The Colocalization Potential of HIV-Specific CD8+ and CD4+ T-Cells is Mediated by Integrin β7 but Not CCR6 and Regulated by Retinoic Acid

CD4+ T-cells from gut-associated lymphoid tissues (GALT) are major targets for HIV-1 infection. Recruitment of excess effector CD8+ T-cells in the proximity of target cells is critical for the control of viral replication. Here, we investigated the colocalization potential of HIV-specific CD8+ and CD4+ T-cells into the GALT and explored the role of retinoic acid (RA) in regulating this process in a cohort of HIV-infected subjects with slow disease progression. The expression of the gut-homing molecules integrin β7, CCR6, and CXCR3 was identified as a “signature” for HIV-specific but not CMV-specific CD4+ T-cells thus providing a new explanation for their enhanced permissiveness to infection in vivo. HIV-specific CD8+ T-cells also expressed high levels of integrin β7 and CXCR3; however CCR6 was detected at superior levels on HIV-specific CD4+ versus CD8+ T-cells. All trans RA (ATRA) upregulated the expression of integrin β7 but not CCR6 on HIV-specific T-cells. Together, these results suggest that HIV-specific CD8+ T-cells may colocalize in excess with CD4+ T-cells into the GALT via integrin β7 and CXCR3, but not via CCR6. Considering our previous findings that CCR6+CD4+ T-cells are major cellular targets for HIV-DNA integration in vivo, a limited ability of CD8+ T-cells to migrate in the vicinity of CCR6+CD4+ T-cells may facilitate HIV replication and dissemination at mucosal sites

Single-cell analysis identifies cellular markers of the HIV permissive cell.

Cellular permissiveness to HIV infection is highly heterogeneous across individuals. Heterogeneity is also found across CD4+ T cells from the same individual, where only a fraction of cells gets infected. To explore the basis of permissiveness, we performed single-cell RNA-seq analysis of non-infected CD4+ T cells from high and low permissive individuals. Transcriptional heterogeneity translated in a continuum of cell states, driven by T-cell receptor-mediated cell activation and was strongly linked to permissiveness. Proteins expressed at the cell surface and displaying the highest correlation with T cell activation were tested as biomarkers of cellular permissiveness to HIV. FACS sorting using antibodies against several biomarkers of permissiveness led to an increase of HIV cellular infection rates. Top candidate biomarkers included CD25, a canonical activation marker. The combination of CD25 high expression with other candidate biomarkers led to the identification of CD298, CD63 and CD317 as the best biomarkers for permissiveness. CD25highCD298highCD63highCD317high cell population showed an enrichment of HIV-infection of up to 28 fold as compared to the unsorted cell population. The purified hyper-permissive cell subpopulation was characterized by a downregulation of interferon-induced genes and several known restriction factors. Single-cell RNA-seq analysis coupled with functional characterization of cell biomarkers provides signatures of the "HIV-permissive cell"

A Key Role for Neurotensin in Chronic-Stress-Induced Anxiety-Like Behavior in Rats

Accepted ManuscriptChronic stress is a major cause of anxiety disorders that can be reliably modeled preclinically, providing insight into alternative therapeutic targets for this mental health illness. Neuropeptides have been targeted in the past to no avail possibly due to our lack of understanding of their role in pathological models. In this study we use a rat model of chronic stress-induced anxiety-like behaviors and hypothesized that neuropeptidergic modulation of synaptic transmission would be altered in the bed nucleus of the stria terminalis (BNST), a brain region suspected to contribute to anxiety disorders. We use brain slice neurophysiology and behavioral pharmacology to compare the role of locally released endogenous neuropeptides on synaptic transmission in the oval (ov) BNST of non-stressed (NS) or chronic unpredictably stressed (CUS) rats. We found that in NS rats, post-synaptic depolarization induced the release of vesicular neurotensin (NT) and corticotropin-releasing factor (CRF) that co-acted to increase ovBNST inhibitory synaptic transmission in 59% of recorded neurons. CUS bolstered this potentiation (100% of recorded neurons) through an enhanced contribution of NT over CRF. In contrast, locally released opioid neuropeptides decreased ovBNST excitatory synaptic transmission in all recorded neurons, regardless of stress. Consistent with CUS-induced enhanced modulatory effects of NT, blockade of ovBNST NT receptors completely abolished stress-induced anxiety-like behaviors in the elevated plus maze paradigm. The role of NT has been largely unexplored in stress and our findings highlight its potential contribution to an important behavioral consequence of chronic stress, that is, exaggerated avoidance of open space in rats.CPN was funded by CIHR Vanier Graduate Scholarship (338319); APVS was funded by Fundação para a Ciência e Tecnologia (SFRH/BPD/52078/2013); ERH was funded by CIHR Postdoctoral Fellowship (MFE-123712); SA was funded by a Queen Elizabeth II Graduate Scholarship in Science and Technology; ÉCD was funded by the Canadian Institute of Health Research (MOP-25953)info:eu-repo/semantics/publishedVersio

Visual Scan Paths and Recognition of Facial Identity in Autism Spectrum Disorder and Typical Development

Background: Previous research suggests that many individuals with autism spectrum disorder (ASD) have impaired facial identity recognition, and also exhibit abnormal visual scanning of faces. Here, two hypotheses accounting for an association between these observations were tested: i) better facial identity recognition is associated with increased gaze time on the Eye region; ii) better facial identity recognition is associated with increased eye-movements around the face. Methodology and Principal Findings: Eye-movements of 11 children with ASD and 11 age-matched typically developing (TD) controls were recorded whilst they viewed a series of faces, and then completed a two alternative forced-choice recognition memory test for the faces. Scores on the memory task were standardized according to age. In both groups, there was no evidence of an association between the proportion of time spent looking at the Eye region of faces and age-standardized recognition performance, thus the first hypothesis was rejected. However, the 'Dynamic Scanning Index' - which was incremented each time the participant saccaded into and out of one of the core-feature interest areas - was strongly asso ciated with age-standardized face recognition scores in both groups, even after controlling for various other potential predictors of performance. Conclusions and Significance: In support of the second hypothesis, results suggested that increased saccading between core-features was associated with more accurate face recognition ability, both in typical development and ASD. Causal directions of this relationship remain undetermined.10 page(s

Physical training in boys with Duchenne Muscular Dystrophy: the protocol of the No Use is Disuse study

Contains fulltext : 89740.pdf (publisher's version ) (Open Access)BACKGROUND: "Use it or lose it" is a well known saying which is applicable to boys with Duchenne Muscular Dystrophy (DMD). Besides the direct effects of the muscular dystrophy, the increasing effort to perform activities, the fear of falling and the use of personal aids indirectly impair leg and arm functions as a result of disuse. Physical training could oppose this secondary physical deterioration. The No Use is Disuse (NUD) study is the first study in human subjects with DMD that will examine whether a low-intensity physical training is beneficial in terms of preservation of muscle endurance and functional abilities. The study consists of two training intervention studies: study 1 "Dynamic leg and arm training for ambulant and recently wheelchair-dependent boys with DMD and, study 2 "Functional training with arm support for boys with DMD who have been confined to a wheelchair for several years". This paper describes the hypotheses and methods of the NUD study. METHODS: Study 1 is an explorative randomized controlled trial with multiple baseline measurements. Thirty boys with a DNA-established diagnosis of DMD will be included. The intervention consists of a six-months physical training during which boys train their legs and arms with active and/or assisted cycling training equipment. The primary study outcomes are muscle endurance and functional abilities, assessed with a Six-Minute Bicycle Test and the Motor Function Measure. Study 2 has a within-group repeated measurements design and will include ten boys with DMD who have already been confined to a wheelchair for several years. The six-months physical training program consists of 1) a computer-assisted training and 2) a functional training with an arm support. The primary study outcome is functional abilities of the upper extremity, assessed with the Action Research Arm Test. DISCUSSION: The NUD study will fill part of the gap in the current knowledge about the possible effects of training in boys with DMD and will increase insight into what type of exercise should be recommended to boys with DMD. The study will finish at the end of 2010 and results are expected in 2011. TRIAL REGISTRATION: The Netherlands National Trial Register1631

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta