Characterization of a novel population of low-density granulocytes associated with disease severity in HIV-1 infection

The mechanisms resulting in progressive immune dysfunction during the chronic phase of HIV infection are not fully understood. We have previously shown that arginase, an enzyme with potent immunosuppressive properties, is increased in HIV seropositive (HIV+) patients with low CD4(+) T cell counts. Here we show that the cells expressing arginase in peripheral blood mononuclear cells of HIV+ patients are low-density granulocytes (LDGs) and that whereas these cells have a similar morphology to normal-density granulocyte, they are phenotypically different. Importantly, our results reveal that increased frequencies of LDGs correlate with disease severity in HIV+ patients

Adding New Tasks to a Single Network with Weight Transformations using Binary Masks

Visual recognition algorithms are required today to exhibit adaptive abilities. Given a deep model trained on a specific, given task, it would be highly desirable to be able to adapt incrementally to new tasks, preserving scalability as the number of new tasks increases, while at the same time avoiding catastrophic forgetting issues. Recent work has shown that masking the internal weights of a given original conv-net through learned binary variables is a promising strategy. We build upon this intuition and take into account more elaborated affine transformations of the convolutional weights that include learned binary masks. We show that with our generalization it is possible to achieve significantly higher levels of adaptation to new tasks, enabling the approach to compete with fine tuning strategies by requiring slightly more than 1 bit per network parameter per additional task. Experiments on two popular benchmarks showcase the power of our approach, that achieves the new state of the art on the Visual Decathlon Challenge

Antiretroviral therapy abrogates association between arginase activity and HIV disease severity.

Arginase-induced L-arginine deprivation is emerging as a key mechanism for the downregulation of immune responses. We hypothesised that arginase activity increases with disease severity in HIV-seropositive patients. Our results show that peripheral blood mononuclear cells (PBMCs) from 23 HIV-seropositive patients with low CD4(+) T cell counts (≤350 cells/μl) expressed significantly more arginase compared with 21 patients with high CD4(+) T cell counts. Furthermore, we found a significant association between the two principal prognostic markers used to monitor HIV disease (CD4(+) T cell count and plasma viral load) and PBMC arginase activity in antiretroviral therapy naïve patients but not in patients undergoing therapy

Visceral leishmaniasis patients display altered composition and maturity of neutrophils as well as impaired neutrophil effector functions

Immunologically, active visceral leishmaniasis (VL) is characterised by profound immunosuppression, severe systemic inflammatory responses and an impaired capacity to control parasite replication. Neutrophils are highly versatile cells, which play a crucial role in the induction as well as the resolution of inflammation, the control of pathogen replication and the regulation of immune responses. Neutrophil functions have been investigated in human cutaneous leishmaniasis, however, their role in human visceral leishmaniasis is poorly understood. In the present study we evaluated the activation status and effector functions of neutrophils in patients with active VL and after successful anti-leishmanial treatment. Our results show that neutrophils are highly activated and have degranulated; high levels of arginase, myeloperoxidase and elastase, all contained in neutrophils’ granules, were found in the plasma of VL patients. In addition, we show that a large proportion of these cells are immature. We also analysed effector functions of neutrophils that are essential for pathogen clearance and show that neutrophils have an impaired capacity to release neutrophil extracellular traps, produce reactive oxygen species and phagocytose bacterial particles, but not Leishmania parasites. Our results suggest that impaired effector functions, increased activation and immaturity of neutrophils play a key role in the pathogenesis of VL

The role of metabolic remodeling in macrophage polarization and its effect on skeletal muscle regeneration

Macrophages are crucial for tissue homeostasis. Based on their activation, they might display classical/M1 or alternative/M2 phenotypes. M1 macrophages produce pro-inflammatory cytokines, reactive oxygen species (ROS), and nitric oxide (NO). M2 macrophages upregulate arginase-1 and reduce NO and ROS levels; they also release anti-inflammatory cytokines, growth factors, and polyamines, thus promoting angiogenesis and tissue healing. Moreover, M1 and M2 display key metabolic differences; M1 polarization is characterized by an enhancement in glycolysis and in the pentose phosphate pathway (PPP) along with a decreased oxidative phosphorylation (OxPhos), whereas M2 are characterized by an efficient OxPhos and reduced PPP. Recent Advances: The glutamine-related metabolism has been discovered as crucial for M2 polarization. Vice versa, flux discontinuities in the Krebs cycle are considered additional M1 features; they lead to increased levels of immunoresponsive gene 1 and itaconic acid, to isocitrate dehydrogenase 1-downregulation and to succinate, citrate, and isocitrate over-expression

Reduced Self-Reactivity of an Autoreactive T Cell After Activation with Cross-reactive Non–Self-Ligand

Autoreactive CD4+ T lymphocytes are critical to the induction of autoimmune disease, but because of the degenerate nature of T cell receptor (TCR) activation such receptors also respond to other ligands. Interaction of autoreactive T cells with other non–self-ligands has been shown to activate and expand self-reactive cells and induce autoimmunity. To understand the effect on the autoreactivity of naive cross-reactive T cells of activation with a potent nonself ligand, we have generated a TCR transgenic mouse which expresses a TCR with a broad cross-reactivity to a number of ligands including self-antigen. The activation of naive transgenic recombination activating gene (Rag)2−/− T cells with a potent non–self-ligand did not result in a enhancement of reactivity to self, but made these T cells nonresponsive to the self-ligand and anti-CD3, although they retained a degree of responsiveness to the non–self-ligand. These desensitized cells had many characteristics of anergic T cells. Interleukin (IL)-2 production was selectively reduced compared with interferon (IFN)-γ. p21ras activity was reduced and p38 mitogen-activated protein kinase (MAPK) was relatively spared, consistent with known biochemical characteristics of anergy. Surprisingly, calcium fluxes were also affected and the anergic phenotype could not be reversed by exogenous IL-2. Therefore, activation with a hyperstimulating non–self-ligand changes functional specificity of an autoreactive T cell without altering the TCR. This mechanism may preserve the useful reactivity of peripheral T cells to foreign antigen while eliminating responses to self

Moisture sensitivity of crumb rubber modified modifier warm mix asphalt additive for two different compaction temperatures

Crumb rubber obtained from scrap tires has been incorporated with asphalt binder to improve the performance of asphalt mixtures in the past decades. Pavements containing crumbrubber modified (CRM) binders present one major drawback: larger amounts of greenhouse gas emissions are produced as there is rise in the energy consumption at the asphalt plant due to the higher viscosity of these type of binders compared with a conventional mixture. The objective of this paper is to calculate the optimum bitumen content for each percentage and evaluate the moisture sensitivity of crumb rubber modified asphalt at two different compacting temperatures. In this study, crumb rubber modified percentages was 0%, 5%, 10% and 15% from the binder weight, with adding 1.5% warm mix asphalt additive (Sasobit) and crush granite aggregate of 9.5mm Nominal maximum size was used after assessing its properties. Ordinary Portland Cement (OPC) used by 2% from fine aggregate. The wet method was using to mix the CRM with bitumen, the CRM conducted at 177°C for 30 min with 700rpm and Sasobit conducted at 120°C for 10 min with 1000rpm. As a result, from this study the optimum bitumen content (OBC) was increased with increased crumb rubber content. For performance test, it was conducted using the AASHTO T283 (2007): Resistance of Compacted Bituminous Mixture to Moisture-Induced Damage. The result was as expected and it was within the specification of the test, the result show that the moisture damage increased with increased the crumb rubber content but it is not exceeding the limit of specification 80% for indirect tension strength ratio (ITSR). For the temperature was with lowing the temperature the moisture damage increased

Leishmania amazonensis Arginase Compartmentalization in the Glycosome Is Important for Parasite Infectivity

In Leishmania, de novo polyamine synthesis is initiated by the cleavage of L-arginine to urea and L-ornithine by the action of arginase (ARG, E.C. 3.5.3.1). Previous studies in L. major and L. mexicana showed that ARG is essential for in vitro growth in the absence of polyamines and needed for full infectivity in animal infections. The ARG protein is normally found within the parasite glycosome, and here we examined whether this localization is required for survival and infectivity. First, the localization of L. amazonensis ARG in the glycosome was confirmed in both the promastigote and amastigote stages. As in other species, arg− L. amazonensis required putrescine for growth and presented an attenuated infectivity. Restoration of a wild type ARG to the arg− mutant restored ARG expression, growth and infectivity. In contrast, restoration of a cytosol-targeted ARG lacking the glycosomal SKL targeting sequence (argΔSKL) restored growth but failed to restore infectivity. Further study showed that the ARGΔSKL protein was found in the cytosol as expected, but at very low levels. Our results indicate that the proper compartmentalization of L. amazonensis arginase in the glycosome is important for enzyme activity and optimal infectivity. Our conjecture is that parasite arginase participates in a complex equilibrium that defines the fate of L-arginine and that its proper subcellular location may be essential for this physiological orchestration

The RIPI-f (Reporting Integrity of Psychological Interventions delivered face-to-face) checklist was developed to guide reporting of treatment integrity in face-to-face psychological interventions.

Objectives: Intervention integrity is the degree to which the study intervention is delivered as intended. This article presents the RIPI-f checklist (Reporting Integrity of Psychological Interventions delivered face-to-face) and summarizes its development methods. RIPI-f proposes guidance for reporting intervention integrity in evaluative studies of face-to-face psychological interventions. Study Design and Setting: We followed established procedures for developing reporting guidelines. We examined 56 documents (reporting guidelines, bias tools, and methodological guidance) for relevant aspects of face-to-face psychological intervention integrity. Eighty four items were identified and grouped as per the template for intervention description and replication (TIDieR) domains. Twenty nine experts from psychology and medicine and other scholars rated the relevance of each item in a single-round Delphi survey.Amultidisciplinary panel of 11 experts discussed the survey results in three online consensus meetings and drafted the final version of the checklist. Results: We propose RIPI-f, a checklist with 50 items. Our checklist enhances TIDieR with important extensions, such as therapeutic alliance, provider’s allegiance, and the adherence of providers and participants. Conclusion: RIPI-f can improve the reporting of face-to-face psychological interventions. The tool can help authors, researchers, systematic reviewers, and guideline developers. We suggest using RIPI-f alongside other reporting guidelines.post-print504 K

Local Suppression of T Cell Responses by Arginase-Induced L-Arginine Depletion in Nonhealing Leishmaniasis

The balance between T helper (Th) 1 and Th2 cell responses is a major determinant of the outcome of experimental leishmaniasis, but polarized Th1 or Th2 responses are not sufficient to account for healing or nonhealing. Here we show that high arginase activity, a hallmark of nonhealing disease, is primarily expressed locally at the site of pathology. The high arginase activity causes local depletion of L-arginine, which impairs the capacity of T cells in the lesion to proliferate and to produce interferon-γ, while T cells in the local draining lymph nodes respond normally. Healing, induced by chemotherapy, resulted in control of arginase activity and reversal of local immunosuppression. Moreover, competitive inhibition of arginase as well as supplementation with L-arginine restored T cell effector functions and reduced pathology and parasite growth at the site of lesions. These results demonstrate that in nonhealing leishmaniasis, arginase-induced L-arginine depletion results in impaired T cell responses. Our results identify a novel mechanism in leishmaniasis that contributes to the failure to heal persistent lesions and suggest new approaches to therapy