Increased Bone Marrow Interleukin-7 (IL-7)/IL-7R Levels but Reduced IL-7 Responsiveness in HIV-Positive Patients Lacking CD4+ Gain on Antiviral Therapy

Background: The bone marrow (BM) cytokine milieu might substantially affect T-lymphocyte homeostasis in HIV-positive individuals. Interleukin-7 (IL-7) is a bone marrow-derived cytokine regulating T-cell homeostasis through a CD4+-driven feedback loop. CD4+ T-lymphopenia is associated with increased free IL-7 levels and reduced IL-7R expression/function, which are only partially reverted by highly active antiretroviral therapy (HAART). We investigated the BM production, peripheral expression and signaling (pStat5+ and Bcl-2+ CD4+/CD8+ T cells) of IL-7/IL-7Ra in 30 HAART-treated HIV-positive patients who did not experience CD4+ recovery (CD4+ #200/ml) and who had different levels of HIV viremia; these patients included 18 immunological nonresponders (INRs; HIV-RNA#50), 12 complete failures (CFs; HIV-RNA.1000), and 23 HIVseronegative subjects. Methods: We studied plasma IL-7 levels, IL-7Ra+CD4+/CD8+ T-cell proportions, IL-7Ra mRNA expression in PBMCs, spontaneous IL-7 production by BM mononuclear cells (BMMCs), and IL-7 mRNA/IL-7Ra mRNA in BMMC-derived stromal cells (SCs). We also studied T-cell responsiveness to IL-7 by measuring the proportions of pStat5+ and Bcl-2+ CD4+/CD8+ T cells. Results: Compared to HIV-seronegative controls, CFs and INRs presented elevated plasma IL-7 levels and lower IL-7Ra CD4+/CD8+ cell-surface expression and peripheral blood production, confirming the most relevant IL-7/IL-7R disruption. Interestingly, BM investigation revealed a trend of higher spontaneous IL-7 production in INRs (p = .09 vs. CFs) with a nonsignificant trend toward higher IL-7-Ra mRNA levels in BMMC-derived stromal cells. However, upon IL-7 stimulation, the proportion of pStat5+CD4+ T cells did not increase in INRs despite higher constitutive levels (p = .06); INRs also displayed lower Bcl-2+CD8+ T-cell proportions than controls (p = .04). Conclusions: Despite severe CD4+ T-lymphopenia and a disrupted IL-7/IL-7R profile in the periphery, INRs display elevated BM IL-7/IL-7Ra expression but impaired T-cell responsiveness to IL-7, suggesting the activity of a central compensatory pathway targeted to replenish the CD4+ compartment, which is nevertheless inappropriate to compensate the dysfunctional signaling through IL-7 receptor

Mechanisms Underlying Stage-1 TRPL Channel Translocation in Drosophila Photoreceptors

Background: TRP channels function as key mediators of sensory transduction and other cellular signaling pathways. In Drosophila, TRP and TRPL are the light-activated channels in photoreceptors. While TRP is statically localized in the signaling compartment of the cell (the rhabdomere), TRPL localization is regulated by light. TRPL channels translocate out of the rhabdomere in two distinct stages, returning to the rhabdomere with dark-incubation. Translocation of TRPL channels regulates their availability, and thereby the gain of the signal. Little, however, is known about the mechanisms underlying this trafficking of TRPL channels. Methodology/Principal Findings: We first examine the involvement of de novo protein synthesis in TRPL translocation. We feed flies cycloheximide, verify inhibition of protein synthesis, and test for TRPL translocation in photoreceptors. We find that protein synthesis is not involved in either stage of TRPL translocation out of the rhabdomere, but that re-localization to the rhabdomere from stage-1, but not stage-2, depends on protein synthesis. We also characterize an ex vivo eye preparation that is amenable to biochemical and genetic manipulation. We use this preparation to examine mechanisms of stage-1 TRPL translocation. We find that stage-1 translocation is: induced with ATP depletion, unaltered with perturbation of the actin cytoskeleton or inhibition of endocytosis, and slowed with increased membrane sterol content. Conclusions/Significance: Our results indicate that translocation of TRPL out of the rhabdomere is likely due to protei

Longitudinal serum bicarbonate and mortality risk in older patients with advanced chronic kidney disease: Analyses from the EQUAL cohort

Background. We aimed to explore the relationship between serum bicarbonate (SBC) and mortality in advanced chronic kidney disease (CKD) during three distinct treatment periods: during the pre-kidney replacement therapy (KRT) period, during the transition phase surrounding the start of KRT (transition-CKD) and during KRT. Methods. Using the European QUALity Study on treatment in advanced CKD (EQUAL) cohort, which includes patients aged ≥65 years and estimated glomerular filtration rate (eGFR) ≤20 mL/min/1.73 m2 from six European countries, we explored the association between longitudinal SBC and all-cause mortality in three separate CKD populations: pre-KRT, transition-CKD and in the KRT populations, using multivariable time-dependent Cox regression models. We evaluated effect modification by pre-specified variables on the relationship between SBC and mortality Results. We included 1485 patients with a median follow-up of 2.9 (interquartile range 2.7) years, during which 529 (35.6%) patients died. A U-shaped relationship between SBC levels and all-cause mortality was observed in the pre-KRT population (P = .03). Low cumulative exposure, defined as the area under the SBC trajectory before KRT initiation, was associated with increased mortality risk after transitioning to KRT (P = .01). Similarly, in the KRT population, low SBC levels showed a trend towards increased mortality risk (P = .13). We observed effect modification by subjective global assessment category (P-value for interaction = .02) and KRT (P-value for interaction = .02). Conclusions. A U-shaped relationship describes the association between SBC and mortality in the advanced CKD pre-KRT population, whereas in the KRT population a trend towards an increased mortality risk was observed for low SBC levels

Characterization of the I-phase regime at TCV

The I-phase is an H-mode confinement regime of tokamaks characterized by limit cycle oscillations, the so-called LCOs or bursts. These bursts are the manifestation of a periodic flattening of the plasma edge pressure profile. The profile flattening is caused by increased radial transport, driven by a high-frequency plasma edge mode that periodically appears. This short-living mode is intrinsically connected to each burst. It vanishes once the profiles are fully flattened, and it reestablishes during profile recovery once critical gradients are reached and a new cycle begins. In this paper, we describe for the first time the unambiguous presence of the I-phase at the tokamak `a configuration variable (TCV). As the I-phase confinement regime is found in the parameter regime between the L-mode and the fully developed H-mode, it is often confused with dithers between H-mode and L-mode. Therefore, we are highlighting the differences between these two phenomena. Furthermore, we show the two-dimensional dynamics of the I-phase mode and bursts and the associated filamentary transport, enabled by the outstanding capabilities of the 2D TCV Gas Puff Imaging diagnostics

Measurements of radial neutral density profiles from Balmer-α emission in Wendelstein 7-X

Radial neutral density profiles are estimated from measurements of passive Hα emission in the Wendelstein 7-X stellarator. To parametrize the generally three-dimensional distribution with a low number of degrees of freedom, the neutral density is reduced to a flux surface quantity. Accounting for emission from excitation and recombination processes, neutral density profiles are derived independently for each of the available lines of sight. Density profiles obtained from the different viewing geometries are found to vary within one order of magnitude. Toroidally oriented lines of sight predict systematically lower neutral densities when compared to poloidally oriented ones. This discrepancy is attributed to the simplifications inherent in the imposed model and significant differences in integration volumes across the viewing geometries. In line with expectations, obtained neutral densities are found to decrease with increasing plasma density. Key restrictions of the model include the reduction of the neutral density to a flux surface quantity, uncertainties in the plasma profiles and instrument function, and line integration effects outside the last closed flux surface

Search for non-resonant Higgs boson pair production in the 2b+2l+ETmiss final state in pp collisions at s = 13 TeV with the ATLAS detector

A search for non-resonant Higgs boson pair (HH) production is presented, in which one of the Higgs bosons decays to a b-quark pair (bb ̄) and the other decays to WW*, ZZ*, or τ+τ−, with in each case a final state with l+l−+ neutrinos (l = e, μ). The analysis targets separately the gluon-gluon fusion and vector boson fusion production modes. Data recorded by the ATLAS detector in proton-proton collisions at a centre-of-mass energy of 13 TeV at the Large Hadron Collider, corresponding to an integrated luminosity of 140 fb−1, are used in this analysis. Events are selected to have exactly two b-tagged jets and two leptons with opposite electric charge and missing transverse momentum in the final state. These events are classified using multivariate analysis algorithms to separate the HH events from other Standard Model processes. No evidence of the signal is found. The observed (expected) upper limit on the cross-section for non-resonant Higgs boson pair production is determined to be 9.7 (16.2) times the Standard Model prediction at 95% confidence level. The Higgs boson self-interaction coupling parameter κλ and the quadrilinear coupling parameter κ2V are each separately constrained by this analysis to be within the ranges [−6.2, 13.3] and [−0.17, 2.4], respectively, at 95% confidence level, when all other parameters are fixed

Determination of the Relative Sign of the Higgs Boson Couplings to W and Z Bosons Using WH Production via Vector-Boson Fusion with the ATLAS Detector

The associated production of Higgs and W bosons via vector-boson fusion is highly sensitive to the relative sign of the Higgs boson couplings to W and Z bosons. In this Letter, two searches for this process are presented, using 140 fb^{-1} of proton-proton collision data at sqrt[s]=13 TeV recorded by the ATLAS detector at the LHC. The first search targets scenarios with opposite-sign couplings of the W and Z bosons to the Higgs boson, while the second targets standard model-like scenarios with same-sign couplings. Both analyses consider Higgs boson decays into a pair of b quarks and W boson decays with an electron or muon. The data exclude the opposite-sign coupling hypothesis with a significance beyond 5σ, and the observed (expected) upper limit set on the cross section for vector-boson fusion WH production is 9.0 (8.7) times the standard model value at 95% confidence level

Combination of searches for heavy spin-1 resonances using 139 fb−1 of proton-proton collision data at s = 13 TeV with the ATLAS detector

A combination of searches for new heavy spin-1 resonances decaying into different pairings of W, Z, or Higgs bosons, as well as directly into leptons or quarks, is presented. The data sample used corresponds to 139 fb−1 of proton-proton collisions at = 13 TeV collected during 2015–2018 with the ATLAS detector at the CERN Large Hadron Collider. Analyses selecting quark pairs (qq, bb, , and tb) or third-generation leptons (τν and ττ) are included in this kind of combination for the first time. A simplified model predicting a spin-1 heavy vector-boson triplet is used. Cross-section limits are set at the 95% confidence level and are compared with predictions for the benchmark model. These limits are also expressed in terms of constraints on couplings of the heavy vector-boson triplet to quarks, leptons, and the Higgs boson. The complementarity of the various analyses increases the sensitivity to new physics, and the resulting constraints are stronger than those from any individual analysis considered. The data exclude a heavy vector-boson triplet with mass below 5.8 TeV in a weakly coupled scenario, below 4.4 TeV in a strongly coupled scenario, and up to 1.5 TeV in the case of production via vector-boson fusion