Herpes Simplex Virus Type 2 Antibodies: High Prevalence in Monogamous Women in Costa Rica

We studied the prevalence of antibody to Herpes simplex virus types I and 2 (HSV-I and HSV-2) in 766 randomly selected Costa Rican women 25-59 years of age in a national household survey in 1984-1985. Overall, 97.1% were seropositive for HSV-l and 39.4% for HSV -2. Only 1.1% of HSV -2 seropositive women gave a history of symptomatic genital herpes. HSV-2 virus antibody increased with age and with the number of lifetime sexual partners. HSV -2 seroprevalence among women who reported only 1 lifetime sexual partner was almost twice as high as the prevalence among women who denied sexual experience (30.5% vs. 17.7%) and reached 79.2% among women with \u3c 4 partners. HSV-2 seroprevalence was lower among women whose partners used condoms: 28.9% for those who had used condoms for at least 2 years vs. 44.3% for those who never used condoms

Market split and basis reduction: towards a solution of the Cornuejols-Dawande instances

Previously, G. Cornuejols and M. Dawande (1998) proposed a set of 0-1 linear programming instances that proved to be very hard to solve by traditional methods, and in particular by linear programming based branch-and-bound. They offered these market split instances as a challenge to the integer programming community. The market split problem can be formulated as a system of linear diophantine equations in 0-1 variables. We use the algorithm of K. Aardal et al. (1998) based on lattice basis reduction. This algorithm is not restricted to deal with market split instances only but is a general method for solving systems of linear diophantine equations with bounds on the variables. We show computational results from solving both feasibility and optimization versions of the market split instances with up to 7 equations and 60 variables and discuss various branching strategies and their effect on the number of enumerated nodes. To our knowledge, the largest feasibility and optimization instances solved before had 6 equations and 50 variables, and 4 equations and 30 variables, respectively. We also present a probabilistic analysis describing how to compute the probability of generating infeasible market split instances. By generating instances in the way prescribed by Cornuejols and Dawande, one obtains relatively many feasible instances for sizes larger than 5 equations and 40 variable

Stress Increases Peripheral Axon Growth and Regeneration Through Glucocorticoid Receptor-Dependent Transcriptional Programs

Stress and glucocorticoid (GC) release are common behavioral and hormonal responses to injury or disease. In the brain, stress/GCs can alter neuron structure and function leading to cognitive impairment. Stress and GCs also exacerbate pain, but whether a corresponding change occurs in structural plasticity of sensory neurons is unknown. Here, we show that in female mice (Mus musculus) basal GC receptor (Nr3c1, also known as GR) expression in dorsal root ganglion (DRG) sensory neurons is 15-fold higher than in neurons in canonical stress-responsive brain regions (M. musculus). In response to stress or GCs, adult DRG neurite growth increases through mechanisms involving GR-dependent gene transcription. In vivo, prior exposure to an acute systemic stress increases peripheral nerve regeneration. These data have broad clinical implications and highlight the importance of stress and GCs as novel behavioral and circulating modifiers of neuronal plasticity

Machine-learning prediction of tumor antigen immunogenicity in the selection of therapeutic epitopes

Current tumor neoantigen calling algorithms primarily rely on epitope/major histocompatibility complex (MHC) binding affinity predictions to rank and select for potential epitope targets. These algorithms do not predict for epitope immunogenicity using approaches modeled from tumor-specific antigen data. Here, we describe peptide-intrinsic biochemical features associated with neoantigen and minor histocompatibility mismatch antigen immunogenicity and present a gradient boosting algorithm for predicting tumor antigen immunogenicity. This algorithm was validated in two murine tumor models and demonstrated the capacity to select for therapeutically active antigens. Immune correlates of neoantigen immunogenicity were studied in a pan-cancer data set from The Cancer Genome Atlas and demonstrated an association between expression of immunogenic neoantigens and immunity in colon and lung adenocarcinomas. Lastly, we present evidence for expression of an out-of-frame neoantigen that was capable of driving antitumor cytotoxic T-cell responses. With the growing clinical importance of tumor vaccine therapies, our approach may allow for better selection of therapeutically relevant tumor-specific antigens, including nonclas-sic out-of-frame antigens capable of driving antitumor immunity

Decomposition, Reformulation, and Diving in University Course Timetabling

In many real-life optimisation problems, there are multiple interacting components in a solution. For example, different components might specify assignments to different kinds of resource. Often, each component is associated with different sets of soft constraints, and so with different measures of soft constraint violation. The goal is then to minimise a linear combination of such measures. This paper studies an approach to such problems, which can be thought of as multiphase exploitation of multiple objective-/value-restricted submodels. In this approach, only one computationally difficult component of a problem and the associated subset of objectives is considered at first. This produces partial solutions, which define interesting neighbourhoods in the search space of the complete problem. Often, it is possible to pick the initial component so that variable aggregation can be performed at the first stage, and the neighbourhoods to be explored next are guaranteed to contain feasible solutions. Using integer programming, it is then easy to implement heuristics producing solutions with bounds on their quality. Our study is performed on a university course timetabling problem used in the 2007 International Timetabling Competition, also known as the Udine Course Timetabling Problem. In the proposed heuristic, an objective-restricted neighbourhood generator produces assignments of periods to events, with decreasing numbers of violations of two period-related soft constraints. Those are relaxed into assignments of events to days, which define neighbourhoods that are easier to search with respect to all four soft constraints. Integer programming formulations for all subproblems are given and evaluated using ILOG CPLEX 11. The wider applicability of this approach is analysed and discussed.Comment: 45 pages, 7 figures. Improved typesetting of figures and table

DHODH modulates transcriptional elongation in the neural crest and melanoma

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

Pevonedistat (MLN4924), a First‐in‐Class NEDD8‐activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111220/1/bjh13323.pd