Mapping Physiological Suitability Limits for Malaria in Africa Under Climate Change

We mapped current and future temperature suitability for malaria transmission in Africa using a published model that incorporates nonlinear physiological responses to temperature of the mosquito vector Anopheles gambiae and the malaria parasite Plasmodium falciparum. We found that a larger area of Africa currently experiences the ideal temperature for transmission than previously supposed. Under future climate projections, we predicted a modest increase in the overall area suitable for malaria transmission, but a net decrease in the most suitable area. Combined with human population density projections, our maps suggest that areas with temperatures suitable for year-round, highest-risk transmission will shift from coastal West Africa to the Albertine Rift between the Democratic Republic of Congo and Uganda, whereas areas with seasonal transmission suitability will shift toward sub-Saharan coastal areas. Mapping temperature suitability places important bounds on malaria transmissibility and, along with local level demographic, socioeconomic, and ecological factors, can indicate where resources may be best spent on malaria control

Mtrr hypomorphic mutation alters liver morphology, metabolism and fuel storage in mice.

Nonalcoholic fatty liver disease (NAFLD) is associated with dietary folate deficiency and mutations in genes required for one‑carbon metabolism. However, the mechanism through which this occurs is unclear. To improve our understanding of this link, we investigated liver morphology, metabolism and fuel storage in adult mice with a hypomorphic mutation in the gene methionine synthase reductase (Mtrrgt ). MTRR enzyme is a key regulator of the methionine and folate cycles. The Mtrrgt mutation in mice was previously shown to disrupt one‑carbon metabolism and cause a wide-spectrum of developmental phenotypes and late adult-onset macrocytic anaemia. Here, we showed that livers of Mtrrgt/gt female mice were enlarged compared to control C57Bl/6J livers. Histological analysis of these livers revealed eosinophilic hepatocytes with decreased glycogen content, which was associated with down-regulation of genes involved in glycogen synthesis (e.g., Ugp2 and Gsk3a genes). While female Mtrrgt/gt livers showed evidence of reduced β-oxidation of fatty acids, there were no other associated changes in the lipidome in female or male Mtrrgt/gt livers compared with controls. Defects in glycogen storage and lipid metabolism often associate with disruption of mitochondrial electron transfer system activity. However, defects in mitochondrial function were not detected in Mtrrgt/gt livers as determined by high-resolution respirometry analysis. Overall, we demonstrated that adult Mtrrgt/gt female mice showed abnormal liver morphology that differed from the NAFLD phenotype and that was accompanied by subtle changes in their hepatic metabolism and fuel storage

N-arachidonylglycine is a caloric state-dependent circulating metabolite which regulates human CD4+T cell responsiveness

Acknowledgments We thank Drs. Zoe Hall and Sonia Liggi of the University of Cambridge Biochemistry Department for their contributions to metabolomics analysis and data processing. Shahin Hassanzadeh of the Laboratory of Mitochondrial Biology and Metabolism for developing the PBMC RNAseq library.Matthew Rodman of the Laboratory of Mitochondrial Biology and Metabolism for preparing lean/obese samples. Dr. Duck-Yeon Lee of the NHLBI Biochemistry Core for NAGly analysis in cell culture. Special thanks to the National Institutes of Health Oxford-Cambridge Scholars Program and the International Biomedical Research Alliance for their sponsorship and support. Funding: NHLBI Division of Intramural Research (MNS – ZIA-HL005199) and the UK MRC (JLG – MR/P011705/2; UKDRI-5002; MAPUK).Peer reviewedPublisher PD

Understanding uncertainty in temperature effects on vector-borne disease: A Bayesian approach

Extrinsic environmental factors influence the distribution and population dynamics of many organisms, including insects that are of concern for human health and agriculture. This is particularly true for vector-borne infectious diseases, like malaria, which is a major source of morbidity and mortality in humans. Understanding the mechanistic links between environment and population processes for these diseases is key to predicting the consequences of climate change on transmission and for developing effective interventions. An important measure of the intensity of disease transmission is the reproductive number $R_0$. However, understanding the mechanisms linking $R_0$ and temperature, an environmental factor driving disease risk, can be challenging because the data available for parameterization are often poor. To address this we show how a Bayesian approach can help identify critical uncertainties in components of $R_0$ and how this uncertainty is propagated into the estimate of $R_0$. Most notably, we find that different parameters dominate the uncertainty at different temperature regimes: bite rate from 15-25$^\circ$ C; fecundity across all temperatures, but especially $\sim$25-32$^\circ$ C; mortality from 20-30$^\circ$ C; parasite development rate at $\sim$15-16$^\circ$C and again at $\sim$33-35$^\circ$C. Focusing empirical studies on these parameters and corresponding temperature ranges would be the most efficient way to improve estimates of $R_0$. While we focus on malaria, our methods apply to improving process-based models more generally, including epidemiological, physiological niche, and species distribution models.Comment: 27 pages, including 1 table and 3 figure

Polyolefin–polar block copolymers from versatile new macromonomers

A new metallocene-based polymerization mechanism is elucidated in which a zirconium hydride center inserts α-methylstyrene at the start of a polymer chain. The hydride is then regenerated by hydrogenation to release a polyolefin containing a single terminal α-methylstyrenyl group. Through the use of the difunctional monomer 1,3-diisopropenylbenzene, this catalytic hydride insertion polymerization is applied to the production of linear polyethylene and ethylene–hexene copolymers containing an isopropenylbenzene end group. Conducting simple radical polymerizations in the presence of this new type of macromonomer leads to diblock copolymers containing a polyolefin attached to an acrylate, methacrylate, vinyl ester, or styrenic segments. The new materials are readily available and exhibit interfacial phenomena, including the mediation of the mixing of immiscible polymer blends

Divergent trajectories of cellular bioenergetics, intermediary metabolism and systemic redox status in survivors and non-survivors of critical illness.

BACKGROUND: Numerous pathologies result in multiple-organ failure, which is thought to be a direct consequence of compromised cellular bioenergetic status. Neither the nature of this phenotype nor its relevance to survival are well understood, limiting the efficacy of modern life-support. METHODS: To explore the hypothesis that survival from critical illness relates to changes in cellular bioenergetics, we combined assessment of mitochondrial respiration with metabolomic, lipidomic and redox profiling in skeletal muscle and blood, at multiple timepoints, in 21 critically ill patients and 12 reference patients. RESULTS: We demonstrate an end-organ cellular phenotype in critical illness, characterized by preserved total energetic capacity, greater coupling efficiency and selectively lower capacity for complex I and fatty acid oxidation (FAO)-supported respiration in skeletal muscle, compared to health. In survivors, complex I capacity at 48 h was 27% lower than in non-survivors (p = 0.01), but tended to increase by day 7, with no such recovery observed in non-survivors. By day 7, survivors' FAO enzyme activity was double that of non-survivors (p = 0.048), in whom plasma triacylglycerol accumulated. Increases in both cellular oxidative stress and reductive drive were evident in early critical illness compared to health. Initially, non-survivors demonstrated greater plasma total antioxidant capacity but ultimately higher lipid peroxidation compared to survivors. These alterations were mirrored by greater levels of circulating total free thiol and nitrosated species, consistent with greater reductive stress and vascular inflammation, in non-survivors compared to survivors. In contrast, no clear differences in systemic inflammatory markers were observed between the two groups. CONCLUSION: Critical illness is associated with rapid, specific and coordinated alterations in the cellular respiratory machinery, intermediary metabolism and redox response, with different trajectories in survivors and non-survivors. Unravelling the cellular and molecular foundation of human resilience may enable the development of more effective life-support strategies.MRC, Evelyn Trust, Intensive Care Society, Royal Free Charit

Enhanced hepatic respiratory capacity and altered lipid metabolism support metabolic homeostasis during short-term hypoxic stress.

BACKGROUND: Tissue hypoxia is a key feature of several endemic hepatic diseases, including alcoholic and non-alcoholic fatty liver disease, and organ failure. Hypoxia imposes a severe metabolic challenge on the liver, potentially disrupting its capacity to carry out essential functions including fuel storage and the integration of lipid metabolism at the whole-body level. Mitochondrial respiratory function is understood to be critical in mediating the hepatic hypoxic response, yet the time-dependent nature of this response and the role of the respiratory chain in this remain unclear. RESULTS: Here, we report that hepatic respiratory capacity is enhanced following short-term exposure to hypoxia (2 days, 10% O2) and is associated with increased abundance of the respiratory chain supercomplex III2+IV and increased cardiolipin levels. Suppression of this enhanced respiratory capacity, achieved via mild inhibition of mitochondrial complex III, disrupted metabolic homeostasis. Hypoxic exposure for 2 days led to accumulation of plasma and hepatic long chain acyl-carnitines. This was observed alongside depletion of hepatic triacylglycerol species with total chain lengths of 39-53 carbons, containing palmitic, palmitoleic, stearic, and oleic acids, which are associated with de novo lipogenesis. The changes to hepatic respiratory capacity and lipid metabolism following 2 days hypoxic exposure were transient, becoming resolved after 14 days in line with systemic acclimation to hypoxia and elevated circulating haemoglobin concentrations. CONCLUSIONS: The liver maintains metabolic homeostasis in response to shorter term hypoxic exposure through transient enhancement of respiratory chain capacity and alterations to lipid metabolism. These findings may have implications in understanding and treating hepatic pathologies associated with hypoxia.GlaxoSmithKlin

A pipeline for high throughput detection and mapping of SNPs from EST databases

Single nucleotide polymorphisms (SNPs) represent the most abundant type of genetic variation that can be used as molecular markers. The SNPs that are hidden in sequence databases can be unlocked using bioinformatic tools. For efficient application of these SNPs, the sequence set should be error-free as much as possible, targeting single loci and suitable for the SNP scoring platform of choice. We have developed a pipeline to effectively mine SNPs from public EST databases with or without quality information using QualitySNP software, select reliable SNP and prepare the loci for analysis on the Illumina GoldenGate genotyping platform. The applicability of the pipeline was demonstrated using publicly available potato EST data, genotyping individuals from two diploid mapping populations and subsequently mapping the SNP markers (putative genes) in both populations. Over 7000 reliable SNPs were identified that met the criteria for genotyping on the GoldenGate platform. Of the 384 SNPs on the SNP array approximately 12% dropped out. For the two potato mapping populations 165 and 185 SNPs segregating SNP loci could be mapped on the respective genetic maps, illustrating the effectiveness of our pipeline for SNP selection and validation

A parthenogenetic quasi-program causes teratoma-like tumors during aging in wild-type C. elegans

A long-standing belief is that aging (senescence) is the result of stochastic damage accumulation. Alternatively, senescent pathology may also result from late-life, wild-type gene action (i.e., antagonistic pleiotropy, as argued by Williams) leading to non-adaptive run-on of developmental programs (or quasi-programs) (as suggested more recently by Blagosklonny). In this study, we use existing and new data to show how uterine tumors, a prominent form of senescent pathology in the nematode Caenorhabditis elegans, likely result from quasi-programs. Such tumors develop from unfertilized oocytes which enter the uterus and become hypertrophic and replete with endoreduplicated chromatin masses. Tumor formation begins with ovulation of unfertilized oocytes immediately after exhaustion of sperm stocks. We show that the timing of this transition between program and quasi-program (i.e., the onset of senescence), and the onset of tumor formation, depends upon the timing of sperm depletion. We identify homology between uterine tumors and mammalian ovarian teratomas, which both develop from oocytes that fail to mature after meiosis I. In teratomas, futile activation of developmental programs leads to the formation of differentiated structures within the tumor. We report that older uterine tumors express markers of later embryogenesis, consistent with teratoma-like activation of developmental programs. We also present evidence of coupling of distal gonad atrophy to oocyte hypertrophy. This study shows how the Williams Blagosklonny model can provide a mechanistic explanation of this component of C. elegans aging. It also suggests etiological similarity between teratoma and some forms of senescent pathology, insofar as both are caused by quasi-programs

The NOX toolbox: validating the role of NADPH oxidases in physiology and disease

Reactive oxygen species (ROS) are cellular signals but also disease triggers; their relative excess (oxidative stress) or shortage (reductive stress) compared to reducing equivalents are potentially deleterious. This may explain why antioxidants fail to combat diseases that correlate with oxidative stress. Instead, targeting of disease-relevant enzymatic ROS sources that leaves physiological ROS signaling unaffected may be more beneficial. NADPH oxidases are the only known enzyme family with the sole function to produce ROS. Of the catalytic NADPH oxidase subunits (NOX), NOX4 is the most widely distributed isoform. We provide here a critical review of the currently available experimental tools to assess the role of NOX and especially NOX4, i.e. knock-out mice, siRNAs, antibodies, and pharmacological inhibitors. We then focus on the characterization of the small molecule NADPH oxidase inhibitor, VAS2870, in vitro and in vivo, its specificity, selectivity, and possible mechanism of action. Finally, we discuss the validation of NOX4 as a potential therapeutic target for indications including stroke, heart failure, and fibrosis