Blocking Type I Interferon Production: A New Therapeutic Option to Reduce the HIV-1-Induced Immune Activation

Highly active antiretroviral therapy has dramatically improved the morbidity and mortality of HIV-1-infected individuals. A total of 25 licensed drugs provide the basis for an optimized virus-suppressive treatment of nearly each subject. The promises of immune reconstitution and normal life expectancy, however, fall short for a number of patients, either through inadequate recovery of CD4+ T-cell counts or the occurrence of non-AIDS defining malignancies. In this respect, the prevalence of Epstein-Barr virus-associated Hodgkin lymphoma and human papillomavirus-related anal neoplasia is rising in aging HIV-1-infected individuals despite antiretroviral therapy. An important cause appears to be the HIV-1-induced chronic immune activation, propagated by inappropriate release of proinflammatory cytokines and type I interferons. This immune dysregulation can be reduced in vitro by inhibitors blocking the endosomal acidification. Recent data suggest that this concept is also of relevance in vivo, which opens the door for adjuvant immunomodulatory therapies in HIV-1 infection

Chronic Immune Activation in HIV-1 Infection Contributes to Reduced Interferon Alpha Production via Enhanced CD40:CD40 Ligand Interaction

Although a signature of increased interferon (IFN-)alpha production is observed in HIV-1 infection, the response of circulating plasmacytoid dendritic cells (PDC) to Toll-like receptor ligand stimulation is substantially impaired. This functional PDC deficit, which we specifically observed in HIV-1 infected individuals with less than 500 CD4+ T cells/µl, is not well understood. We provide evidence that the peripheral IFN-alpha production in HIV-1 infection is actively suppressed by the enhanced interaction of CD40 ligand (CD40L), a member of the tumor necrosis factor family, and its receptor CD40, which are both upregulated upon immune activation. Plasma levels of soluble CD40L were significantly higher in untreated HIV-1 infected individuals (n = 52) than in subjects on long-term antiretroviral therapy (n = 62, p<0.03) and in uninfected control donors (n = 16, p<0.001). Concomitantly, cell-associated CD40L and the expression of the receptor CD40 on the PDC were significantly upregulated in HIV-1 infection (p<0.05). Soluble and cell-associated CD40L inhibited the PDC-derived IFN-alpha production by CpG oligodeoxynucleotides dose-dependently. This suppressive effect was observed at much lower, physiological CD40L concentrations in peripheral blood mononuclear cells (PBMC) of HIV-1 infected individuals compared to controls (p<0.05). The CpG-induced IFN-alpha production in PBMC of HIV-1 infected donors was directly correlated with PDC and CD4+ T cell counts, and inversely correlated with the viral loads (p<0.001). In HIV-1 infected donors with less than 500 CD4+ T cells/µl, the CpG-induced IFN-alpha production was significantly correlated with the percentage of CD40-expressing PDC and the level of CD40 expression on these cells (p<0.05), whereas CD40L plasma levels played a minor role. In addition, low-dose CD40L contributed to the enhanced production of interleukin 6 and 8 in PBMC of HIV-1 infected donors compared to controls. Our data support the conclusion that the chronic immune activation in HIV-1 infection impairs peripheral PDC innate immune responses at least in part via enhanced CD40:CD40L interactions

Activation of brain regions vulnerable to Alzheimer\u27s disease: The effect of mild cognitive impairment

This study examined the functionality of the medial temporal lobe (MTL) and posterior cingulate (PC) in mild cognitive impairment amnestic type (MCI), a syndrome that puts patients at greater risk for developing Alzheimer disease (AD). Functional MRI (fMRI) was used to identify regions normally active during encoding of novel items and recognition of previously learned items in a reference group of 77 healthy young and middle-aged adults. The pattern of activation in this group guided further comparisons between 14 MCI subjects and 14 age-matched controls. The MCI patients exhibited less activity in the PC during recognition of previously learned items, and in the right hippocampus during encoding of novel items, despite comparable task performance to the controls. Reduced fMRI signal change in the MTL supports prior studies implicating the hippocampus for encoding new information. Reduced signal change in the PC converges with recent research on its role in recognition in normal adults as well as metabolic decline in people with genetic or cognitive risk for AD. Our results suggest that a change in function in the PC may account, in part, for memory recollection failure in AD. © 2005 Elsevier Inc. All rights reserved

The effects of elevated temperature and dissolved �CO2 on a marine foundation species

Understanding how climate change and other environmental stressors will affect species is a fundamental concern of modern ecology. Indeed, numerous studies have documented how climate stressors affect species distributions and population persistence. However, relatively few studies have investigated how multiple climate stressors might affect species. In this study, we investigate the impacts of how two climate change factors affect an important foundation species. Specifically, we tested how ocean acidification from dissolution of CO2 and increased sea surface temperatures affect multiple characteristics of juvenile eastern oysters (Crassostrea virginica). We found strong impacts of each stressor, but no interaction between the two. Simulated warming to mimic heat stressed summers reduced oyster growth, survival, and filtration rates. Additionally, we found that CO2-induced acidification reduced strength of oyster shells, which could potentially facilitate crab predation. As past studies have detected few impacts of these stressors on adult oysters, these results indicate that early life stages of calcareous marine organisms may be more susceptible to effects of ocean acidification and global warming. Overall, these data show that predicted changes in temperature and CO2 can differentially influence direct effects on individual species, which could have important implications for the nature of their trophic interactions.ECU Open Access Publishing Fun

Reduced hippocampal activation during episodic encoding in middle-aged individuals at genetic risk of Alzheimer's Disease: a cross-sectional study

BACKGROUND: The presence of the apolipoprotein E (APOE) ε4 allele is a major risk factor for the development of Alzheimer's disease (AD), and has been associated with metabolic brain changes several years before the onset of typical AD symptoms. Functional MRI (fMRI) is a brain imaging technique that has been used to demonstrate hippocampal activation during measurement of episodic encoding, but the effect of the ε4 allele on hippocampal activation has not been firmly established. METHODS: The present study examined the effects of APOE genotype on brain activation patterns in the medial temporal lobe (MTL) during an episodic encoding task using a well-characterized novel item versus familiar item contrast in cognitively normal, middle-aged (mean = 54 years) individuals who had at least one parent with AD. RESULTS: We found that ε3/4 heterozygotes displayed reduced activation in the hippocampus and MTL compared to ε3/3 homozygotes. There were no significant differences between the groups in age, education or neuropsychological functioning, suggesting that the altered brain activation seen in ε3/4 heterozygotes was not associated with impaired cognitive function. We also found that participants' ability to encode information on a neuropsychological measure of learning was associated with greater activation in the anterior MTL in the ε3/3 homozygotes, but not in the ε3/4 heterozygotes. CONCLUSION: Together with previous studies reporting reduced glucose metabolism and AD-related neuropathology, this study provides convergent validity for the idea that the MTL exhibits functional decline associated with the APOE ε4 allele. Importantly, these changes were detected in the absence of meaningful neuropsychological differences between the groups. A focus of ongoing work in this laboratory is to determine if these findings are predictive of subsequent cognitive decline

Robust Feature Bundling

Abstract. In this work we present a feature bundling technique that aggregates individual local features with features from their spatial neighborhood into bundles. The resulting bundles carry more information of the underlying image content than single visual words. As in practice an exact search for such bundles is infeasible, we employ a robust approximate similarity search with min-hashing in order to retrieve images containing similar bundles. We demonstrate the benefits of these bundles for small object retrieval, i.e. logo recognition, and generic image retrieval. Multiple bundling strategies are explored and thoroughly evaluated on three different datasets.

Do the radial head prosthesis components fit with the anatomical structures of the proximal radioulnar joint?

The fitting accuracy of radial head components has been investigated in the capitulo-radial joint, and reduced contact after prosthetic replacement of the radial head has been observed. The kinematics of the proximal radioulnar joint (PRUJ) are affected by radial head arthroplasty as well, but have not yet been investigated in this regard. The elbow joints of 60 upper extremities of formalin-fixed body donors were disarticulated to obtain a good view of the PRUJ. Each specimen was mounted on the examining table and radial head position in the native PRUJ was assessed in neutral position, full pronation, and full supination. Measurements were repeated after implantation of mono- and bi-polar prostheses. Analysis of the distribution of the joint contacts in the compartments showed significant differences after radial head replacement. In comparison to the native joint, after bipolar and monopolar radial head replacement, the physiological shift of the proximal radius was altered. The physiological shift of the joint contact of the radial head from anterior to posterior during forearm rotation that was found in the native joint in our cadaver model was not observed after prosthetic replacement. With higher conformity and physiological kinematic of radial head prostheses, possibly lower shear forces and lower contact pressures would be generated. The tested radial head prostheses do not replicate the physiological kinematics of the radial head. Further development in the prosthesis design has to be made. The meticulous reconstruction of the annular ligament seems to be of importance to increase joint contact

Application of time-of-flight aerosol mass spectrometry for the online measurement of gaseous molecular iodine

Here we present a new application of a time-offlight aerosol mass spectrometer (TOF-AMS) for the measurement of atmospheric trace gases in real-time. Usually, TOF-AMS instruments are not sensitive to gas-phase species due to the aerodynamic particle focusing inlet system which reduces the gas phase species by a factor of about 107 relative to the particle phase. This efficient removal of the gas phase and the resulting high relative enrichment of particles is one reason for the very high sensitivity of TOF-AMS instruments for particle phase compounds (detection limits in the µg/m³-range for online measurements with 1 min integration time), which allows application of the instruments even under clean atmospheric conditions. Here we use artificially generated particles as sampling probes to transfer selected atmospheric trace gases into the particle phase before entering the AMS (gaseous compound trapping in artificially generated particles-AMS, GTRAP-AMS). The sampling probe particles are mixed with the gaseous analytes upstream of the TOF-AMS in a 0.5 L flow tube. As an exemplary application of the method, the measurement of trace levels of gaseous molecular iodine is demonstrated. ?-Cyclodextrin (?-CD/NH4Br) particles are used as selective sampling probes to transfer molecular iodine into the AMS. A detection limit in the subparts-per-billion (sub-ppb) range was achieved. The method was compared to a recently developed off-line method that combines denuder sampling of gaseous I2 and gas chromatography/mass spectrometry (GC/MS) analysis. To demonstrate the usability of the method, temporally resolved I2 emission profiles from a brown algae species (Laminaria saccharina) under exposure of ambient ozone levels were investigated. Total I2 release rates of 36.5 pmol min-1 grams fresh weight (gFW)-1 at 100 pbb O3 and 33.4 pmol min-1 gFW-1 at 50 ppb O3 were obtained within the first hour of ozone exposure