Emerging Roles of Cellular Metabolism in Regulating Dendritic Cell Subsets and Function

Dendritic cells (DCs) are the bridge between innate and T cell-dependent adaptive immunity and are promising therapeutic targets for cancer and immune-mediated disorders. Upon stimulation by pathogen or danger-sensing receptors, DCs become activated and poised to induce T cell priming. Recent studies have identified critical roles of metabolic pathways, including glycolysis, oxidative phosphorylation, and fatty acid metabolism, in orchestrating DC function. In this review, we discuss the shared and distinct metabolic programs shaping the functional specification of different DC subsets, including conventional DCs, bone marrow-derived DCs, and plasmacytoid DCs. We also briefly discuss the signaling networks that tune metabolic programs in DC subsets

Clinical evaluation of the Immulite® 1000 chemiluminescent immunoassay for measurement of equine serum insulin

IntroductionAccurate quantitative analysis of equine insulin in blood samples is critical for assessing hyperinsulinemia in horses. Although there are various laboratory methods for evaluating equine serum insulin, different immunoassays show significant discrepancies between the determined insulin concentrations and are often not comparable. The aim of this study was to evaluate the Immulite® 1000 chemiluminescent immunoassay (CLIA) to establish independent laboratory and assay-specific cut values to provide an accurate diagnosis of hyperinsulinemia in horses. Thus, the analytical and clinical performance of Immulite® 1000 CLIA in terms of precision (intra- and inter-assay coefficient of variance, CV) and recovery upon dilution were evaluated and compared with radioimmunoassay (RIA), which has been previously validated for use in horses.Material and methodsArchived serum samples (n = 106) from six Quarter horse mares enrolled in the glucose phase of a Frequently Sampled Insulin and Glucose Test (FSIGT) study were used to measure blood insulin.ResultsThe Immulite® 1000 CLIA had good precision with acceptable intra- and inter-assay CVs, adequate recovery on dilution, and a strong correlation with the RIA (r = 0.974, P < 0.0001), with constant bias resulting in consistently lower values.DiscussionOn this basis, the Immulite® 1000 Insulin Assay is valid for measuring equine serum insulin for diagnostic and monitoring purposes when cut values are appropriately adjusted

Renal Hemodynamics During Sympathetic Activation Following Aerobic and Anaerobic Exercise

We tested the hypotheses that prior aerobic (Study 1) or anaerobic (Study 2) exercise attenuates the increase in renal vascular resistance (RVR) during sympathetic stimulation. Ten healthy young adults (5 females) participated in both Study 1 (aerobic exercise) and Study 2 (anaerobic exercise). In Study 1, subjects completed three minutes of face cooling pre- and post- 30 min of moderate intensity aerobic exercise (68 ± 1% estimate maximal heart rate). In Study 2, subjects completed two minutes of the cold pressor test pre- and post- the completion of a 30 s maximal effort cycling test (Wingate Anaerobic Test). Both face cooling and the cold pressor test stimulate the sympathetic nervous system and elevate RVR. The primary dependent variable in both Studies was renal blood velocity, which was measured at baseline and every minute during sympathetic stimulation. Renal blood velocity was measured via the coronal approach at the distal segment of the right renal artery with pulsed wave Doppler ultrasound. RVR was calculated from the quotient of mean arterial pressure and renal blood velocity. In Study 1, renal blood velocity and RVR did not differ between pre- and post- aerobic exercise (P ≥ 0.24). Face cooling decreased renal blood velocity (P < 0.01) and the magnitude of this decrease did not differ between pre- and post- aerobic exercise (P = 0.52). RVR increased with face cooling (P < 0.01) and the extent of these increases did not differ between pre- and post- aerobic exercise (P = 0.74). In Study 2, renal blood velocity was 2 ± 2 cm/s lower post- anaerobic exercise (P = 0.02), but RVR did not differ (P = 0.08). The cold pressor test decreased renal blood velocity (P < 0.01) and the magnitude of this decrease did not differ between pre- and post- anaerobic exercise (P = 0.26). RVR increased with the cold pressor test (P < 0.01) and the extent of these increases did not differ between pre- and post- anaerobic exercise (P = 0.12). These data indicate that 30 min of moderate intensity aerobic exercise or 30 s of maximal effort anaerobic exercise does not affect the capacity to increase RVR during sympathetic stimulation following exercise

Alichur Dome, South Pamir, Western India-Asia Collisional Zone: Detailing the Neogene Shakhdara-Alichur Syn-collisional Gneiss-Dome Complex and Connection to Lithospheric Processes

Neogene, syn‐collisional extensional exhumation of Asian lower–middle crust produced the Shakhdara–Alichur gneiss‐dome complex in the South Pamir. The <1 km‐thick, mylonitic–brittle, top‐NNE, normal‐sense Alichur shear zone (ASZ) bounds the 125 × 25 km Alichur dome to the north. The Shakhdara dome is bounded by the <4 km‐thick, mylonitic–brittle, top‐SSE South Pamir normal‐sense shear zone (SPSZ) to the south, and the dextral Gunt wrench zone to its north. The Alichur dome comprises Cretaceous granitoids/gneisses cut by early Miocene leucogranites; its hanging wall contains non/weakly metamorphosed rocks. The 22–17 Ma Alichur‐dome‐injection‐complex leucogranites transition from foliation‐parallel, centimeter‐ to meter‐thick sheets within the ASZ into discordant intrusions that may comprise half the volume of the dome core. Secondary fluid inclusions in mylonites and mylonitization‐temperature constraints suggest Alichur‐dome exhumation from 10–15 km depth. Thermochronologic dates bracket footwall cooling between ~410–130 °C from ~16–4 Ma; tectonic cooling/exhumation rates (~42 °C/Myr, ~1.1 km/Myr) contrast with erosion‐dominated rates in the hanging wall (~2 °C/Myr, <0.1 km/Myr). Dome‐scale boudinage, oblique divergence of the ASZ and SPSZ hanging walls, and dextral wrenching reflect minor approximately E–W material flow out of the orogen. We attribute broadly southward younging extensional exhumation across the central South Pamir between ~20–4 Ma to: (i) Mostly northward, foreland‐directed flow of hot crust into a cold foreland during the growth of the Pamir orocline; and (ii) Contrasting effects of basal shear related to underthrusting Indian lithosphere, enhancing extension in the underthrust South Pamir and inhibiting extension in the non‐underthrust Central Pamir

Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser.

G-protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent pathways. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography. Together with extensive biochemical and mutagenesis data, the structure reveals an overall architecture of the rhodopsin-arrestin assembly in which rhodopsin uses distinct structural elements, including transmembrane helix 7 and helix 8, to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a ∼20° rotation between the amino and carboxy domains, which opens up a cleft in arrestin to accommodate a short helix formed by the second intracellular loop of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology

Ancient Host–Pathogen Associations Maintained by Specificity of Chemotaxis and Antibiosis

Switching by parasites to novel hosts has profound effects on ecological and evolutionary disease dynamics. Switching requires that parasites are able to establish contact with novel hosts and to overcome host defenses. For most host–parasite associations, it is unclear as to what specific mechanisms prevent infection of novel hosts. Here, we show that parasitic fungal species in the genus Escovopsis, which attack and consume the fungi cultivated by fungus-growing ants, are attracted to their hosts via chemotaxis. This response is host-specific: Escovopsis spp. grow towards their natural host cultivars more rapidly than towards other closely related fungi. Moreover, the cultivated fungi secrete compounds that can suppress Escovopsis growth. These antibiotic defenses are likewise specific: in most interactions, cultivars can inhibit growth of Escovopsis spp. not known to infect them in nature but cannot inhibit isolates of their naturally infecting pathogens . Cases in which cultivars are susceptible to novel Escovopsis are limited to a narrow set of host–parasite strain combinations. Targeted chemotactic and antibiotic responses therefore explain why Escovopsis pathogens do not readily switch to novel hosts, consequently constraining long-term dynamics of host–parasite coevolution within this ancient association

Ternary structure reveals mechanism of a membrane diacylglycerol kinase

Diacylglycerol kinase catalyses the ATP-dependent conversion of diacylglycerol to phosphatidic acid in the plasma membrane of Escherichia coli. The small size of this integral membrane trimer, which has 121 residues per subunit, means that available protein must be used economically to craft three catalytic and substrate-binding sites centred about the membrane/cytosol interface. How nature has accomplished this extraordinary feat is revealed here in a crystal structure of the kinase captured as a ternary complex with bound lipid substrate and an ATP analogue. Residues, identified as essential for activity by mutagenesis, decorate the active site and are rationalized by the ternary structure. The g-phosphate of the ATP analogue is positioned for direct transfer to the primary hydroxyl of the lipid whose acyl chain is in the membrane. A catalytic mechanism for this unique enzyme is proposed. The active site architecture shows clear evidence of having arisen by convergen

The ecology and epidemiology of malaria parasitism in wild chimpanzee reservoirs

Chimpanzees (Pan troglodytes) harbor rich assemblages of malaria parasites, including three species closely related to P. falciparum (sub-genus Laverania), the most malignant human malaria parasite. Here, we characterize the ecology and epidemiology of malaria infection in wild chimpanzee reservoirs. We used molecular assays to screen chimpanzee fecal samples, collected longitudinally and cross-sectionally from wild populations, for malaria parasite mitochondrial DNA. We found that chimpanzee malaria parasitism has an early age of onset and varies seasonally in prevalence. A subset of samples revealed Hepatocystis mitochondrial DNA, with phylogenetic analyses suggesting that Hepatocystis appears to cross species barriers more easily than Laverania. Longitudinal and cross-sectional sampling independently support the hypothesis that mean ambient temperature drives spatiotemporal variation in chimpanzee Laverania infection. Infection probability peaked at similar to 24.5 degrees C, consistent with the empirical transmission optimum of P. falciparum in humans. Forest cover was also positively correlated with spatial variation in Laverania prevalence, consistent with the observation that forest-dwelling Anophelines are the primary vectors. Extrapolating these relationships across equatorial Africa, we map spatiotemporal variation in the suitability of chimpanzee habitat for Laverania transmission, offering a hypothetical baseline indicator of human exposure risk

The ecology and epidemiology of malaria parasitism in wild chimpanzee reservoirs

This work was supported by grants from the National Institutes of Health R01AI091595, R01AI120810, R01AI050529, and P30AI045008 (B.H.H.); R01HL139337 (M.T.D.), the National Geographic Society (E.J.S.), the International Primatological Society (E.J.S.), and the American Society of Primatologists (E.J.S.), as well as fellowships from Harvard University (E.J.S.) and the National Science Foundation (E.J.S.).Chimpanzees (Pan troglodytes) harbor rich assemblages of malaria parasites, including three species closely related to P. falciparum (sub-genus Laverania), the most malignant human malaria parasite. Here, we characterize the ecology and epidemiology of malaria infection in wild chimpanzee reservoirs. We used molecular assays to screen chimpanzee fecal samples, collected longitudinally and cross-sectionally from wild populations, for malaria parasite mitochondrial DNA. We found that chimpanzee malaria parasitism has an early age of onset and varies seasonally in prevalence. A subset of samples revealed Hepatocystis mitochondrial DNA, with phylogenetic analyses suggesting that Hepatocystis appears to cross species barriers more easily than Laverania. Longitudinal and cross-sectional sampling independently support the hypothesis that mean ambient temperature drives spatiotemporal variation in chimpanzee Laverania infection. Infection probability peaked at ~24.5 °C, consistent with the empirical transmission optimum of P. falciparum in humans. Forest cover was also positively correlated with spatial variation in Laverania prevalence, consistent with the observation that forest-dwelling Anophelines are the primary vectors. Extrapolating these relationships across equatorial Africa, we map spatiotemporal variation in the suitability of chimpanzee habitat for Laverania transmission, offering a hypothetical baseline indicator of human exposure risk.Publisher PDFPeer reviewe

Overview of Spirit Microscopic Imager Results

This paper provides an overview of Mars Exploration Rover Spirit Microscopic Imager (MI) operations and the calibration, processing, and analysis of MI data. The focus of this overview is on the last five Earth years (2005-2010) of Spirit's mission in Gusev crater, supplementing the previous overview of the first 450 sols of the Spirit MI investigation. Updates to radiometric calibration using in-flight data and improvements in high-level processing are summarized. Released data products are described, and a table of MI observations, including target/feature names and associated data sets, is appended. The MI observed natural and disturbed exposures of rocks and soils as well as magnets and other rover hardware. These hand-lens-scale observations have provided key constraints on interpretations of the formation and geologic history of features, rocks, and soils examined by Spirit. MI images complement observations by other Spirit instruments, and together show that impact and volcanic processes have dominated the origin and evolution of the rocks in Gusev crater, with aqueous activity indicated by the presence of silica-rich rocks and sulfate-rich soils. The textures of some of the silica-rich rocks are similar to terrestrial hot spring deposits, and observations of subsurface cemented layers indicate recent aqueous mobilization of sulfates in places. Wind action has recently modified soils and abraded many of the rocks imaged by the MI, as observed at other Mars landing sites. Plain Language Summary The Microscopic Imager (MI) on NASA's Spirit rover returned the highest-resolution images of the Martian surface available at the time of the 2004-2010 mission. Designed to survive 90 Mars days (sols) and search for evidence of water in the past, Spirit returned data for 2210 sols, far exceeding all expectations. This paper summarizes the scientific insights gleaned from the thousands of MI images acquired during the last 5years of the mission, supplementing the summary of the first 450 sols of the Spirit MI investigation published previously (Herkenhoff et al., ). Along with data from the other instruments on Spirit, MI images guided the scientific interpretation of the geologic history of the rocks and soils observed in Gusev crater on Mars. We conclude that the geologic history of the area explored by Spirit has been dominated by impacts and volcanism, and that water, perhaps very hot water, was involved in the evolution of some of the rocks and soils. More recently, winds have moved soil particles and abraded rocks, as observed elsewhere on Mars. These results have improved our understanding of Mars' history and informed planning of future missions to Mars.National Aeronautics and Space AdministrationPublic domain articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]