Co-infection with Chikungunya virus alters trafficking of pathogenic CD8(+) T cells into the brain and prevents Plasmodium-induced neuropathology

Arboviral diseases have risen significantly over the last 40 years, increasing the risk of co‐infection with other endemic disease such as malaria. However, nothing is known about the impact arboviruses have on the host response toward heterologous pathogens during co‐infection. Here, we investigate the effects of Chikungunya virus (CHIKV ) co‐infection on the susceptibility and severity of malaria infection. Using the Plasmodium berghei ANKA (PbA) experimental cerebral malaria (ECM ) model, we show that concurrent co‐infection induced the most prominent changes in ECM manifestation. Concurrent co‐infection protected mice from ECM mortality without affecting parasite development in the blood. This protection was mediated by the alteration of parasite‐specific CD8+ T‐cell trafficking through an IFN γ‐mediated mechanism. Co‐infection with CHIKV induced higher splenic IFN γ levels that lead to high local levels of CXCL 9 and CXCL 10. This induced retention of CXCR 3‐expressing pathogenic CD8+ T cells in the spleen and prevented their migration to the brain. This then averts all downstream pathogenic events such as parasite sequestration in the brain and disruption of blood–brain barrier that prevents ECM ‐induced mortality in co‐infected mice

Polymorphisms in the WNK1 gene are asociated with blood pressure variation and urinary potassium excretion

WNK1 - a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control - is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively). The major allele (A) of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95%CI:1.23–4.9), DBP 1.9 mmHg (95%CI:0.7–3.2) and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0–1.7]).We genotyped this variant in six independent populations (n = 14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p = 7×10−3, combined with BRIGHT data-set p = 2×10−4, n = 17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p10 mmHg reduction) and risk for hypertension (OR<0.60). Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH

Oxidative stress-dependent cyclooxygenase-2-derived prostaglandin F2α impairs endothelial function in renovascular hypertensive rats

Abstract Aims: The role of endothelium-derived contracting factors (EDCFs) in regulating renovascular function is yet to be elucidated in renovascular hypertension (RH). The current study investigated whether oxidative stress-dependent cyclooxygenase (COX)-2-derived prostaglandin F(2alpha) (PGF(2alpha)) impairs endothelial function in renal arteries of renovascular hypertensive rats (RHR). Results: Renal hypertension was induced in rats by renal artery stenosis of both kidneys using the 2-kidney 2-clip model. Acute treatment with reactive oxygen species (ROS) scavengers, COX-2 inhibitors, and thromboxane-prostanoid receptor antagonists, but not COX-1 inhibitors, improved endothelium-dependent relaxations and eliminated endothelium-dependent contractions in RHR renal arteries. Five weeks of treatment with celecoxib or tempol reduced blood pressure, increased renal blood flow, and restored endothelial function in RHRs. Increased ROS production in RHR arteries was inhibited by ROS scavengers, but unaffected by COX-2 inhibitors; whereas increased PGF(2alpha) release was reduced by both ROS scavengers and COX-2 inhibitors. ROS also induced COX-2-dependent contraction in RHR renal arteries, which was accompanied by the release of COX-2-derived PGF(2alpha). Further, chronic tempol treatment reduced COX-2 and BMP4 upregulation, p38MAPK phosphorylation, and the nitrotyrosine level in RHR renal arteries. Conclusion: These findings demonstrate the functional importance of oxidative stress, which serves as an initiator of increased COX-2 activity, and that COX-2-derived PGF(2alpha) plays an important role in mediating endothelial dysfunction in RH. Innovation: The current study, thus, suggests that drugs targeting oxidative stress-dependent COX-2-derived PGF(2alpha) may be useful in the prevention and management of RH. Antioxid. Redox Signal. 16, 363-373.published_or_final_versio

Virus infection drives IL-2 antibody complexes into pro-inflammatory agonists in mice

The use of IL-2/JES6-1 Ab complex (IL-2 Ab Cx) has been considered as a potential therapeutic for inflammatory diseases due to its selective expansion of regulatory T cells (Tregs) in mice. Here, IL-2 Ab Cx was explored as a therapeutic agent to reduce joint inflammation induced by chikungunya virus, an alphavirus causing debilitating joint disease globally. Virus-infected mice treated with IL-2 Ab Cx exhibited exacerbated joint inflammation due to infiltration of highly activated CD4(+) effector T cells (Teffs). Virus infection led to upregulation of CD25 on the Teffs, rendering them sensitive towards IL2 Ab Cx. Ready responsiveness of Teffs to IL-2 was further demonstrated in healthy human donors, suggesting that the use of IL-2 Ab Cx in humans is not suitable. Changes in IL-2 sensitivity during active virus infection could change the responsive pattern towards the IL-2 Ab Cx, resulting in the expansion of pro-inflammatory rather than anti-inflammatory responses

The ultimate commission: The key for the gospel according to Matthew

It is frequently acknowledged that the ultimate commission is important for understanding the whole gospel of Matthew. In this article, we investigate how several themes incorporated in the ultimate commission (28:18-20) are connected to the whole gospel. Thus readers of Matthew will not be surprised at their encounter with the ultimate commission at the end. The themes within this commission are not sudden, but are already visible in every section of the whole gospel. Having read the gospel from the beginning, readers will be well prepared for the ultimate commission

Design, synthesis and biological characterization of novel inhibitors of CD38

Human CD38 is a novel multi-functional protein that acts not only as an antigen for B-lymphocyte activation, but also as an enzyme catalyzing the synthesis of a Ca 2+ messenger molecule, cyclic ADP-ribose, from NAD +. It is well established that this novel Ca 2+ signaling enzyme is responsible for regulating a wide range of physiological functions. Based on the crystal structure of the CD38/NAD + complex, we synthesized a series of simplified N-substituted nicotinamide derivatives (Compound1-14). A number of these compounds exhibited moderate inhibition of the NAD + utilizing activity of CD38, with Compound4 showing the highest potency. The crystal structure of CD38/Compound4 complex and computer simulation of Compound7 docking to CD38 show a significant role of the nicotinamide moiety and the distal aromatic group of the compounds for substrate recognition by the active site of CD38. Biologically, we showed that both Compounds4 and 7 effectively relaxed the agonist-induced contraction of muscle preparations from rats and guinea pigs. This study is a rational design of inhibitors for CD38 that exhibit important physiological effects, and can serve as a model for future drug development. © 2011 The Royal Society of Chemistry.postprin

A cross-sectional study of vascular risk factors in a rural South African population : data from the Southern African Stroke Prevention Initiative (SASPI)

Background: Rural sub-Saharan Africa is at an early stage of economic and health transition. It is predicted that the 21st century will see a serious added economic burden from non-communicable disease including vascular disease in low-income countries as they progress through the transition. The stage of vascular disease in a population is thought to result from the prevalence of vascular risk factors. Already hypertension and stroke are common in adults in sub-Saharan Africa. Using a multidisciplinary approach we aimed to assess the prevalence of several vascular risk factors in Agincourt, a rural demographic surveillance site in South Africa. Methods: We performed a cross sectional random sample survey of adults aged over 35 in Agincourt (population ≈ 70 000). Participants were visited at home by a trained nurse who administered a questionnaire, carried out clinical measurements and took a blood sample. From this we assessed participants' history of vascular risk, blood pressure using an OMRON 705 CP monitor, waist circumference, body mass index (BMI), ankle brachial index (ABI), and total and HDL cholesterol. Results: 402 people (24% men) participated. There was a high prevalence of smoking in men, but the number of cigarettes smoked was small. There was a striking difference in mean BMI between men and women (22.8 kg/m2 versus 27.2 kg/m2), but levels of blood pressure were very similar. 43% of participants had a blood pressure greater than 140/90 or were on anti-hypertensive treatment and 37% of participants identified with measured high blood pressure were on pharmacological treatment. 12% of participants had an ABI of < 0.9, sugesting the presence of sub-clinical atheroma. 25.6% of participants had a total cholesterol level > 5 mmol/l. Conclusion: We found a high prevalence of hypertension, obesity in women, and a suggestion of subclinical atheroma despite relatively favourable cholesterol levels in a rural South African population. South Africa is facing the challenge of an emerging epidemic of vascular disease. Research to establish the social determinates of these risk factors and interventions to reduce both individual and population risk are required

Improved Constraints on Sterile Neutrino Mixing from Disappearance Searches in the MINOS, MINOS+, Daya Bay, and Bugey-3 Experiments.

Searches for electron antineutrino, muon neutrino, and muon antineutrino disappearance driven by sterile neutrino mixing have been carried out by the Daya Bay and MINOS+ collaborations. This Letter presents the combined results of these searches, along with exclusion results from the Bugey-3 reactor experiment, framed in a minimally extended four-neutrino scenario. Significantly improved constraints on the θ_{μe} mixing angle are derived that constitute the most constraining limits to date over five orders of magnitude in the mass-squared splitting Δm_{41}^{2}, excluding the 90%&nbsp;C.L. sterile-neutrino parameter space allowed by the LSND and MiniBooNE observations at 90%&nbsp;CL_{s} for Δm_{41}^{2}&lt;13  eV^{2}. Furthermore, the LSND and MiniBooNE 99%&nbsp;C.L. allowed regions are excluded at 99% CL_{s} for Δm_{41}^{2}&lt;1.6 eV^{2}

Star forming dwarf galaxies

Star forming dwarf galaxies (SFDGs) have a high gas content and low metallicities, reminiscent of the basic entities in hierarchical galaxy formation scenarios. In the young universe they probably also played a major role in the cosmic reionization. Their abundant presence in the local volume and their youthful character make them ideal objects for detailed studies of the initial stellar mass function (IMF), fundamental star formation processes and its feedback to the interstellar medium. Occasionally we witness SFDGs involved in extreme starbursts, giving rise to strongly elevated production of super star clusters and global superwinds, mechanisms yet to be explored in more detail. SFDGs is the initial state of all dwarf galaxies and the relation to the environment provides us with a key to how different types of dwarf galaxies are emerging. In this review we will put the emphasis on the exotic starburst phase, as it seems less important for present day galaxy evolution but perhaps fundamental in the initial phase of galaxy formation.Comment: To appear in JENAM Symposium "Dwarf Galaxies: Keys to Galaxy Formation and Evolution", P. Papaderos, G. Hensler, S. Recchi (eds.). Lisbon, September 2010, Springer Verlag, in pres