Uniting mathematics and biology for control of visceral leishmaniasis

The neglected tropical disease (NTD) visceral leishmaniasis (VL) has been targeted by the WHO for elimination as a public health problem on the Indian subcontinent by 2017 or earlier. To date there is a surprising scarcity of mathematical models capable of capturing VL disease dynamics, which are widely considered central to planning and assessing the efficacy of interventions. The few models that have been developed are examined, highlighting the necessity for better data to parameterise and fit these and future models. In particular, the characterisation and infectiousness of the different disease stages will be crucial to elimination. Modelling can then assist in establishing whether, when, and how the WHO VL elimination targets can be met

Critical and Non-Critical Einstein-Weyl Supergravity

We construct N=1 supersymmetrisations of some recently-proposed theories of critical gravity, conformal gravity, and extensions of critical gravity in four dimensions. The total action consists of the sum of three separately off-shell supersymmetric actions containing Einstein gravity, a cosmological term and the square of the Weyl tensor. For generic choices of the coefficients for these terms, the excitations of the resulting theory around an AdS_4 background describe massive spin-2 and massless spin-2 modes coming from the metric; massive spin-1 modes coming from a vector field in the theory; and massless and massive spin-3/2 modes (with two unequal masses) coming from the gravitino. These assemble into a massless and a massive N=1 spin-2 multiplet. In critical supergravity, the coefficients are tuned so that the spin-2 mode in the massive multiplet becomes massless. In the supersymmetrised extensions of critical gravity, the coefficients are chosen so that the massive modes lie in a "window" of lowest energies E_0 such that these ghostlike fields can be truncated by imposing appropriate boundary conditions at infinity, thus leaving just positive-norm massless supergravity modes.Comment: 29 page

“Wrapping myself in cotton wool“: Australian women's experience of being diagnosed with vasa praevia

© 2014 Javid et al.; licensee BioMed Central Ltd. Background: Vasa praevia (VP) is an obstetric condition that is associated with significant perinatal mortality and morbidity. Although the incidence of VP is low, it is one of the few causes of perinatal death that can be potentially prevented through detection and appropriate care. The experience of women diagnosed with or suspected to have VP is largely unknown. The aim of this study was to explore the experiences and impact that a diagnosis or suspected diagnosis of VP had on a group of Australian women.Method: A qualitative study using a descriptive exploratory design was conducted and Australian women diagnosed with VP were recruited via online methods in 2012. An inductive approach was undertaken and interviews were analysed using the stages of thematic analysis. Results: Of the 14 women interviewed, 11 were diagnosed with VP during pregnancy with 5 subsequently found not to have VP (non-confirmed diagnosis). Three women were diagnosed during childbirth with one neonatal death. Five major themes were identified: feeling like a ticking time bomb; getting diagnosis right; being taken seriously; coping with inconsistent information; and, just a massive relief when it was all over.Conclusions: This is the first study to describe women's experience of being diagnosed with or suspected to have VP. The findings from this research reveal the dilemmas these women face even if their baby is ultimately born healthy. Their need for clear and consistent information, sensitive care, support and continuity is evident. Clinicians can use these findings in developing information, counselling and models of care for these women

Variations in visceral leishmaniasis burden, mortality and the pathway to care within Bihar, India

BACKGROUND: Visceral leishmaniasis (VL) has been targeted by the WHO for elimination as a public health problem (< 1 case/10,000 people/year) in the Indian sub-continent (ISC) by 2020. Bihar State in India, which accounts for the majority of cases in the ISC, remains a major target for this elimination effort. However, there is considerable spatial, temporal and sub-population variation in occurrence of the disease and the pathway to care, which is largely unexplored and a threat to achieving the target. METHODS: Data from 6081 suspected VL patients who reported being clinically diagnosed during 2012-2013 across eight districts in Bihar were analysed. Graphical comparisons and Chi-square tests were used to determine differences in the burden of identified cases by season, district, age and sex. Log-linear regression models were fitted to onset (of symptoms)-to-diagnosis and onset-to-treatment waiting times to estimate their associations with age, sex, district and various socio-economic factors (SEFs). Logistic regression models were used to identify factors associated with mortality. RESULTS: Comparisons of VL caseloads suggested an annual cycle peaking in January-March. A 17-fold variation in the burden of identified cases across districts and under-representation of young children (0-5 years) relative to age-specific populations in Bihar were observed. Women accounted for a significantly lower proportion of the reported cases than men (41 vs 59%, P < 0.0001). Age, district of residence, house wall materials, caste, treatment cost, travelling for diagnosis and the number of treatments for symptoms before diagnosis were identified as correlates of waiting times. Mortality was associated with age, district of residence, onset-to-treatment waiting time, treatment duration, cattle ownership and cost of diagnosis. CONCLUSIONS: The distribution of VL in Bihar is highly heterogeneous, and reported caseloads and associated mortality vary significantly across different districts, posing different challenges to the elimination campaign. Socio-economic factors are important correlates of these differences, suggesting that elimination will require tailoring to population and sub-population circumstances

Impacts of climate variability and future climate change on harmful algal blooms and human health

This is the final version of the article. Available from BioMed Central via the DOI in this record.Anthropogenically-derived increases in atmospheric greenhouse gas concentrations have been implicated in recent climate change, and are projected to substantially impact the climate on a global scale in the future. For marine and freshwater systems, increasing concentrations of greenhouse gases are expected to increase surface temperatures, lower pH, and cause changes to vertical mixing, upwelling, precipitation, and evaporation patterns. The potential consequences of these changes for harmful algal blooms (HABs) have received relatively little attention and are not well understood. Given the apparent increase in HABs around the world and the potential for greater problems as a result of climate change and ocean acidification, substantial research is needed to evaluate the direct and indirect associations between HABs, climate change, ocean acidification, and human health. This research will require a multidisciplinary approach utilizing expertise in climatology, oceanography, biology, epidemiology, and other disciplines. We review the interactions between selected patterns of large-scale climate variability and climate change, oceanic conditions, and harmful algae.This work was funded in part through grants from the NSF/NIEHS Centers for Oceans and Human Health, grant numbers NSF OCE04-32479 and NIEHS P50 ES012740 (EAL), NSF OCE-0432368 and NIEHS P50 ES012736 (LEF), NIEHS P50 ES012762 and NSF OCE-0434087 (SKM, MSP). SKM, VLT and NJM also were supported in part by the West Coast Center for Oceans and Human Health (WCCOHH) as part of the NOAA Oceans and Human Health Initiative, and this is WCCOHH publication no. 26. The WCCOHH is part of the National Marine Fisheries Service's Northwest Fisheries Science Center, Seattle, Washington

Quantifying redox transcription factor dynamics as a tool to investigate redox signalling

\ua9 2024 The Authors. A critical feature of the cellular antioxidant response is the induction of gene expression by redox-sensitive transcription factors. In many cells, activating these transcription factors is a dynamic process involving multiple redox steps, but it is unclear how these dynamics should be measured. Here, we show how the dynamic profile of the Schizosaccharomyces pombe Pap1 transcription factor is quantifiable by three parameters: signal amplitude, signal time and signal duration. In response to increasing hydrogen peroxide concentrations, the Pap1 amplitude decreased while the signal time and duration showed saturable increases. In co-response plots, these parameters showed a complex, non-linear relationship to the mRNA levels of four Pap1-regulated genes. We also demonstrate that hydrogen peroxide and tert-butyl hydroperoxide trigger quantifiably distinct Pap1 activation profiles and transcriptional responses. Based on these findings, we propose that different oxidants and oxidant concentrations modulate the Pap1 dynamic profile, leading to specific transcriptional responses. We further show how the effect of combination and pre-exposure stresses on Pap1 activation dynamics can be quantified using this approach. This method is therefore a valuable addition to the redox signalling toolbox that may illuminate the role of dynamics in determining appropriate responses to oxidative stress

Balancing Selection at the Tomato RCR3 Guardee Gene Family Maintains Variation in Strength of Pathogen Defense

Coevolution between hosts and pathogens is thought to occur between interacting molecules of both species. This results in the maintenance of genetic diversity at pathogen antigens (or so-called effectors) and host resistance genes such as the major histocompatibility complex (MHC) in mammals or resistance (R) genes in plants. In plant-pathogen interactions, the current paradigm posits that a specific defense response is activated upon recognition of pathogen effectors via interaction with their corresponding R proteins. According to the''Guard-Hypothesis,'' R proteins (the ``guards'') can sense modification of target molecules in the host (the ``guardees'') by pathogen effectors and subsequently trigger the defense response. Multiple studies have reported high genetic diversity at R genes maintained by balancing selection. In contrast, little is known about the evolutionary mechanisms shaping the guardee, which may be subject to contrasting evolutionary forces. Here we show that the evolution of the guardee RCR3 is characterized by gene duplication, frequent gene conversion, and balancing selection in the wild tomato species Solanum peruvianum. Investigating the functional characteristics of 54 natural variants through in vitro and in planta assays, we detected differences in recognition of the pathogen effector through interaction with the guardee, as well as substantial variation in the strength of the defense response. This variation is maintained by balancing selection at each copy of the RCR3 gene. Our analyses pinpoint three amino acid polymorphisms with key functional consequences for the coevolution between the guardee (RCR3) and its guard (Cf-2). We conclude that, in addition to coevolution at the ``guardee-effector'' interface for pathogen recognition, natural selection acts on the ``guard-guardee'' interface. Guardee evolution may be governed by a counterbalance between improved activation in the presence and prevention of auto-immune responses in the absence of the corresponding pathogen

Random Planar Lattices and Integrated SuperBrownian Excursion

In this paper, a surprising connection is described between a specific brand of random lattices, namely planar quadrangulations, and Aldous' Integrated SuperBrownian Excursion (ISE). As a consequence, the radius r_n of a random quadrangulation with n faces is shown to converge, up to scaling, to the width r=R-L of the support of the one-dimensional ISE. More generally the distribution of distances to a random vertex in a random quadrangulation is described in its scaled limit by the random measure ISE shifted to set the minimum of its support in zero. The first combinatorial ingredient is an encoding of quadrangulations by trees embedded in the positive half-line, reminiscent of Cori and Vauquelin's well labelled trees. The second step relates these trees to embedded (discrete) trees in the sense of Aldous, via the conjugation of tree principle, an analogue for trees of Vervaat's construction of the Brownian excursion from the bridge. From probability theory, we need a new result of independent interest: the weak convergence of the encoding of a random embedded plane tree by two contour walks to the Brownian snake description of ISE. Our results suggest the existence of a Continuum Random Map describing in term of ISE the scaled limit of the dynamical triangulations considered in two-dimensional pure quantum gravity.Comment: 44 pages, 22 figures. Slides and extended abstract version are available at http://www.loria.fr/~schaeffe/Pub/Diameter/ and http://www.iecn.u-nancy.fr/~chassain

Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.

BackgroundMucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.MethodsThis 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.ResultsThe two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.ConclusionsLaronidase seemed to improve growth in participants &lt;8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made

Valuing Governance

Book Summary: As has been abundantly documented in the popular and academic press, the humanities are facing challenging times marked by national debate regarding the importance of the humanities in higher education, program and budget cuts, and an ever-decreasing number of tenure-track jobs. In addition, the humanities face quite literally a quantification of their value as the Academy adopts a more corporate mindset. This volume provides advice to professionals in the humanities on how to forge a useful, compelling, and productive career. The book’s 13 chapters address professional approaches to developing and maintaining an active research agenda, fomenting the ideals of the teacher-scholar model, managing the service demands within and outside the college or university, and navigating institutional politics. The collection offers practical and theoretical approaches to higher education, personal anecdotes, intelligent advice, and interviews with colleagues in the humanities. Specific themes addressed include the transition from graduate student to humanities professional, diverging from prescribed paths, the humanities professor as creative writer, moving from secondary to post-secondary education, humanities in an international, market-based context, and participation in governance structures. [From the publisher] Chapter Summary: This essay focuses on providing insight and practical advice on how committed participation in the governance process offers many positives at any stage of the academic ladder. Drawing upon a practical, theoretical, and anecdotal approach, this article reflects on four areas that are enhanced by participation in governance: 1) visibility; 2) knowledge of the institution and its culture; 3) establishing meaningful friendships campus-wide; and 4) governance as a resource of invaluable advice