monogenic disease locus for every member in a real cattle pedigree.</p

Improved techniques for sampling complex pedigrees with the Gibbs sampler

Markov chain Monte Carlo (MCMC) methods have been widely used to overcome computational problems in linkage and segregation analyses. Many variants of this approach exist and are practiced; among the most popular is the Gibbs sampler. The Gibbs sampler is simple to implement but has (in its simplest form) mixing and reducibility problems; furthermore in order to initiate a Gibbs sampling chain we need a starting genotypic or allelic configuration which is consistent with the marker data in the pedigree and which has suitable weight in the joint distribution. We outline a procedure for finding such a configuration in pedigrees which have too many loci to allow for exact peeling. We also explain how this technique could be used to implement a blocking Gibbs sampler

Fattening comparisons steers vs. heifers

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Fattening early and late lambs

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Corn substitutes for fattening cattle

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Community acceptance of COVID-19 and demystifying stigma in a severely affected population in Ghana

Objective: We assessed the level of community acceptance of COVID-19, identified and implemented strategies to demystifying stigma in a severely affected population in Tema.Design and Setting: We conducted a cross-sectional study to assess stigma among the Tema community, then identified and implemented interventions to demystify COVID-19 stigma. We interviewed positive cases, their contacts, contact tracers, case management team members, and community members who shared their first hand experiences and knowledge on the current pandemic.Intervention: Based on the information received, we came up with ways of reducing stigma and implemented them in their community.Main Outcome: Stigma demystifiedResults: Cases and contacts reported being avoided, discriminated against, insulted or had derogatory words used on them by family, friends, work colleagues or the community. Cases and their contacts stated that stigmatisation was fueled by the presence of COVID -19 branded vehicles and security officials at their homes or workplaces. Stakeholder engagement, education and extensive sensitisation of community members were implemented to reduce stigma.Conclusion: We observed deeply entrenched stigma to COVID - 19 positive patients and their contacts in the community. Health care response mechanisms such as the presence of security personnel with contact tracers and case managers and the use of COVID -19 branded vehicles fueled stigma. A multifaceted approach through the engagement of key stakeholders, training of health workers and extensive education and community sensitisation was essential in reducing stigma

Bringing Molecular Biology to Bear on Adhesion Prevention: Postsurgical Adhesion Reduction Using Intraperitoneal Inoculation of Hyaluronic Acid–Inducing Adenoviral Vector in a Murine Model

Objective: Seprafilm (Genzyme, Cambridge, MA) an absorbable adhesion barrier incorporating hyaluronic acid (HA), a high molecular mass glycosaminoglycan and important component of the extracellular matrix, has been shown to prevent adhesions in both experimental models and human subjects. Yet, the application of HA as a sheet at the time of surgery has several important logistic limitations. Recently, our laboratory has identified and cloned the genes encoding murine hyaluronic acid synthase 2 (mHAS2) and 3 (mHAS3) and engineered adenoviruses incorporating these genes, which, on intraperitoneal injection, significantly increases HA in peritoneal fluid. We hypothesized that intraperitoneal gene therapy with mHAS2 or mHAS3 via an adenoviral vector prior to a standardized cecal abrasion surgery would lead to a reduction in postoperative adhesion severity. Methods: Mice were assigned to one of four groups: (1) intraperitoneal inoculation with adenovirus encoding mHAS2; (2) mHAS3; (3) a control reporter adenovirus (RV) encoding GFP; or (4) intraoperative placement of a commercially available and murine-validated hyaluronic acid adhesion barrier (Seprafilm, SF). An a priori sample size calculation was performed. Mice in groups 1, 2, and 3 underwent injection of 2 x 107 viral particles in 1 ml of fluid on day -1. Sham injection was performed on group 4 SF mice. On day 0, laparotomy was performed in random sequence by surgeon blinded to the experimental group. On day 7, adhesion scores (0-3) were assigned independently by two blinded investigators. Results: Mean adhesion scores (n = 247) were 0.68 (mHAS2), 0.91 (mHAS3), 1.28 (RV), and 0.47 (SF). Pairwise comparisons using Wilcoxon rank-sum test revealed significant reduction in severity of adhesions between mHAS2, mHAS3, and SF compared to RV (p = 0.0004, 0.039, and 0.0001, respectively). Significance persisted despite correction for multiple comparisons (p = 0.0002, Kruskal-Wallis). There was a direct relationship between intraperitoneal HA concentration and adhesion reduction. Only one death (RV) was secondary to adhesive disease; differential risk of death between groups was statistically significant (p = 0.008) (highest in mHAS2 group). Conclusions: In a dose-response relationship, an intraperitoneal gene therapy approach to adhesion prevention in a murine model was successful, with adenoviruses most productive of HA resulting in the most significant reduction in adhesion scores compared to empty virus (RV). Although SF best reduced postoperative adhesions, the adenoviral gene delivery approach may prove to be more effective in clinical use when peritoneal injury is less localized or at laparoscopy where the application of SF is not possible. Further studies to elucidate the reason for the differential death rates (time bias may have played a role) and to validate results are in progress

The Na/K-ATPase Oxidant Amplification Loop Regulates Aging

As aging involves oxidant injury, we examined the role of the recently described Na/K-ATPase oxidant amplification loop (NKAL). First, C57Bl6 old mice were given a western diet to stimulate oxidant injury or pNaKtide to antagonize the NKAL. The western diet accelerated functional and morphological evidence for aging whereas pNaKtide attenuated these changes. Next, human dermal fibroblasts (HDFs) were exposed to different types of oxidant stress in vitro each of which increased expression of senescence markers, cell-injury, and apoptosis as well as stimulated the NKAL. Further stimulation of the NKAL with ouabain augmented cellular senescence whereas treatment with pNaKtide attenuated it. Although N-Acetyl Cysteine and Vitamin E also ameliorated overall oxidant stress to a similar degree as pNaKtide, the pNaKtide produced protection against senescence that was substantially greater than that seen with either antioxidant. In particular, pNaKtide appeared to specifically ameliorate nuclear oxidant stress to a greater degree. These data demonstrate that the NKAL is intimately involved in the aging process and may serve as a target for anti-aging interventions