A model for phenotype change in a stochastic framework

some species, an inducible secondary phenotype will develop some time after the environmental change that evokes it. Nishimura (2006) [4] showed how an individual organism should optimize the time it takes to respond to an environmental change ("waiting time''). If the optimal waiting time is considered to act over the population, there are implications for the expected value of the mean fitness in that population. A stochastic predator-prey model is proposed in which the prey have a fixed initial energy budget. Fitness is the product of survival probability and the energy remaining for non-defensive purposes. The model is placed in the stochastic domain by assuming that the waiting time in the population is a normally distributed random variable because of biological variance inherent in mounting the response. It is found that the value of the mean waiting time that maximises fitness depends linearly on the variance of the waiting time

Epigenetic Gene Promoter Methylation at Birth Is Associated With Child’s Later Adiposity

Objective: fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans.Research design and methods: using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5? from five candidate genes in umbilical cord tissue DNA from healthy neonates. Methylation varied greatly at particular CpGs: for 31 CpGs with median methylation ?5% and a 5–95% range ?10%, we related methylation status to maternal pregnancy diet and to child’s adiposity at age 9 years. Replication was sought in a second independent cohort.Results: in cohort 1, retinoid X receptor-? (RXRA) chr9:136355885+ and endothelial nitric oxide synthase (eNOS) chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient [?] 17% per SD change in methylation [95% CI 4–31], P = 0.009, n = 64, and ? = 20% [9–32], P < 0.001, n = 66, respectively) and %fat mass (? = 10% [1–19], P = 0.023, n = 64 and ? =12% [4–20], P = 0.002, n = 66, respectively). Regression analyses including sex and neonatal epigenetic marks explained >25% of the variance in childhood adiposity. Higher methylation of RXRA chr9:136355885+, but not of eNOS chr7:150315553+, was associated with lower maternal carbohydrate intake in early pregnancy, previously linked with higher neonatal adiposity in this population. In cohort 2, cord eNOS chr7:150315553+ methylation showed no association with adiposity, but RXRA chr9:136355885+ methylation showed similar associations with fat mass and %fat mass (? = 6% [2–10] and ? = 4% [1–7], respectively, both P = 0.002, n = 239).Conclusions: our findings suggest a substantial component of metabolic disease risk has a prenatal developmental basis. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic diseas

Trapping Dynamics with Gated Traps: Stochastic Resonance-Like Phenomenon

We present a simple one-dimensional trapping model prompted by the problem of ion current across biological membranes. The trap is modeled mimicking the ionic channel membrane behaviour. Such voltage-sensitive channels are open or closed depending on the value taken by a potential. Here we have assumed that the external potential has two contributions: a determinist periodic and a stochastic one. Our model shows a resonant-like maximum when we plot the amplitude of the oscillations in the absorption current vs. noise intensity. The model was solved both numerically and using an analytic approximation and was found to be in good accord with numerical simulations.Comment: RevTex, 5 pgs, 3 figure

Prenatal factors contribute to the emergence of kwoshiorkor or marasmus in severe undernutrition: evidence for the predictive adaptation model

Severe acute malnutrition in childhood manifests as oedematous (kwashiorkor, marasmic kwashiorkor) and non-oedematous (marasmus) syndromes with very different prognoses. Kwashiorkor differs from marasmus in the patterns of protein, amino acid and lipid metabolism when patients are acutely ill as well as after rehabilitation to ideal weight for height. Metabolic patterns among marasmic patients define them as metabolically thrifty, while kwashiorkor patients function as metabolically profligate. Such differences might underlie syndromic presentation and prognosis. However, no fundamental explanation exists for these differences in metabolism, nor clinical pictures, given similar exposures to undernutrition. We hypothesized that different developmental trajectories underlie these clinical-metabolic phenotypes: if so this would be strong evidence in support of predictive adaptation model of developmental plasticity

Knowledge Exchange Through Science Diplomacy to Assist Disaster Risk Reduction. Progress in Disaster Science

This paper analyses science diplomacy efforts to reduce disaster risks and proposes establishing national knowledge exchange centers (KECs) to help individual states adhere to their Sendai Framework goals. KECs are considered to be interconnected globally and work together to promote resilience efforts by facilitating sharing of information and strategies in risk monitoring, assessment, and ultimately reduction across the globe. KECs can provide high-quality scientific evidence for informed decisionmaking along with a component related to disaster science media to ensure that appropriate knowledge reaches a variety of people who need it in different forms tailored for them. KECs can promote transdisciplinary education in disaster-related science diplomacy (i.e., disaster diplomacy). The United Nations Office for Disaster Risk Reduction (UNDRR) and the International Science Council (ISC) can provide assistance to KECs through UNDRR National Platforms and ISC Members

Stochastic synchronization in globally coupled phase oscillators

Cooperative effects of periodic force and noise in globally Cooperative effects of periodic force and noise in globally coupled systems are studied using a nonlinear diffusion equation for the number density. The amplitude of the order parameter oscillation is enhanced in an intermediate range of noise strength for a globally coupled bistable system, and the order parameter oscillation is entrained to the external periodic force in an intermediate range of noise strength. These enhancement phenomena of the response of the order parameter in the deterministic equations are interpreted as stochastic resonance and stochastic synchronization in globally coupled systems.Comment: 5 figure

Abstract 219: Use of Machine Learning Models to Identify Atherosclerotic Cardiovascular Disease Patients at Very High Risk for Future Events in a Multi-state Health Care System

Background: In the 2018 AHA/ACC Blood Cholesterol Guideline, it is recommended that ASCVD patients be classified as very high-risk (VHR) vs not-VHR (NVHR) to guide treatment decisions. This has important implications for ezetimibe and PCSK9 inhibitor eligibility. We aimed to develop a tool that could assist in more easily identifying VHR patients based on machine learning (ML) techniques. This approach offers a powerful, assumption-free alternative to conventional methods, such as logistic regression, to identify potential interactions among risk factors while incorporating the hierarchy of interaction among variables. Method: We used EHR-derived ICD-10 codes to identify patients within our health system with ASCVD. VHR was defined by ≥2 major ASCVD events (ACS ≤12 months, history of MI \u3e12 months, ischemic stroke, or symptomatic PAD) or 1 major ASCVD event and ≥2 high-risk conditions (age ≥65, diabetes, hypertension, smoking, heterozygous familial hypercholesterolemia, CKD, CHF, persistently elevated LDL-C ≥100 mg/dl, or prior CABG/PCI). Patients not meeting these criteria were classified as NVHR. We randomly assigned patients into a training set and a testing set. Classification and regression tree (CART) modeling was performed on the training set and validated on the testing set. The results were compared with a random forest model. Variables in both models included age, sex, race, ethnicity, and each of the VHR criteria above. The primary outcome for both models was VHR classification. Performance of the two models were compared using area under the curve (AUC). Result: A total of 180,669 ASCVD patients were identified in 2018: 104,123 (58%) were VHR and 76,546 (42%) were NVHR. Mean age and sex were 73.1±11.9 years, 55% male and 70.1±13.4 years, 54% male for the VHR and NVHR groups, respectively. Half the population was randomly selected as the training dataset (n=90,334) and the other half was used as the testing dataset (n=90,335). Both CART and random forest models identified recent ACS, ischemic stroke, hypertension, PAD, and history of MI as the top five predictors of VHR status. Ninety-six percent of patients with recent ACS were classified as VHR. Among patients with no recent ACS, 95% were classified as VHR if they had a stroke and hypertension. Among patients with no ACS or stroke, 89% were classified as VHR if they had PAD. Finally, among patients with no ACS, stroke or PAD, 90% were classified as VHR if they had a history of MI. The misclassification rate of the CART model on the testing set was 4.3%. The AUC for the CART and random forest models was 0.949 and 0.968, respectively. Conclusion: Both ML methods were highly predictive of VHR status among those with ASCVD. Use of this approach affords a simplified means to drive clinical decision making at the point of care

Fludarabine-Based Reduced Intensity Conditioning for Stem Cell Transplantation of Fanconi Anemia Patients from Fully Matched Related and Unrelated Donors

AbstractReduced intensity conditioning has been suggested as a desirable therapeutic modality for the treatment of patients with malignant and nonmalignant indications, but it seems particularly attractive for patients with Fanconi anemia due to their increased sensitivity to chemoradiotherapy. Between November 1996 and September 2003, 7 patients (1 male and 6 female; age range, 3-31 years; median age, 9.5) were conditioned with a fludarabine-based protocol for stem cell transplantation without radiation. In vivo T-cell depletion was accomplished with anti-thymocytic globulin or Campath-1H (alemtuzumab). Graft-versus-host disease prophylaxis consisted of low-dose cyclosporine alone. Eight transplantations were carried out for 7 patients using bone marrow, peripheral blood, and/or cord blood as sources of stem cells. All patients received transplants from HLA-A, -B, -C, and -DR matched donors, 5 from family members and 2 from matched unrelated donors. One patient did not engraft her first matched unrelated donor and underwent a second transplantation from another matched unrelated donor, after which she engrafted well. All 7 patients are alive and well, fully reconstituted with donor cells, and with 100% performance status. In conclusion, fludarabine-based preparative protocols are well tolerated, facilitate rapid engraftment with minimal toxicity, and should be considered an essential component of choice for patients with Fanconi anemia

Towards understanding the myometrial physiome: approaches for the construction of a virtual physiological uterus

Premature labour (PTL) is the single most significant factor contributing to neonatal morbidity in Europe with enormous attendant healthcare and social costs. Consequently, it remains a major challenge to alleviate the cause and impact of this condition. Our ability to improve the diagnosis and treatment of women most at risk of PTL is, however, actually hampered by an incomplete understanding of the ways in which the functions of the uterine myocyte are integrated to effect an appropriate biological response at the multicellular whole organ system. The level of organization required to co-ordinate labouring uterine contractile effort in time and space can be considered immense. There is a multitude of what might be considered mini-systems involved, each with their own regulatory feedback cycles, yet they each, in turn, will influence the behaviour of a related system. These include, but are not exclusive to, gestational-dependent regulation of transcription, translation, post-translational modifications, intracellular signaling dynamics, cell morphology, intercellular communication and tissue level morphology. We propose that in order to comprehend how these mini-systems integrate to facilitate uterine contraction during labour (preterm or term) we must, in concert with biological experimentation, construct detailed mathematical descriptions of our findings. This serves three purposes: firstly, providing a quantitative description of series of complex observations; secondly, proferring a database platform that informs further testable experimentation; thirdly, advancing towards the establishment of a virtual physiological uterus and in silico clinical diagnosis and treatment of PTL