Simulations of hydrodynamic interactions among immersed particles in stokes flow using a massively parallel computer

In this paper, a massively parallel implementation of the boundary element method to study particle transport in Stokes flow is discussed. The numerical algorithm couples the quasistatic Stokes equations for the fluid with kinematic and equilibrium equations for the particles. The formation and assembly of the discretized boundary element equations is based on the torus-wrap mapping as opposed to the more traditional row- or column-wrap mappings. The equation set is solved using a block Jacobi iteration method. Results are shown for an example application problem, which requires solving a dense system of 6240 equations more than 1200 times

Leveraging mathematical models of disease dynamics and machine learning to improve development of novel malaria interventions

BACKGROUND: Substantial research is underway to develop next-generation interventions that address current malaria control challenges. As there is limited testing in their early development, it is difficult to predefine intervention properties such as efficacy that achieve target health goals, and therefore challenging to prioritize selection of novel candidate interventions. Here, we present a quantitative approach to guide intervention development using mathematical models of malaria dynamics coupled with machine learning. Our analysis identifies requirements of efficacy, coverage, and duration of effect for five novel malaria interventions to achieve targeted reductions in malaria prevalence. METHODS: A mathematical model of malaria transmission dynamics is used to simulate deployment and predict potential impact of new malaria interventions by considering operational, health-system, population, and disease characteristics. Our method relies on consultation with product development stakeholders to define the putative space of novel intervention specifications. We couple the disease model with machine learning to search this multi-dimensional space and efficiently identify optimal intervention properties that achieve specified health goals. RESULTS: We apply our approach to five malaria interventions under development. Aiming for malaria prevalence reduction, we identify and quantify key determinants of intervention impact along with their minimal properties required to achieve the desired health goals. While coverage is generally identified as the largest driver of impact, higher efficacy, longer protection duration or multiple deployments per year are needed to increase prevalence reduction. We show that interventions on multiple parasite or vector targets, as well as combinations the new interventions with drug treatment, lead to significant burden reductions and lower efficacy or duration requirements. CONCLUSIONS: Our approach uses disease dynamic models and machine learning to support decision-making and resource investment, facilitating development of new malaria interventions. By evaluating the intervention capabilities in relation to the targeted health goal, our analysis allows prioritization of interventions and of their specifications from an early stage in development, and subsequent investments to be channeled cost-effectively towards impact maximization. This study highlights the role of mathematical models to support intervention development. Although we focus on five malaria interventions, the analysis is generalizable to other new malaria interventions

Immunomodulation of inflammatory leukocyte markers during intravenous immunoglobulin treatment associated with clinical efficacy in chronic inflammatory demyelinating polyradiculoneuropathy

© 2016 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. Objective: The objective of the study was to profile leukocyte markers modulated during intravenous immunoglobulin (IVIg) treatment, and to identify markers and immune pathways associated with clinical efficacy of IVIg for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with potential for monitoring treatment efficacy. Methods: Response to IVIg treatment in newly diagnosed IVIg-naïve and established IVIg-experienced patients was assessed by changes in expression of inflammatory leukocyte markers by flow cytometry. The adjusted INCAT disability and Medical Research Council sum scores defined clinical response. Results: Intravenous immunoglobulin modulated immunopathogenic pathways associated with inflammatory disease in CIDP. Leukocyte markers of clinical efficacy included reduced CD185 + follicular helper T cells, increased regulatory markers (CD23 and CD72) on B cells, and reduction in the circulating inflammatory CD16 + myeloid dendritic cell (mDC) population and concomitant increase in CD62L and CD195 defining a less inflammatory lymphoid homing mDC phenotype. A decline in inflammatory CD16 + dendritic cells was associated with clinical improvement or stability, and correlated with magnitude of improvement in neurological assessment scores, but did not predict relapse. IVIg also induced a nonspecific improvement in regulatory and reduced inflammatory markers not associated with clinical response. Conclusions: Clinically effective IVIg modulated inflammatory and regulatory pathways associated with ongoing control or resolution of CIDP disease. Some of these markers have potential for monitoring outcome

<em>NODULE ROOT</em> and <em>COCHLEATA</em> Maintain Nodule Development and Are Legume Orthologs of Arabidopsis <em>BLADE-ON-PETIOLE</em> Genes

During their symbiotic interaction with rhizobia, legume plants develop symbiosis-specific organs on their roots, called nodules, that house nitrogen-fixing bacteria. The molecular mechanisms governing the identity and maintenance of these organs are unknown. Using Medicago truncatula nodule root (noot) mutants and pea (Pisum sativum) cochleata (coch) mutants, which are characterized by the abnormal development of roots from the nodule, we identified the NOOT and COCH genes as being necessary for the robust maintenance of nodule identity throughout the nodule developmental program. NOOT and COCH are Arabidopsis thaliana BLADE-ON-PETIOLE orthologs, and we have shown that their functions in leaf and flower development are conserved in M. truncatula and pea. The identification of these two genes defines a clade in the BTB/POZ-ankyrin domain proteins that shares conserved functions in eudicot organ development and suggests that NOOT and COCH were recruited to repress root identity in the legume symbiotic organ

Maternal protein-energy malnutrition during early pregnancy in sheep impacts the fetal ornithine cycle to reduce fetal kidney microvascular development

This paper identifies a common nutritional pathway relating maternal through to fetal protein-energy malnutrition (PEM) and compromised fetal kidney development. Thirty-one twin-bearing sheep were fed either a control (n=15) or low-protein diet (n=16, 17 vs. 8.7 g crude protein/MJ metabolizable energy) from d 0 to 65 gestation (term, ∼ 145 d). Effects on the maternal and fetal nutritional environment were characterized by sampling blood and amniotic fluid. Kidney development was characterized by histology, immunohistochemistry, vascular corrosion casts, and molecular biology. PEM had little measureable effect on maternal and fetal macronutrient balance (glucose, total protein, total amino acids, and lactate were unaffected) or on fetal growth. PEM decreased maternal and fetal urea concentration, which blunted fetal ornithine availability and affected fetal hepatic polyamine production. For the first time in a large animal model, we associated these nutritional effects with reduced micro- but not macrovascular development in the fetal kidney. Maternal PEM specifically impacts the fetal ornithine cycle, affecting cellular polyamine metabolism and microvascular development of the fetal kidney, effects that likely underpin programming of kidney development and function by a maternal low protein diet

Understanding diabetes in patients with HIV/AIDS

This paper reviews the incidence, pathogenetic mechanisms and management strategies of diabetes mellitus in patients with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). It classifies patients based on the aetiopathogenetic mechanisms, and proposes rational methods of management of the condition, based on aetiopathogenesis and concomitant pharmacotherapy

Unravelling enzymatic discoloration in potato through a combined approach of candidate genes, QTL, and expression analysis

Enzymatic discoloration (ED) of potato tubers was investigated in an attempt to unravel the underlying genetic factors. Both enzyme and substrate concentration have been reported to influence the degree of discoloration and as such this trait can be regarded as polygenic. The diploid mapping population C × E, consisting of 249 individuals, was assayed for the degree of ED and levels of chlorogenic acid and tyrosine. Using this data, Quantitative Trait Locus (QTL) analysis was performed. Three QTLs for ED have been found on parental chromosomes C3, C8, E1, and E8. For chlorogenic acid a QTL has been identified on C2 and for tyrosine levels, a QTL has been detected on C8. None of the QTLs overlap, indicating the absence of genetic correlations between these components underlying ED, in contrast to earlier reports in literature. An obvious candidate gene for the QTL for ED on Chromosome 8 is polyphenol oxidase (PPO), which was previously mapped on chromosome 8. With gene-specific primers for PPO gene POT32 a CAPS marker was developed. Three different alleles (POT32-1, -2, and -3) could be discriminated. The segregating POT32 alleles were used to map the POT32 CAPS marker and QTL analysis was redone, showing that POT32 coincides with the QTL peak. A clear correlation between allele combinations and degree of discoloration was observed. In addition, analysis of POT32 gene expression in a subset of genotypes indicated a correlation between the level of gene expression and allele composition. On average, genotypes having two copies of allele 1 had both the highest degree of discoloration as well as the highest level of POT32 gene expression

Prevalence of metabolic syndrome among HIV-positive and HIV-negative populations in sub-Saharan Africa-a systematic review and meta-analysis

BACKGROUND: Metabolic syndrome (MetS) is a constellation of conditions that increase the risk of cardiovascular diseases. It is an emerging concern in sub-Saharan African (SSA) countries, particularly because of an increasingly aging population and lifestyle changes. There is an increased risk of MetS and its components among people living with Human immune deficiency syndrome (HIV) individuals; however, the prevalence of metabolic syndrome in the SSA population and its differential contribution by HIV status is not yet established. This systematic review and meta-analysis were conducted to estimate the pooled prevalence of metabolic syndrome in people living with HIV and uninfected populations, its variation by sub-components. METHODS: We performed a comprehensive search on major databases-MEDLINE (PubMed), EBSCOhost, and Cochrane Database of Systematic Reviews and Web of sciences for original epidemiological research articles that compared proportions of the MetS and its subcomponents between people living with HIV and uninfected patients and published between January 1990-December 2017. The inclusion criteria were adults aged ≥ 18 years, with confirmed HIV status. We assessed the risk of bias using a prevalence studies tool, and random effect meta-analyses were used to compute the pooled overall prevalence. RESULTS: A total of four cross-sectional studies comprising 496 HIV uninfected and 731 infected participants were included in the meta-analysis. The overall prevalence of MetS among people living with HIV was 21.5% (95% CI 15.09-26.86) versus uninfected 12.0% (95% CI 5.00-21.00%), with substantial heterogeneity. The reported relative risk estimate for MetS among the two groups was twofold (RR 1.83, 95% CI 0.98-3.41), with an estimated predictive interval of 0.15 to 22.43 and P = 0.055 higher for the infected population. Hypertension was the most prevalent MetS sub-components, with diverse proportions of people living with HIV (5.2-50.0%) and uninfected (10.0-59.0%) populations. CONCLUSIONS: The high range of MetS prevalence in the HIV-infected population compared to the uninfected population highlights the possible presence of HIV related drivers of MetS. Also, the reported high rate of MetS, irrespective of HIV status, indicates a major metabolic disorder epidemic that requires urgent prevention and management programs in SSA. Similarly, in the era of universal test and treat strategy among people living with HIV cohorts, routine check-up of MetS sub-components is required in HIV management as biomarkers. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016045727