An injectable bone marrow-like scaffold enhances T cell immunity after hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for multiple disorders, but deficiency and dysregulation of T cells limit its utility. Here we report a biomaterial-based scaffold that mimics features of T cell lymphopoiesis in the bone marrow. The bone marrow cryogel (BMC) releases bone morphogenetic protein-2 to recruit stromal cells and presents the Notch ligand Delta-like ligand-4 to facilitate T cell lineage specification of mouse and human hematopoietic progenitor cells. BMCs subcutaneously injected in mice at the time of HSCT enhanced T cell progenitor seeding of the thymus, T cell neogenesis and diversification of the T cell receptor repertoire. Peripheral T cell reconstitution increased ~6-fold in mouse HSCT and ~2-fold in human xenogeneic HSCT. Furthermore, BMCs promoted donor CD4+ regulatory T cell generation and improved survival after allogeneic HSCT. In comparison to adoptive transfer of T cell progenitors, BMCs increased donor chimerism, T cell generation and antigen-specific T cell responses to vaccination. BMCs may provide an off-the-shelf approach for enhancing T cell regeneration and mitigating graft-versus-host disease in HSCT

An in vitro model to assess the immunosuppressive effect of tick saliva on the mobilization of inflammatory monocyte-derived cells

Tick-borne pathogens cause potent infections. These pathogens benefit from molecules contained in tick saliva that have evolved to modulate host innate and adaptive immune responses. This is called "saliva-activated transmission" and enables tick-borne pathogens to evade host immune responses. Ticks feed on their host for relatively long periods; thus, mechanisms counteracting the inflammation-driven recruitment and activation of innate effector cells at the bite site, are an effective strategy to escape the immune response. Here, we developed an original in vitro model to evaluate and to characterize the immunomodulatory effects of tick saliva that prevent the establishment of a local inflammatory immune response. This model mimics the tick bite and enables the assessment of the effect of saliva on the inflammatory-associated dynamic recruitment of cells from the mononuclear phagocyte system. Using this model, we were able to recapitulate the dual effect of tick saliva on the mobilization of inflammatory monocyte-derived cells, i.e. (i) impaired recruitment of monocytes from the blood to the bite wound; and (ii) poor mobilization of monocyte-derived cells from the skin to the draining lymph node. This simple tool reconstitutes the effect of tick saliva in vivo, which we characterized in the mouse, and should enable the identification of important factors facilitating pathogen infection. Furthermore, this model may be applied to the characterization of any pathogen-derived immunosuppressive molecule affecting the establishment of the inflammatory immune response

HIV-infected T cells are migratory vehicles for viral dissemination

After host entry through mucosal surfaces, HIV-1 disseminates to lymphoid tissues to establish a generalized infection of the immune system. The mechanisms by which this virus spreads among permissive target cells locally during early stages of transmission, and systemically during subsequent dissemination are not known1. In vitro studies suggest that formation of virological synapses (VSs) during stable contacts between infected and uninfected T cells greatly increases the efficiency of viral transfer2. It is unclear, however, if T cell contacts are sufficiently stable in vivo to allow for functional synapse formation under the conditions of perpetual cell motility in epithelial3 and lymphoid tissues4. Here, using multiphoton intravital microscopy (MP-IVM), we examined the dynamic behavior of HIV-infected T cells in lymph nodes (LNs) of humanized mice. We found that most productively infected T cells migrated robustly, resulting in their even distribution throughout the LN cortex. A subset of infected cells formed multinucleated syncytia through HIV envelope (Env)-dependent cell fusion. Both uncoordinated motility of syncytia as well as adhesion to CD4+ LN cells led to the formation of long membrane tethers, increasing cell lengths to up to 10 times that of migrating uninfected T cells. Blocking the egress of migratory T cells from LNs into efferent lymph, and thus interrupting T cell recirculation, limited HIV dissemination and strongly reduced plasma viremia. Thus, we have found that HIV-infected T cells are motile, form syncytia, and establish tethering interactions that may facilitate cell-to-cell transmission through VSs. While their migration in LNs spreads infection locally, T cell recirculation through tissues is important for efficient systemic viral spread, suggesting new molecular targets to antagonize HIV infection

Cardiovascular and renal effectiveness of empagliflozin in routine care in East Asia: Results from the EMPRISE East Asia study

Aim: To evaluate the effectiveness of empagliflozin in clinical practice in East Asia in the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) East Asia study. Materials and methods: Data were obtained from the Medical Data Vision database (Japan), National Health Insurance Service database (South Korea) and National Health Insurance database (Taiwan). Patients aged ≥ 18 years with type 2 diabetes initiating empagliflozin or a dipeptidyl peptidase-4 (DPP-4) inhibitor were 1:1 propensity score (PS) matched into sequentially built cohorts of new users naïve to both drug classes. This design reduces confounding due to switching treatments, time lag and immortal time biases. Outcomes included hospitalization for heart failure (HHF), end-stage renal disease (ESRD) and all-cause mortality. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional models, controlling for > 130 baseline characteristics in each data source and pooled by random-effects meta-analysis. Results: Overall, 28 712 pairs of PS-matched patients were identified with mean follow-up of 5.7-6.8 months. Compared with DPP-4 inhibitors, the risk of HHF was reduced by 18% and all-cause mortality was reduced by 36% with empagliflozin (HR 0.82; 95% CI 0.71-0.94, and HR 0.64; 95% CI 0.50-0.81, respectively). Reductions were consistent across countries, and in patients with and without baseline cardiovascular disease. ESRD was also significantly reduced with empagliflozin versus DPP-4 inhibitors (HR 0.37; 95% CI 0.24-0.58). Conclusions: Empagliflozin treatment was associated with reduced risk for HHF, all-cause mortality and ESRD compared with DPP-4 inhibitors in routine clinical practice in Japan, South Korea and Taiwan

Healthcare resource utilization in patients treated with empagliflozin in East Asia

AIMS/INTRODUCTION: We investigated the utilization of healthcare resources in patients with type 2 diabetes treated with empagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, versus dipeptidyl peptidase-4 (DPP-4) inhibitors in clinical practice in Japan, South Korea, and Taiwan. MATERIALS AND METHODS: We analyzed the Japanese Medical Data Vision database (December 2014-April 2018), the South Korean National Health Information Database, and the Taiwanese National Health Insurance claims database (both May 2016-December 2017). Patients with type 2 diabetes starting empagliflozin, 10 or 25 mg, or a DPP-4 inhibitor were matched 1:1 via propensity scores (PS). We compared inpatient care needs, emergency room (ER) visits, and outpatient visits between the treatment groups using Poisson regression and Cox proportional hazards models, pooled across countries by random-effects meta-analysis. RESULTS: We identified 28,712 pairs of PS-matched patients; the mean follow-up was 5.7-6.8 months. Empagliflozin-treated patients had a 27% lower risk of all-cause hospitalization compared with DPP-4 inhibitor-treated patients (rate ratio [RR] 0.73, 95% CI 0.67-0.79), and 23% reduced risk for first hospitalization (hazard ratio 0.77, 95% CI 0.73-0.81). The risk for an ER visit was 12% lower with empagliflozin than with DPP-4 inhibitors (RR 0.88, 95% CI 0.83-0.94) while the risk for outpatient visit was 4% lower (RR 0.96, 95% CI 0.96-0.97). These findings were generally consistent across countries, regardless of baseline cardiovascular disease, and in the subgroup starting empagliflozin with the 10 mg dose. CONCLUSIONS: Empagliflozin treatment was associated with lower inpatient care needs and other healthcare resource utilization than DPP-4 inhibitors in routine clinical practice in East Asia in this study

Molecular identification of Palearctic members of Anopheles maculipennis in northern Iran

BACKGROUND: Members of Anopheles maculipennis complex are effective malaria vectors in Europe and the Caspian Sea region in northern Iran, where malaria has been re-introduced since 1994. The current study has been designed in order to provide further evidence on the status of species composition and to identify more accurately the members of the maculipennis complex in northern Iran. METHODS: The second internal transcribed spacer of ribosomal DNA (rDNA-ITS2) was sequenced in 28 out of 235 specimens that were collected in the five provinces of East Azerbayjan, Ardebil, Guilan, Mazandaran and Khorassan in Iran. RESULTS: The length of the ITS2 ranged from 283 to 302 bp with a GC content of 49.33 – 54.76%. No intra-specific variations were observed. Construction of phylogenetic tree based on the ITS2 sequence revealed that the six Iranian members of the maculipennis complex could be easily clustered into three groups: the An. atroparvus – Anopheles labranchiae group; the paraphyletic group of An. maculipennis, An. messeae, An. persiensis; and An. sacharovi as the third group. CONCLUSION: Detection of three species of the An. maculipennis complex including An. atroparvus, An. messae and An. labranchiae, as shown as new records in northern Iran, is somehow alarming. A better understanding of the epidemiology of malaria on both sides of the Caspian Sea may be provided by applying the molecular techniques to the correct identification of species complexes, to the detection of Plasmodium composition in Anopheles vectors and to the status of insecticide resistance by looking to related genes

Structural Basis of Chemokine Sequestration by CrmD, a Poxvirus-Encoded Tumor Necrosis Factor Receptor

Pathogens have evolved sophisticated mechanisms to evade detection and destruction by the host immune system. Large DNA viruses encode homologues of chemokines and their receptors, as well as chemokine-binding proteins (CKBPs) to modulate the chemokine network in host response. The SECRET domain (smallpox virus-encoded chemokine receptor) represents a new family of viral CKBPs that binds a subset of chemokines from different classes to inhibit their activities, either independently or fused with viral tumor necrosis factor receptors (vTNFRs). Here we present the crystal structures of the SECRET domain of vTNFR CrmD encoded by ectromelia virus and its complex with chemokine CX3CL1. The SECRET domain adopts a β-sandwich fold and utilizes its β-sheet I surface to interact with CX3CL1, representing a new chemokine-binding manner of viral CKBPs. Structure-based mutagenesis and biochemical analysis identified important basic residues in the 40s loop of CX3CL1 for the interaction. Mutation of corresponding acidic residues in the SECRET domain also affected the binding for other chemokines, indicating that the SECRET domain binds different chemokines in a similar manner. We further showed that heparin inhibited the binding of CX3CL1 by the SECRET domain and the SECRET domain inhibited RAW264.7 cell migration induced by CX3CL1. These results together shed light on the structural basis for the SECRET domain to inhibit chemokine activities by interfering with both chemokine-GAG and chemokine-receptor interactions

A Deep Insight into the Sialotranscriptome of the Gulf Coast Tick, Amblyomma maculatum

Background: Saliva of blood sucking arthropods contains compounds that antagonize their hosts ’ hemostasis, which include platelet aggregation, vasoconstriction and blood clotting; saliva of these organisms also has anti-inflammatory and immunomodullatory properties. Perhaps because hosts mount an active immune response against these compounds, the diversity of these compounds is large even among related blood sucking species. Because of these properties, saliva helps blood feeding as well as help the establishment of pathogens that can be transmitted during blood feeding. Methodology/Principal Findings: We have obtained 1,626,969 reads by pyrosequencing a salivary gland cDNA library from adult females Amblyomma maculatum ticks at different times of feeding. Assembly of this data produced 72,441 sequences larger than 149 nucleotides from which 15,914 coding sequences were extracted. Of these, 5,353 had.75 % coverage to their best match in the non-redundant database from the National Center for Biotechnology information, allowing for the deposition of 4,850 sequences to GenBank. The annotated data sets are available as hyperlinked spreadsheets. Putative secreted proteins were classified in 133 families, most of which have no known function. Conclusions/Significance: This data set of proteins constitutes a mining platform for novel pharmacologically activ

Сравнительная характеристика армированных пластиков, применительно к космической отрасли

Atherosclerosis is a chronic inflammatory disease of the arterial wall that is characterized by a disturbed equilibrium of immune responses and lipid accumulation, leading to the development of plaques. The atherogenic influx of mononuclear cells is orchestrated by chemokines and their receptors. Studies using gene-deficient mice and antagonists based on peptides and small molecules have generated insight into targeting chemokine-receptor axes for treating atherosclerosis, which might complement lipid-lowering strategies and risk factor modulation. Combined inhibition of multiple chemokine axes could interfere with the contributions of chemokines to disease progression at specific cells, stages or sites. In addition, the recently characterized heterophilic interactions of chemokines might present a novel target for the treatment and prevention of inflammatory diseases such as atherosclerosis