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Epigenetics is coming to the fore as a key process which underpins health. In particular emerging experimental evidence has associated alterations to DNA methylation status with healthspan and aging. Mammalian DNA methylation status is maintained by an intricate array of biochemical and molecular processes. It can be argued changes to these fundamental cellular processes ultimately drive the formation of aberrant DNA methylation patterns, which are a hallmark of diseases, such as cancer, Alzheimer’s disease and cardiovascular disease. In recent years mathematical models have been used as effective tools to help advance our understanding of the dynamics which underpin DNA methylation. In this paper we present linear and nonlinear models which encapsulate the dynamics of the molecular mechanisms which define DNA methylation. Applying a recently developed Bayesian algorithm for parameter estimation and model selection, we are able to estimate distributions of parameters which include nominal parameter values. Using limited noisy observations, the method also identified which methylation model the observations originated from, signaling that our method has practical applications in identifying what models best match the biological data for DNA methylation.

Effective intervention strategies for epidemics rely on the identification of their origin and on the robustness of the predictions made by network disease models. We introduce a Bayesian uncertainty quantification framework to infer model parameters for a disease spreading on a network of communities from limited, noisy observations; the state-of-the-art computational framework compensates for the model complexity by exploiting massively parallel computing architectures. Using noisy, synthetic data, we show the potential of the approach to perform robust model fitting and additionally demonstrate that we can effectively identify the disease origin via Bayesian model selection. As disease-related data are increasingly available, the proposed framework has broad practical relevance for the prediction and management of epidemics., Royal Society Open Science, 8 (1), ISSN:2054-5703

A number of problems of interest in applied mathematics and biology involve the quantification of uncertainty in computational and real-world models. A recent approach to Bayesian uncertainty quantification using transitional Markov chain Monte Carlo (TMCMC) is extremely parallelizable and has opened the door to a variety of applications which were previously too computationally intensive to be practical. In this chapter, we first explore the machinery required to understand and implement Bayesian uncertainty quantification using TMCMC. We then describe dissipative particle dynamics, a computational particle simulation method which is suitable for modeling biological structures on the subcellular level, and develop an example simulation of a lipid membrane in fluid. Finally, we apply the algorithm to a basic model of uncertainty in our lipid simulation, effectively recovering a target set of parameters (along with distributions corresponding to the uncertainty) and demonstrating the practicality of Bayesian uncertainty quantification for complex particle simulations.

The utilization of existing social networks is increasingly being recognized as a powerful strategy for delivering healthcare services to underserved populations in low- and middle-income countries. In Guatemala, multiple barriers prevent access to healthcare services for rural and indigenous populations, and strategies for delivering healthcare in more efficient ways are needed. The case study we describe here is a unique collaboration between a microfinance institution (Friendship Bridge) and a primary care organization (Wuqu' Kawoq | Maya Health Alliance) to scale up healthcare through an existing lending-borrowing social network. The program provides primary care services to female clients of Friendship Bridge in rural areas of Guatemala, with nurses working as frontline primary care providers, providing door-to-door healthcare services. Over the first 22 months of the project, we have reached over 3500 of Friendship Bridge's clients, with overall high acceptance of services. All clinical documentation and program monitoring and evaluation are done through audit trails within an electronical medical record system, which improves efficiency and lowers the associated time and resources costs. We utilize quality improvement methodologies to aid in decision making and programmatic adjustments scale up. These strategies have allowed us to expand services rapidly under challenging geographic and logistical constraints, while concurrently iteratively improving staff training and supervision, clinical care, and client engagement processes.

Patient-specific modelling of haemodynamics in arterial networks has so far relied on parameter estimation for inexpensive or small-scale models. We describe here a Bayesian uncertainty quantification framework which makes two major advances: an efficient parallel implementation, allowing parameter estimation for more complex forward models, and a system for practical model selection, allowing evidence-based comparison between distinct physical models. We demonstrate the proposed methodology by generating simulated noisy flow velocity data from a branching arterial tree model in which a structural defect is introduced at an unknown location; our approach is shown to accurately locate the abnormality and estimate its physical properties even in the presence of significant observational and systemic error. As the method readily admits real data, it shows great potential in patient- specific parameter fitting for haemodynamical flow models., Royal Society Open Science, 6 (10), ISSN:2054-5703

A 30-year-old palomino Standardbred horse was seen with a persistent penile squamous cell carcinoma. After failure using multiple treatments, surgical removal was successfully carried out under local anesthesia using Mohs micrographically controlled surgery. Subsequent examination of the malignant tissue identified bovine papillomavirus exclusively within the nuclei and cytoplasm of tumor cells. The use of Mohs surgery would appear to be useful as an effective, precisely controlled treatment for managing genital squamous cell carcinoma in equine subjects. The presence of papillomavirus within tumor cells would suggest the possibility of causation by an oncogenic papilloma virus and would indicate that careful monitoring of the surgical site should be performed.

Samples collected from urban streams in the cities of Sacramento and Stockton, California, USA, during the precipitation season were analyzed for diazinon and chlorpyrifos. Concentrations were determined with enzyme-linked immunosorbent assays specific for each pesticide. Two hundred thirty-one samples from the two cities were analyzed for diazinon; 85% exceeded California Department of Fish and Game water-quality criteria for this pesticide. Chlorpyrifos was measured in 90 of the samples collected from Sacramento and Stockton; 80% exceeded the California Department of Fish and Game criterion for this pesticide. Thirty-six of 47 samples (76.6%) tested for toxicity produced total mortality within 72 h with Ceriodaphnia dubia. Toxicity identification evaluations on selected samples confirmed that toxicity was primarily due to one or both of these pesticides. Uses of diazinon and chlorpyrifos in urban areas include dormant sprays on fruit trees, professional landscape and maintenance uses, and structural pest control. Pesticide concentrations were lower in a catchment favoring commercial and industrial activities compared with a catchment receiving largely residential inputs. Aerial drift from agricultural applications may play a role in storm-water concentrations.

The Pharmacia BlAcore biosensor was used to measure the real-time interaction of Escherichia coli SSB protein with poly(deoxythymidylic acid), (dT) 70 . The rationale for an experimental protocol for this type of binding reaction is presented. This approach may have general applicability in the design and analysis of BiAcore binding experiments. A chip is modified with three different surface densities of biotinylated oligonucleotide and a fourth channel is modified with only streptavidin. This allows examination of collected data for surface crowding effects, for flow limiting or reaction limiting binding, and for surface saturation. These observations are used to develop a mathematical model to describe the family of sensorgrams from a series of surface densities and protein concentrations with a single set of parameters. Each part of the model, as well as its relationship to the overall binding reaction, is described. The model presented is consistent with kinetic data for the association and dissociation rate constants for E. coli SSB and permits calculation of a thermodynamic binding constant. The concept of steric cooperativity is introduced to explain the observed increasing rate of binding as the surface binds more SSB protein.

The mainstay of therapy for pyoderma gangrenosum has been corticosteroids, but many patients respond poorly. During the past 2 years we have treated seven patients who had pyoderma gangrenosum with cyclosporine after their condition proved resistant to conventional therapy. No evidence of permanent toxicity from cyclosporine was detected and treatment with other immunosuppressive agents was discontinued in five of seven cases. Tuberculosis was reactivated in one patient. Three patients had a remission, three had an intermediate response, and one did not respond. These results indicate that cyclosporine is useful in the treatment of patients with refractory pyoderma gangrenosum and suggest an immune mechanism in the pathogenesis of this disorder.

Understanding Face-to-Face Interaction: Issues Linking Goals and Discourse. Karen Tracy. ed. Communication Textbook Series. Hillsdale, N.J.: Lawrence Erlbaum, 1991. 212 pp. $39.95 (cloth), $19.95 (paper)

Recently, magnetic resonance imaging (MRI) has been reported to be clinically useful, in selected cases, in patients with melanocytic skin lesions. This report describes good resolution, clinically useful MRI scans of squamous cell carcinoma, dermatofibroma, and primary cutaneous B-cell lymphoma. The tumor depth measured by MRI was in excellent correlation with Breslow's depth measurements, indicating that MRI is probably the radiologic technique of choice for preoperative evaluation of the extent and depth of primary and recurrent skin tumors. This report also provides the authors' recommendations for obtaining optimal MRI images of cutaneous lesions.

The HIV-1 nucleocapsid (NC) protein is a small, basic protein containing two retroviral zinc fingers. It is a highly active nucleic acid chaperone; because of this activity, it plays a crucial role in virus replication as a cofactor during reverse transcription, and is probably important in other steps of the replication cycle as well. We previously reported that NC binds with high-affinity to the repeating sequence d(TG)n. We have now analyzed the interaction between NC and d(TG)4 in considerable detail, using surface plasmon resonance (SPR), tryptophan fluorescence quenching (TFQ), fluorescence anisotropy (FA), isothermal titration calorimetry (ITC) and electrospray ionization Fourier transform mass spectrometry (ESI-FTMS). Our results show that the interactions between these two molecules are surprisngly complex: while the K(d) for binding of a single d(TG)4 molecule to NC is only approximately 5 nM in 150 mM NaCl, a single NC molecule is capable of interacting with more than one d(TG)4 molecule, and conversely, more than one NC molecule can bind to a single d(TG)4 molecule. The strengths of these additional binding reactions are quantitated. The implications of this multivalency for the functions of NC in virus replication are discussed.

Processing at a higher temperature for a shorter time would be expected to have fewer degradative effects on the nutritional quality and textural properties of foodstuffs. At present 240° F (10 psig) is the most commonly used temperature for home canning, although home pressure canners can be operated at higher pressures than the currently recommended 10 psi. Accordingly, home canning at a higher pressure (15 psig) for a shorter amount of time was investigated. Process values were determined for asparagus, green beans, carrots, corn, peas, squash, beef, fish, beef stew, and green soybeans, and a mean and standard deviation calculated for each product. The mean was then compared in each case with a target process value (derived from the recommended 10 psi process time) plus one standard deviation. In each experimental run the recommended procedure (10 psi) was used as a control. At 15 psi, products which heat by convection currents require approximately l/3 of the time required at 10 psi. However, this much reduction in process time is not possible with products which heat more by conduction.

In vitro exposure of human peripheral blood mononuclear cells (PBMC) to ultraviolet B (uvB) radiation has been shown to inhibit natural killer (NK) cell-mediated cytotoxicity in a dose-dependent fashion. The purpose of this study was to examine the manner by which uvB produced these deleterious effects. Inhibition of NK activity was not due to lethal injury to NK cells since the viability of cell populations enriched for NK activity was greater than 90% with the uvB doses employed. uvB appeared to directly affect NK cells since procedures which removed suppressor mechanisms, such as removal of monocytes and pharmacologic inhibition of the cyclooxygenase pathway, failed to reverse the response. Furthermore, no suppression of activity of unirradiated NK cells could be produced by coincubation of unirradiated NK cells with uv-irradiated NK cells. When the single cell assay for binding and killing was employed to determine at which stage in the lytic sequence inhibition occurred, it was found that binding was normal but lysis of bound targets and the recycling capacity of active NK cells were markedly reduced. At uvB doses above 50 J/m2, both interferon alpha (IFN-alpha) and interleukin 2 (IL-2) were ineffective in augmenting NK cell-mediated cytotoxic reactions after cells had been irradiated with uvB. Furthermore, incubation of NK cells with IFN-alpha prior to irradiation failed to protect against the inhibitory effects. These studies provide evidence that in vitro exposure of NK cells to uvB radiation inhibits their function by a direct nonlethal effect and that this inhibition occurs selectively at the postbinding stage of target cell lysis.