Immune-mediated competition in rodent malaria is most likely caused by induced changes in innate immune clearance of merozoites

Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter μ, the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, μ was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno-deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but future refinement of the model, challenged with other datasets, may lead to its discovery

Dietary fibre intake and risk of ischaemic and haemorrhagic stroke in the UK Women’s Cohort Study

BACKGROUND: Stroke risk is modifiable through many risk factors, one being healthy dietary habits. Fibre intake was associated with a reduced stroke risk in recent meta-analyses; however, data were contributed by relatively few studies, and few examined different stroke types. METHODS: A total of 27 373 disease-free women were followed up for 14.4 years. Diet was assessed with a 217-item food frequency questionnaire and stroke cases were identified using English Hospital Episode Statistics and mortality records. Survival analysis was applied to assess the risk of total, ischaemic or haemorrhagic stroke in relation to fibre intake. RESULTS: A total of 135 haemorrhagic and 184 ischaemic stroke cases were identified in addition to 138 cases where the stroke type was unknown or not recorded. Greater intake of total fibre, higher fibre density and greater soluble fibre, insoluble fibre and fibre from cereals were associated with a significantly lower risk for total stroke. For total stroke, the hazard ratio per 6 g/day total fibre intake was 0.89 (95% confidence intervals: 0.81–0.99). Different findings were observed for haemorrhagic and ischaemic stroke in healthy-weight or overweight women. Total fibre, insoluble fibre and cereal fibre were inversely associated with haemorrhagic stroke risk in overweight/obese participants, and in healthy-weight women greater cereal fibre was associated with a lower ischaemic stroke risk. In non-hypertensive women, higher fibre density was associated with lower ischaemic stroke risk. CONCLUSIONS: Greater total fibre and fibre from cereals are associated with a lower stroke risk, and associations were more consistent with ischaemic stroke. The different observations by stroke type, body mass index group or hypertensive status indicates potentially different mechanisms

Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy

Sustained glucose and glutamine transport are essential for activated T lymphocytes to support ATP and macromolecule biosynthesis. We now show that glutamine and glucose also fuel an indispensible dynamic regulation of intracellular protein O-GlcNAcylation at key stages of T cell development, transformation and differentiation. Glucose and glutamine are precursors of UDP-GlcNAc, a substrate for cellular glycosyltransferases. Immune activated T cells contained higher concentrations of UDP-GlcNAc and increased intracellular protein O-GlcNAcylation controlled by the enzyme O-GlcNAc glycosyltransferase as compared to naïve cells. We identified Notch, the T cell antigen receptor and c-Myc as key controllers of T cell protein O-GlcNAcylation, via regulation of glucose and glutamine transport. Loss of O-GlcNAc transferase blocked T cell progenitor renewal, malignant transformation, and peripheral T cell clonal expansion. Nutrient-dependent signaling pathways regulated by O-GlcNAc glycosyltransferase are thus fundamental for T cell biology

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Wnt addiction of genetically defined cancers reversed by PORCN inhibition

Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Whether these mutations identify a clinical opportunity is an important question. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. We developed a novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks the secretion and activity of all Wnts. ETC-159 is remarkably effective in treating RSPO-translocation bearing colorectal cancer (CRC) patient-derived xenografts. This is the first example of effective targeted therapy for this subset of CRC. Consistent with a central role of Wnt signaling in regulation of gene expression, inhibition of PORCN in RSPO3-translocated cancers causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell and proliferation genes, and an increase in differentiation markers. Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers

Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia.

Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. On the basis of published and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. A series of animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders show PVI deficits to be all accompanied by oxidative stress in the anterior cingulate cortex. Specifically, oxidative stress is negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune and antioxidant signaling. As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models. This opens up new perspectives for the use of antioxidant treatments to be applied to at-risk individuals, in close temporal proximity to environmental impacts known to induce oxidative stress

Epidemiological surveillance study of female genital mutilation in the UK

OBJECTIVES: Describe cases of female genital mutilation (FGM) presenting to consultant paediatricians and sexual assault referral centres (SARCs), including demographics, medical symptoms, examination findings and outcome. DESIGN: The well-established epidemiological surveillance study performed through the British Paediatric Surveillance Unit included FGM on the monthly returns. SETTING: All consultant paediatricians and relevant SARC leads across the UK and Ireland. PATIENTS: Under 16 years old with FGM. INTERVENTIONS: Data on cases from November 2015 to November 2017 and 12 months later meeting the case definition of FGM. MAIN OUTCOMES MEASURES: Returns included 146 cases, 103 (71%) had confirmed FGM and 43 (29%) did not meet the case definition. There were none from Northern Ireland. RESULTS: The mean reported age was 3 years. Using the WHO classification of FGM, 58% (n=60) had either type 1 or type 2, 8% (n=8) had type 3 and 21% (n=22) had type 4. 13% (n=13) of the cases were not classified and none had piercings or labiaplasty. The majority, 70% had FGM performed in Africa with others from Europe, Middle East and South-East Asia. There were few physical and mental health symptoms. Only one case resulted in a successful prosecution. CONCLUSIONS: There were low numbers of children presenting with FGM and in the 2 years there was only one prosecution. The findings may be consistent with attitude changes in FGM practising communities and those at risk should be protected and supported by culturally competent national policie

Potential for tree rings to reveal spatial patterns of past drought variability across western Australia

Proxy records have provided major insights into the variability of past climates over long timescales. However, for much of the Southern Hemisphere, the ability to identify spatial patterns of past climatic variability is constrained by the sparse distribution of proxy records. This is particularly true for mainland Australia, where relatively few proxy records are located. Here, we (1) assess the potential to use existing proxy records in the Australasian region - starting with the only two multi-century tree-ring proxies from mainland Australia - to reveal spatial patterns of past hydroclimatic variability across the western third of the continent, and (2) identify strategic locations to target for the development of new proxy records. We show that the two existing tree-ring records allow robust reconstructions of past hydroclimatic variability over spatially broad areas (i.e. > 3 3) in inland north- and south-western Australia. Our results reveal synchronous periods of drought and wet conditions between the inland northern and southern regions of western Australia as well as a generally anti-phase relationship with hydroclimate in eastern Australia over the last two centuries. The inclusion of 174 tree-ring proxy records from Tasmania, New Zealand and Indonesia and a coral record from Queensland did not improve the reconstruction potential over western Australia. However, our findings suggest that the addition of relatively few new proxy records from key locations in western Australia that currently have low reconstruction skill will enable the development of a comprehensive drought atlas for the region, and provide a critical link to the drought atlases of monsoonal Asia and eastern Australia and New Zealand

The Ethics of Ethics Reviews in Global Health Research: Case Studies Applying a New Paradigm

With increasing calls for global health research there is growing concern regarding the ethical challenges encountered by researchers from high-income countries (HICs) working in low or middle-income countries (LMICs). There is a dearth of literature on how to address these challenges in practice. In this article, we conduct a critical analysis of three case studies of research conducted in LMICs.We apply emerging ethical guidelines and principles specific to global health research and offer practical strategies that researchers ought to consider. We present case studies in which Canadian health professional students conducted a health promotion project in a community in Honduras; a research capacity-building program in South Africa, in which Canadian students also worked alongside LMIC partners; and a community-university partnered research capacity-building program in which Ecuadorean graduate students, some working alongside Canadian students, conducted community-based health research projects in Ecuadorean communities.We examine each case, identifying ethical issues that emerged and how new ethical paradigms being promoted could be concretely applied.We conclude that research ethics boards should focus not only on protecting individual integrity and human dignity in health studies but also on beneficence and non-maleficence at the community level, explicitly considering social justice issues and local capacity-building imperatives.We conclude that researchers from HICs interested in global health research must work with LMIC partners to implement collaborative processes for assuring ethical research that respects local knowledge, cultural factors, the social determination of health, community participation and partnership, and making social accountability a paramount concern