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Cytomegalovirus (CMV)-seropositive adults have large T cell responses to a wide range of CMV proteins; these responses have been associated with chronic inflammation and frailty in people with or without HIV infection. We analyzed the relationships between chronic HIV infection, frailty, and the breadth and polyfunctionality of CD4 and CD8 T cell responses to CMV. Peripheral blood mononuclear cells from 42 men (20 without HIV and 22 with virologically suppressed HIV) in the Multicenter AIDS Cohort Study (MACS) were stimulated with peptide pools spanning 19 CMV open reading frames (ORFs). As measured by flow cytometry and intracellular cytokine staining for IFN-γ, TNF-α, and IL-2, CD8 T cells from men with HIV responded to significant ly more CMV ORFs than those from men without HIV. This was primarily due to a broader response to ORFs that are expressed during the late phase of CMV replication. The number of ORFs to which a participant's T cells responded was positively correlated with the sum of all that individual's T cell responses; these correlations were weaker in men with than without HIV. Polyfunctional CMV-specific CD4 responses (production of more than one cytokine) were significantly lower in men with than without HIV. Frailty status did not substantially affect the breadth or magnitude of the CMV-specific T cell responses. These results suggest that immune control of CMV infection is affected more by chronic HIV infection than by frailty. The differences between men with and without HIV were similar to those reported between young and older adults without HIV. [ABSTRACT FROM AUTHOR]

Reportative evidential markers are – in contrast to other evidential markers – compatible with distancing interpretations, in which the speaker denies the truth of what is being reported. This exceptional behaviour of reportatives is termed 'reportative exceptionality' (AnderBois 2014). In this paper, which addresses French, Dutch and German reportative markers, we argue that they differ with respect to the frequency with which such distancing interpretations actually arise. The French reportative conditionnel most frequently occurs with distancing interpretations, whereas German sollen hardly occurs with this function. Dutch zou takes up an intermediate position. It is claimed that the higher compatibility of the conditionnel with distancing interpretations can be accounted for by a number of factors: its general preference for contexts in which other perspectives than the speaker's are highly salient; the fact that it has past tense morphology; and its general semantic make-up in which the marking of hypotheticality is a key function. [ABSTRACT FROM AUTHOR]

Background Despite wide use of adjuvanted influenza vaccine in nursing home residents (NHR), little immunogenicity data exist for this population. Methods We collected blood from NHR (n = 85) living in nursing homes participating in a cluster randomized clinical trial comparing MF59-adjuvanted trivalent inactivated influenza vaccine (aTIV) with nonadjuvanted vaccine (TIV) (parent trial, NCT02882100). NHR received either vaccine during the 2016–2017 influenza season. We assessed cellular and humoral immunity using flow cytometry and hemagglutinin inhibition, antineuraminidase (enzyme-linked lectin assay), and microneutralization assays. Results Both vaccines were similarly immunogenic and induced antigen-specific antibodies and T cells, but aTIV specifically induced significantly larger 28 days after vaccination (D28) titers against A/H3N2 neuraminidase than TIV. Conclusions NHRs respond immunologically to TIV and aTIV. From these data, the larger aTIV-induced antineuraminidase response at D28 may help explain the increased clinical protection observed in the parent clinical trial for aTIV over TIV in NHR during the A/H3N2-dominant 2016–2017 influenza season. Additionally, a decline back to prevaccination titers at 6 months after vaccination emphasizes the importance of annual vaccination against influenza. Clinical Trials Registration NCT02882100. [ABSTRACT FROM AUTHOR]

Acute T-cell-mediated rejection (aTCMR) still remains a clinical problem after kidney transplantation despite significant improvements in immunosuppressive regimens. Polyfunctional T cells, i.e. T cells producing multiple pro-inflammatory cytokines, are believed to be the most relevant T cells in an immune response. The aim of this study was to determine whether polyfunctional donor-reactive T cells are associated with aTCMR. In a case–control study, 49 kidney transplant recipients with a biopsy-proven aTCMR in the first year after transplantation were included, as well as 51 controls without aTCMR. Circulating donor-reactive T cells were identified by the expression of CD137 after short-term co-culture with donor antigen-presenting cells. Polyfunctional donor-reactive T cells were further characterized by dissection into different T-cell subsets encompassing the spectrum of naïve to terminally differentiated effector T cells. Prior to kidney transplantation, proportions of donor-reactive CD4+ (0.03% versus 0.02%; P < 0.01) and CD8+ (0.18% versus 0.10%; P < 0.01) CD137++ T cells were significantly higher in recipients with a biopsy-proven aTCMR versus non-rejectors. Polyfunctionality was higher (P = 0.03) in this subset of CD137-expressing T cells. These cells were predominantly of the EM/EMRA-phenotype, with polyfunctional donor-reactive CD137++CD4+ T cells predominantly co-expressing CD28 whereas approximately half of the polyfunctional CD137++CD8+ T cells co-expressed CD28. In addition, at the time of aTCMR, polyfunctional donor-reactive CD137++ CD4+, but not CD8+, T cells, were specifically decreased by 75% compared to before transplantation in recipients with as well as those without an aTCMR. Prior to transplantation, the proportion of polyfunctional donor-reactive CD137++ T cells is associated with the occurrence of a biopsy-proven aTCMR within the first year after transplantation. Acute TCMR remains a clinical problem after kidney transplantation despite significant improvements in immunosuppressive regimens. Poly-functional (producing ≥2 cytokines) T cells are believed to be the most relevant T cells in an immune response. Prior to kidney transplantation proportions of poly-functional CD137 high expressing donor-reactive CD4+ and CD8+ T cells are higher in recipients experiencing an acute TCMR within the first year after transplantation compared to those who remained free of rejection. [ABSTRACT FROM AUTHOR]

In line with several authors (just to give an example, Aikhenvald (2015) who argue that the intersection of different inflective categories is the key to the "polyfunctionality" characteristic of verb forms, we examine the confluence of a certain range of temporal and aspectual information about modal auxiliaries in the determination of specific behaviors. As in current Engl. except for will (

Epoxidation of linseed oil fatty acid ethyl esters promoted by a series of functionalized imidazolium ionic liquids was studied. In this reaction acidic imidazolium ILs behave not only as an acid catalysts but also play an additional role as a specific activator for the reaction of epoxidation of unsaturated fatty derivatives in H2O2/formic acid oxidation system. The obtained results indicate that the hydrogen‐bonding interaction of imidazolium cation with epoxide group influences the selectivity of the epoxidation reaction. In particular, the presence of unprotected weak "acid" C2‐H proton significantly lowers the selectivity to hydroxyl derivatives. The obtained results also point to another example of specific polyfunctionality of ILs, especially imidazolium one, used as surfactants and process activators. [ABSTRACT FROM AUTHOR]

Selective immune pressure contributes to relapse due to target antigen downregulation in patients treated with anti-CD19 chimeric antigen receptor (CAR) T cells. Bispecific lentiviral anti-CD20/anti-CD19 (LV20.19) CAR T cells may prevent progression/relapse due to antigen escape. Highly polyfunctional T cells within a CAR T-cell product have been associated with response in single-antigen-targeted anti-CD19 CAR T cells. The authors performed a single-cell proteomic analysis to assess polyfunctional cells in our LV20.19 CAR T-cell product. Analysis was limited to those treated at a fixed dose of 2.5 × 106 cells/kg (n = 16). Unused pre-infusion CAR T cells were thawed, sorted into CD4/CD8 subsets and stimulated with K562 cells transduced to express CD19 or CD20. Single-cell production of 32 individual analytes was measured and polyfunctionality and polyfunctional strength index (PSI) were calculated. Fifteen patients had adequate leftover cells for analysis upon stimulation with CD19, and nine patients had adequate leftover cells for analysis upon stimulation with CD20. For LV20.19 CAR T cells, PSI was 866–1109 and polyfunctionality was 40–45%, which were higher than previously reported values for other CAR T-cell products. Stimulation with either CD19 or CD20 antigens resulted in similar levels of analyte activation, suggesting that this product may have efficacy in CD19– patient populations. [ABSTRACT FROM AUTHOR]

Specific T cells are crucial to control SARS-CoV-2 infection, avoid reinfection and confer protection after vaccination. We have studied patients with severe or moderate COVID-19 pneumonia, compared to patients who recovered from a severe or moderate infection that had occurred about 4 months before the analyses. In all these subjects, we assessed the polyfunctionality of virus-specific CD4+ and CD8+ T cells by quantifying cytokine production after in vitro stimulation with different SARS-CoV-2 peptide pools covering different proteins (M, N and S). In particular, we quantified the percentage of CD4+ and CD8+ T cells simultaneously producing interferon-γ, tumor necrosis factor, interleukin (IL)-2, IL-17, granzyme B, and expressing CD107a. Recovered patients who experienced a severe disease display high proportions of antigen-specific CD4+ T cells producing Th1 and Th17 cytokines and are characterized by polyfunctional SARS-CoV-2-specific CD4+ T cells. A similar profile was found in patients experiencing a moderate form of COVID-19 pneumonia. No main differences in polyfunctionality were observed among the CD8+ T cell compartments, even if the proportion of responding cells was higher during the infection. The identification of those functional cell subsets that might influence protection can thus help in better understanding the complexity of immune response to SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Background: Measles outbreaks are reported worldwide and pose a serious threat, especially to young unvaccinated infants. Early measles vaccination given to infants under 12 months of age can induce protective antibody levels, but the long-term antibody functionalities are unknown.Methods: Measles-specific antibody functionality was tested using a systems serology approach for children who received an early measles vaccination at 6-8 or 9-12 months, followed by a regular dose at 14 months of age, and children who only received the vaccination at 14 months. Antibody functionalities comprised complement deposition, cellular cytotoxicity, and neutrophil and cellular phagocytosis. We used Pearson's r correlations between all effector functions to investigate the coordination of the response.Results: Children receiving early measles vaccination at 6-8 or 9-12 months of age show polyfunctional antibody responses. Despite significant lower levels of antibodies in these early-vaccinated children, Fc effector functions were comparable with regular-timed vaccinees at 14 months. However, 3-year follow-up revealed significant decreased polyfunctionality in children who received a first vaccination at 6-8 months of age, but not in children who received the early vaccination at 9-12 months.Conclusions: Antibodies elicited in early-vaccinated children are equally polyfunctional to those elicited from children who received vaccination at 14 months. However, these antibody functionalities decay more rapidly than those induced later in life, which may lead to suboptimal, long-term protection. [ABSTRACT FROM AUTHOR]

SARS‐CoV‐2 specific T‐cell response has been associated with disease severity, immune memory and heterologous response to endemic coronaviruses. However, an integrative approach combining a comprehensive analysis of the quality of SARS‐CoV‐2 specific T‐cell response with antibody levels in these three scenarios is needed. In the present study, we found that, in acute infection, while mild disease was associated with high T‐cell polyfunctionality biased to IL‐2 production and inversely correlated with anti‐S IgG levels, combinations only including IFN‐γ with the absence of perforin production predominated in severe disease. Seven months after infection, both non‐hospitalised and previously hospitalised patients presented robust anti‐S IgG levels and SARS‐CoV‐2 specific T‐cell response. In addition, only previously hospitalised patients showed a T‐cell exhaustion profile. Finally, combinations including IL‐2 in response to S protein of endemic coronaviruses were the ones associated with SARS‐CoV‐2 S‐specific T‐cell response in pre‐COVID‐19 healthy donors' samples. These results could have implications for protective immunity against SARS‐CoV‐2 and recurrent COVID‐19 and may help for the design of new prototypes and boosting vaccine strategies. [ABSTRACT FROM AUTHOR]

Background: Characterizing the longevity and quality of cellular immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enhances understanding of coronavirus disease 2019 (COVID-19) immunity that influences clinical outcomes. Prior studies suggest SARS-CoV-2-specific T cells are present in peripheral blood 10 months after infection. Analysis of the function, durability, and diversity of cellular response long after natural infection, over a range of ages and disease phenotypes, is needed to identify preventative and therapeutic interventions.Methods: We identified participants in our multisite longitudinal, prospective cohort study 12 months after SARS-CoV-2 infection representing a range of disease severity. We investigated function, phenotypes, and frequency of T cells specific for SARS-CoV-2 using intracellular cytokine staining and spectral flow cytometry, and compared magnitude of SARS-CoV-2-specific antibodies.Results: SARS-CoV-2-specific antibodies and T cells were detected 12 months postinfection. Severe acute illness was associated with higher frequencies of SARS-CoV-2-specific CD4 T cells and antibodies at 12 months. In contrast, polyfunctional and cytotoxic T cells responsive to SARS-CoV-2 were identified in participants over a wide spectrum of disease severity.Conclusions: SARS-CoV-2 infection induces polyfunctional memory T cells detectable at 12 months postinfection, with higher frequency noted in those who experienced severe disease. [ABSTRACT FROM AUTHOR]

Immunosenescence affects innate and adaptive immunity impairing the response to pathogens and vaccines. Chronic infection with cytomegalovirus (CMV) has been shown to drive "early immunosenescence" and can considerably affect both the function and phenotype of immune cells, especially T cells. We have previously shown that the expression of CD57, CD300a, and CD161 was differentially affected by age and chronic CMV infection, indicating that these markers are a hallmark of CMV infection and T-cell aging. The aim of this present study was to clarify whether these 3 markers define distinct T-cell subpopulations with a specific functional and molecular signature. Specifically, we analyzed the effect of age and chronic CMV infection on the functionality of T cells according to CD161, CD300a, and CD57 expression. We found that these markers defined different T-cell subsets, both at the phenotypic and functional levels. CD57 was the best biomarker for CD4+ T-cell cytotoxicity and was a hallmark of CMV infection. CD300a+ T cells were heterogeneous and included different cell subsets. The population of CD161+ T cells dramatically decreased with age, independently of CMV infection, and represented a sign of age-associated immune system alterations. The latter could contribute to an increased risk of autoimmune disease and infection in older adults. Our results underline the importance of better understanding the factors involved in the immunosenescence process to be able to uncover new biomarkers and open new avenues for the investigation and development of novel age-related disease therapies. [ABSTRACT FROM AUTHOR]

Background: Efficacy of the live-attenuated herpes zoster (HZ) vaccine (ZVL) wanes substantially over time. We evaluated immunogenicity and safety of the adjuvanted recombinant zoster vaccine (RZV) in previous ZVL recipients.Methods: Adults aged ≥65 years who were previously vaccinated with ZVL ≥5 years earlier (n = 215) were group-matched with ZVL-naive individuals (n = 215) and vaccinated with RZV. Glycoprotein E (gE)-specific humoral and cell-mediated immune responses and the correlation between them, polyfunctional gE-specific CD4 T-cell responses, safety, and confirmed HZ cases were assessed.Results: Through 12 months after dose 2, anti-gE antibody concentrations, gE-specific CD4 T-cell frequencies, and activation marker profiles were similar between groups. Safety outcomes were also similar. No HZ episodes were confirmed.Conclusions: RZV induced strong humoral and polyfunctional cell-mediated immune responses that persisted above prevaccination levels through 1 year after dose 2 in adults aged ≥65 years irrespective of previous ZVL vaccination. The RZV safety profile was not affected.Clinical Trials Registration: NCT02581410. [ABSTRACT FROM AUTHOR]

A large number of studies describe the many different functions of polyfunctional discourse markers like well in different contexts and from different theoretical perspectives. In the current paper, we propose to systematize the many different uses identified based on their position with respect to the discourse units they are associated with. Not only can previous findings on well be integrated into a single coherent representation of its uses and functions, but the positions with respect to the discourse units can also be associated with specific functions, thus shedding light on how the polyfunctionality of well is brought about. • This paper explains and relates the polyfunctionality of the English DM well. • Functions are correlated with their position in different discourse units. • Previous findings on well, integrated into a single representation of positions∗DUs. • Discourse positions correlate with pragmatic functions: modal, textual, interactive. [ABSTRACT FROM AUTHOR]

AKT-inhibition is a promising approach to improve T cell therapies; however, its effect on CD4+ T cells is insufficiently explored. Previously, we and others showed that AKT-inhibition during ex vivo CD8+ T cell expansion facilitates the generation of polyfunctional T cells with stem cell memory-like traits. However, most therapeutic T cell products are generated from lymphocytes, containing CD4+ T cells that can affect CD8+ T cells dependent on the Th-subset. Here, we investigated the effect of AKT-inhibition on CD4+ T cells, during separate as well as total T cell expansions. Interestingly, ex vivo AKT-inhibition preserved the early memory phenotype of CD4+ T cells based on higher CD62L, CXCR4 and CCR7 expression. However, in the presence of AKT-inhibition, Th-differentiation was skewed toward more Th2-associated at the expense of Th1-associated cells. Importantly, the favorable effect of AKT-inhibition on the functionality of CD8+ T cells drastically diminished in the presence of CD4+ T cells. Moreover, also the expansion method influenced the effect of AKT-inhibition on CD8+ T cells. These findings indicate that the effect of AKT-inhibition on CD8+ T cells is dependent on cell composition and expansion strategy, where presence of CD4+ T cells as well as polyclonal stimulation impede the favorable effect of AKT-inhibition. [ABSTRACT FROM AUTHOR]

HLA-I-associated human immunodeficiency virus (HIV) adaptation is known to negatively affect disease progression and CD8 T-cell responses. We aimed to assess how HLA-I-associated adaptation affects HIV vaccine-induced CD8 T-cell responses in 2 past vaccine efficacy trials. We found that vaccine-encoded adapted epitopes were less immunogenic than vaccine-encoded nonadapted epitopes, and adapted epitope-specific responses were less polyfunctional than nonadapted epitope-specific responses. Along those lines, vaccine recipients with higher HLA-I adaptation to the Gag vaccine insert mounted less polyfunctional CD8 T-cell responses at the protein level. Breadth of response, which correlated with viral control in recipients who became infected, is also dampened by HLA-I adaptation. These findings suggest that HLA-I-associated adaptation is an important consideration for strategies aiming to induce robust CD8 T-cell responses. [ABSTRACT FROM AUTHOR]

Summary: Primary and chronic human immunodeficiency virus (HIV) infection alters γδ T‐cell features. However, there is no evidence about early combined antiretroviral therapy (cART) and γδ T‐cell dynamics. In the present study, HIV‐positive individuals were divided into those with early primary infection (EPI) and those with late primary infection (LPI). The analysis of γδ T cells was performed by flow cytometry before and after therapy. Polyfunctional profile was assessed after in vitro peripheral blood mononuclear cell (PBMC) exposure to specific antigens. The results show that primary infection induced an expansion of Vδ1 T cells in LPI. Before treatment, a massive activation of γδ T‐cell subsets was observed in both groups of patients, that correlated with disease progression and was significantly reduced after cART introduction. Despite this, CD107A‐expressing Vδ1 T cells in both groups were significantly fewer than in healthy donors, but were restored by therapy introduction. Polyfunctional analysis of Vδ1 T cells from HIV‐positive individuals revealed a lower frequency of CD107A+ CCL‐4+ Vδ1 T‐cell subsets than healthy donors that persists after therapy. Functional profile of Vδ2 was similar to that in healthy donors before therapy but, at 6 months, a lower frequency of CD107A, interferon‐γ‐ or tumor necrosis factor‐α‐producing Vδ2 T cells was observed in the EPI group. Finally, individuals with LPI showed a lower frequency of quadruple‐functional Vδ2 T‐cell subset. In conclusion, during primary HIV infection, the baseline Vδ1 T‐cell activation is correlated with immune reconstitution potential. Moreover, an altered γδ polyfunctional profile occurred, persisting after cART. Further studies are needed to understand whether a longer treatment of primary infection may increase γδ T‐cell functionality. [ABSTRACT FROM AUTHOR]

Background. The actual problem is the synthesis of nitrogen-containing heterocycles of the pyrrole series and its derivatives, due to the manufacture of a number of drugs, including drugs. Pyrrole ring is part of the natural and biologically active compounds. The study of the mechanism of pyrrole formation and the product yield using selective catalysts contributes to its solution. Purpose. Search and study of methods for the synthesis of valuable and single-stage pyrrole systems using acetylene reactions catalyzed with ammonia and amines; finding the optimal process parameters and creating a technology for producing a catalyst for the synthesis of pyrroles. Methodology. Heterogeneous catalysis, physical and chemical methods of research and processing using modern computer programs were used in the work. Originality. Catalytic systems based on fluorine, zinc, chromium and aluminum containing compounds have been developed for one-step production of pyrroles by dehydration - by heterocyclization of acetylene compounds with ammonia and amines. Findings. Dependence of the pyrrole yield on the composition of the catalyst, including carriers, temperature, flow rate and the ratio of initial reagents. It is shown that during the experiments in the temperature range of 320-420°C, the selectivity of the formation of pyrrole from diethanolamine increases to 35%. [ABSTRACT FROM AUTHOR]

Highlights • We show how polyfunctional discourse particles affect real-time dialogue understanding. • Discourse particles modulate comprehenders’ expectations about how a dialogue unfolds. • Listeners make rapid and situation-specific inferences about discourse particle use. Abstract Interpersonal discourse particles (DPs), such as Dutch inderdaad (≈‘indeed’) and eigenlijk (≈‘actually’) are highly frequent in everyday conversational interaction. Despite extensive theoretical descriptions of their polyfunctionality, little is known about how they are used by language comprehenders. In two visual world eye-tracking experiments involving an online dialogue completion task, we asked to what extent inderdaad , confirming an inferred expectation, and eigenlijk , contrasting with an inferred expectation, influence real-time understanding of dialogues. Answers in the dialogues contained a DP or a control adverb, and a critical discourse referent was replaced by a beep; participants chose the most likely dialogue completion by clicking on one of four referents in a display. Results show that listeners make rapid and fine-grained situation-specific inferences about the use of DPs, modulating their expectations about how the dialogue will unfold. Findings further specify and constrain theories about the conversation-managing function and polyfunctionality of DPs. [ABSTRACT FROM AUTHOR]

Background: It remains challenging to characterize the functional attributes of chimeric antigen receptor (CAR)-engineered T cell product targeting CD19 related to potency and immunotoxicity ex vivo, despite promising in vivo efficacy in patients with B cell malignancies. Methods: We employed a single-cell, 16-plex cytokine microfluidics device and new analysis techniques to evaluate the functional profile of CD19 CAR-T cells upon antigen-specific stimulation. CAR-T cells were manufactured from human PBMCs transfected with the lentivirus encoding the CD19-BB-z transgene and expanded with anti-CD3/anti- CD28 coated beads. The enriched CAR-T cells were stimulated with anti-CAR or control IgG beads, stained with anti- CD4 RPE and anti-CD8 Alexa Fluor 647 antibodies, and incubated for 16 h in a single-cell barcode chip (SCBC). Each SCBC contains ~12,000 microchambers, covered with a glass slide that was pre-patterned with a complete copy of a 16-plex antibody array. Protein secretions from single CAR-T cells were captured and subsequently analyzed using proprietary software and new visualization methods. Results: We demonstrate a new method for single-cell profiling of CD19 CAR-T pre-infusion products prepared from 4 healthy donors. CAR-T single cells exhibited a marked heterogeneity of cytokine secretions and polyfunctional (2+ cytokine) subsets specific to anti-CAR bead stimulation. The breadth of responses includes anti-tumor effector (Granzyme B, IFN-γ, MIP-1α, TNF-α), stimulatory (GM-CSF, IL-2, IL-8), regulatory (IL-4, IL-13, IL-22), and inflammatory (IL-6, IL-17A) functions. Furthermore, we developed two new bioinformatics tools for more effective polyfunctional subset visualization and comparison between donors. Conclusions: Single-cell, multiplexed, proteomic profiling of CD19 CAR-T product reveals a diverse landscape of immune effector response of CD19 CAR-T cells to antigen-specific challenge, providing a new platform for capturing CAR-T product data for correlative analysis. Additionally, such high dimensional data requires new visualization methods to further define precise polyfunctional response differences in these products. The presented biomarker capture and analysis system provides a more sensitive and comprehensive functional assessment of CAR-T pre-infusion products and may provide insights into the safety and efficacy of CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

Background: Immunological nonresponse represents the Achilles heel in the combination antiretroviral therapy (cART) effectiveness, and increases risk of clinical events and death. CD8 T cells play a crucial role in controlling HIV replication, and polyfunctional HIV-specific CD8 T cells have been associated with nonprogressive HIV infection. However, the possible role of polyfunctional CD8 T cells in predicting posttreatment immune reconstitution has not yet been explored. The aim of this study was to identify functional markers predictive of immunological response to cART in chronic HIV-infected patients. Methods: A cohort of chronic HIV-infected individuals naive to cART were enrolled in the ALPHA study. CD4/CD8 T-cell subsets, their differentiation/activation, as well as susceptibility to apoptosis were analyzed before and after 12 months of cART. Moreover, CD8 T cells polyfunctional response after HIV antigenic stimulation was also assessed. Results: Results showed a significant correlation between worse CD4 T-cell restoration and low frequency of naive CD4 T cells, high frequency of effector memory CD4 T cells, and high susceptibility to apoptosis of CD4 T cells all before cART. Moreover, CD8 functional subsets expressing total C-C motif chemokine ligand 4 (CCL-4) or in combination with CD107a and interferon gamma (IFNγ) were negatively associated with immune reconstitution Conclusions: In conclusion, our study shows that a more differentiated phenotype of CD4 T cells and CCL-4–producing CD8 T cells could represent valuable predictors of worse immune reconstitution. These parameters may be used as tools for identifying patients at risk of immunological failure during cART and eventually represent the basis for innovative therapeutic strategies. [ABSTRACT FROM AUTHOR]

The number of complementizers in any Oceanic language ranges from zero to (at least) five or six. In languages with more than one, the choice of a complementizer is often determined by the higher predicate. However, complementizers may also be independently meaningful, for example, expressing speaker stance. Examples of complementizers expressing speaker stance are given from several languages. Complementizers also participate in polyfunctionality networks, where an etymon that functions as a complementizer has one or more other grammatical functions. Two types of polyfunctionality networks are discussed: complementizer-relativizer- demonstrative and complementizer-protasis marker, both from synchronic and diachronic perspectives. [ABSTRACT FROM AUTHOR]

Immunogenicity and safety of different adjuvants combined with a model antigen (HBsAg) were compared. Healthy HBV-naïve adults were randomized to receive HBs adjuvanted with alum or Adjuvant Systems AS01B, AS01E, AS03A or AS04 at Days 0 and 30. Different frequencies of HBs-specific CD4 + T cells 14 days post dose 2 but similar polyfunctionality profiles were induced by the different adjuvants with frequencies significantly higher in the AS01B and AS01E groups than in the other groups. Antibody concentrations 30 days post-dose 2 were significantly higher in AS01B, AS01E and AS03A than in other groups. Limited correlations were observed between HBs-specific CD4 + T cell and antibody responses. Injection site pain was the most common solicited local symptom and was more frequent in AS groups than in alum group. Different adjuvants formulated with the same antigen induced different adaptive immune responses and reactogenicity patterns in healthy naïve adults. The results summary for this study (GSK study number 112115 – NCT# NCT00805389 ) is available on the GSK Clinical Study Register and can be accessed at www.gsk-clinicalstudyregister.com . [ABSTRACT FROM AUTHOR]

Association of HIV-1--specific T-cell responses to infection risk in seronegative individuals is controversial. We quantified and phenotypically characterized gp120-specific T-cell responses in HIV-1 exposed, but uninfected subjects enrolled in the global Pre-exposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial. IFNγ ELISpot responses were detected in 24% of subjects irrespective of infection outcome. HIV-1 gp120 envelope-specific T-cell responses were more uniformly IFN-γ+TNF-α+Mip-1β+ in persistently seronegative subjects relative to subjects who later seroconverted (median frequency of 76.5% and 66.5%, respectively). IFNγ responses targeted the V2 loop for subjects who remained seronegative. HIV-1 gp120 envelope V2 loop-specific CD8+ T-cell responses may help to protect against HIV-1 acquisition. [ABSTRACT FROM AUTHOR]

This paper presents a quantitative and qualitative study of the relationship between discourse positions and pragmatic functions of the Spanish discourse markers derived from motion verbs, namely anda , vamos , vaya and venga . These discourse markers are highly polyfunctional and concurrently have a high degree of positional freedom. The results show, first, that the position of a discourse marker and the discourse unit in which the marker is inserted restrict or activate its pragmatic functions. More particularly, discourse markers with an expressive, conative or discourse structuring function present a more increased pragmatic scope than those with a textual function operating at a more profound level of the discourse. Second, the degree of distributional freedom is related to the potential semantic-pragmatic autonomy of the discourse markers, rather than to the degree of functional diversity. In other words, discourse markers that do not necessarily depend on other discourse units (within the same turn) to convey their communicative intentions show a higher degree of positional freedom. [ABSTRACT FROM AUTHOR]

• First demonstration of cytokine-secreting MAIT cell kinetics after human challenge with Salmonella enterica serovar Typhi. • MAIT cell's functional signatures and association with typhoid fever protection. • Predictive value of MAIT cell cytokine pattern. • Lack of association between the number of cytokines expressed by MAIT cells and prevention against typhoid fever. We have previously demonstrated that Mucosal-Associated Invariant T (MAIT) cells secrete multiple cytokines after exposure to Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever in humans. However, whether cytokine secreting MAIT cells can enhance or attenuate the clinical severity of bacterial infections remain debatable. This study characterizes human MAIT cell functions in subjects participating in a wild-type S. Typhi human challenge model. Here, we found that MAIT cells exhibit distinct functional signatures associated with protection against typhoid fever. We also observed that the cytokine patterns of MAIT cell responses, rather than the average number of cytokines expressed, are more predictive of typhoid fever outcomes. These results might enable us to objectively, based on functional parameters, identify cytokine patterns that may serve as predictive biomarkers during natural infection and vaccination. [ABSTRACT FROM AUTHOR]

HIV continues to be a major health problem worldwide even today. Owing to the intricate nature of its interactions with the immune system, HIV has remained an enigma that cleverly utilizes the host machinery to survive. Its ability to evade the host immune system, at both levels, innate and adaptive, allows the pathogen to replicate and transmit from one host to another. It has been shown that HIV has multipronged effects especially on the adaptive immunity, with CD4+ T cells being the worst affected T cell populations. Various analyses have revealed that the exposure to HIV results in clonal expansion and excessive activation of the immune system. Also, an abnormal process of differentiation has been observed suggestive of an alteration and blocks in the maturation of various T cell subsets. Additionally, HIV has shown to accelerate immunosenescence and exhaustion of the overtly activated T cells. Apart from causing phenotypic changes, HIV has adverse effects on the functional aspect of the immune system, with evidences implicating it in the loss of the capacity of T cells to secrete various antiviral cytokines and chemokines. However, there continues to be many aspects of the immunopathogenesis of HIV that are still unknown and thus require further research to convert the malaise of HIV into a manageable epidemic. [ABSTRACT FROM AUTHOR]

The article in question considers the functioning of quantitative units, their language and speech aspects. Introduction focuses upon the major items of paper - definition of numerals, words of weight and measure, aims, methods of investigation, empiric material applied, evolution modifications, and perspectives of further study. [ABSTRACT FROM AUTHOR]

Activation of human natural killer ( NK) cells is associated with the cleavage of CD16 from the cell surface, a process mediated by matrix metalloproteinases ( MMPs). In this report, we examined whether inhibition of MMPs would lead to improved NK cell antibody-dependent cell-mediated cytotoxicity ( ADCC) function. Using an in-vitro ADCC assay, we tested the anti-tumour function of NK cells with three different therapeutic monoclonal antibodies ( mAbs) in the presence of MMPs inhibitor GM6001 or its control. Loss of CD16 was observed when NK cells were co-cultured with tumour targets in the presence of specific anti-tumour antibodies, and was found particularly on the majority of degranulating NK responding cells. Treatment with MMPs inhibitors not only prevented CD16 down-regulation, but improved the quality of the responding cells significantly, as shown by an increase in the percentage of polyfunctional NK cells that are capable of both producing cytokines and degranulation. Furthermore, MMPs inhibition resulted in augmented and sustained CD16-mediated signalling, as shown by increased tyrosine phosphorylation of CD3ζ and other downstream signalling intermediates, which may account for the improved NK cell function. Collectively, our results provide a foundation for combining MMPs inhibitors and therapeutic mAbs in new clinical trials for cancer treatment. [ABSTRACT FROM AUTHOR]

Polyfunctionality is the capacity of a T-cell to execute a variety of effector functions mainly mediated by production of cytokines, chemokines, and cytolytic enzymes. Studies in anti-viral immunity have acknowledged the importance of polyfunctionality in the clearance of infections and maintenance of protection. Although accepted in the field, this concept has not been as well characterized in cancer immunology. Here, we report the polyfunctionality profile analysis of a CD8 T-cell clone isolated from a lung cancer patient and directed against Dickkopf-1, a potentially new tumor-associated antigen (TAA). The clone showed Tc1/Th1 effector tendencies confirmed by secretion of cytokines such as IFN-γ, IP-10, MIP-1β, MIP-1α, IL-2, GM-CSF, and expression of cytolytic enzyme granzyme B. This secretion profile is of particular interest in the context of an anti-tumor response. Although secretion of IL-5 and IL-13 was also detected, absence of IL-4 and IL-10 opposes the idea of cytokine-dependent Th1 inhibition. Establishing a comprehensive cytokine secretion profile may help predict T cells' specific response against a novel TAA in a peptide vaccination context. It may further help in selecting clones with an optimal functional profile from the peripheral blood of cancer patients for expansion and adoptive cell transfer therapy. [ABSTRACT FROM AUTHOR]

This paper explores the polyfunctionality, grammaticalization, and typological relevance of applicatives in Ainu. Applicatives are derived by the valency-increasing prefixes which are generally defined here as instrumental e-, dative ko-, and locative o-. The referential range of the respective constructions stretches over several semantic roles and the exact role is attributed to the interaction between the semantics of the prefix and verb. The typologically unusual properties of Ainu applicatives include the ability of e- applicatives to add the roles of Theme and Content, the ability of the so-called unaccusative intransitives to host applicative prefixes e- and ko-, the possibility of e-ko- and ko-e- double applicatives, the absence of non-applicative paraphrases for some applicatives, and the possibility of applicative object incorporation. [ABSTRACT FROM AUTHOR]

Abstract: HIV-1 specific HLA-B-restricted CD8+ T cell responses differ from HLA-C-restricted responses in antiviral effectiveness. To investigate possible reasons for these differences, we characterized the frequency and polyfunctionality of immmunodominant HLA-B*57/B5801- and HLA-Cw*07-restricted CD8+ T cells occurring concurrently in nine study subjects assessing IFN-γ, TNF-α, IL-2, MIP-1β, and CD107a by flow cytometry and analyzed sequence variation in targeted epitopes. HLA-B*57/5801 and HLA-Cw*07 restricted CD8+ T cells did not differ significantly in polyfunctionality (p=0.84). Possession of three or more functions correlated positively with CD4+ T cell counts (r=0.85; p=0.006) and monofunctional CD8+ T cells inversely correlated with CD4 cell counts (r=−0.79; p=0.05). There were no differences in polyfunctionality of CD8+ T cells specific to wildtype versus mutated epitopes. These results suggest that loss of polyfunctionality and increase in monofunctional HIV-1-specific CD8+ T cells are associated with disease progression independent of restricting HLA allele. Furthermore, sequence variation does not appear to significantly impact CD8+ T cell polyfunctionality in chronic HIV-1 infection. [ABSTRACT FROM AUTHOR]

Abstract: Immunotherapies based on reinfusion of autologous cells incubated ex vivo with peptides reconstituted in toxic solvents, such as DMSO, are now performed on a routine basis. However, the toxic effects of the most common solvent used, DMSO, on T cell responses from human PBMCs, have not previously been evaluated in detail. Here, in preparation for a first-in-man human phase I vaccine trial comprising reinfusion of autologous HIV peptide-pulsed PBMCs, human PBMCs from healthy and HIV-infected donors were exposed in vitro to a range of DMSO concentrations, and for a range of time periods. Polychromatic flow cytometry was used to evaluate the influence of DMSO on functional T cell responses. We report that high concentrations of up to 10% of DMSO for 1hour do not affect the cell viability, the magnitude or the functional profile of CD4+ and CD8+ T cell responses, regardless of antigen specificity and HLA class I restriction. In contrast, >2% for >2hours compromises these responses. These data are relevant in the design of immunotherapies based on pulsing a large number of peptides onto antigen presenting cells prior to reinfusion. [Copyright &y& Elsevier]

Data have been presented on the taurine content in various mammalian and fish tissues as well as on pathways of its formation, turnover, and numerous functions. Based on comparison of the character of the taurine effects on various animal functions as well as of the fact of the presence of taurine in the more ancient by origin potential objects of the mammalian and fish nutrition, it is suggested that the taurine polyfunctionality has appeared at different stages of the biota. [ABSTRACT FROM AUTHOR]

In this paper we investigate the linguistic phenomenon of transcategorization, that is, the categorial shift of a lexical item with no superficial marking, resulting from its employment in a new (morpho)syntactic environment. Our overall aim is to contribute to the description of transcategorization processes from a typological perspective and to highlight their synchronic consequences on the structure of the lexicon. We analyse paradigmatic instances of transcategorization from typologically different languages and discuss the notion of transcategorization with reference to related notions such as conversion, precategoriality, flexibility and polifunctionality. We argue that transcategorization, understood as a diachronic shift from a source to a target category, is more characteristic of languages with clear-cut parts-of-speech distinctions, such as fusional languages. By contrast, isolating languages, where lexical categories are not clearly marked formally, are better characterized as languages with precategorial lexemes. Our main goal is to stress the role that transcategorization plays in shaping the parts-of-speech systems of languages and to highlight its relevance in parts-of-speech theories and models. [ABSTRACT FROM AUTHOR]

Candidate HIV vaccines must show an immune response in order to be considered for further testing and development. What constitutes a “response,” however, is still not clear. While the hunt for a protective vaccine continues, hypotheses are being formed by studying the immune responses across cohorts of people with differing responses to the infection, as well as the immune responses formed by healthy people to other viruses, ones that are generally common and well controlled. Here we examine the functional profile of the immune responses of a group of HIV + long-term non-progressors as measured by intracellular cytokine staining using polychromatic flow cytometry, and compare these responses to those of a larger group of other HIV + people. We describe some of the types of patterns in immune response that are of interest to vaccine researchers, and compare several statistical tests appropriate for this type of data. [ABSTRACT FROM AUTHOR]

This paper presents an overview of a novel approach called Transcendental Psychology Methodology (TPM), largely inspired by Bach-y-Rita's work and developed by A.I. Mirakyan (1929–1995) and his associates. Beginning with the perceptual constancy problem, in which stimuli do not change perceptually despite variations in their physical characteristics, Mirakyan recognized that contemporary accounts of constancy included both theoretical contradictions and empirical discrepancies. This led him to propose TPM as an alternative to the traditional Product Basis Paradigm (PBP). Whilst PBP focuses upon perceptual phenomena, TPM focuses upon the underlying processes and upon the principles that support the flexibility needed to create complex, coherent representations under different stimulus conditions. The central idea that generative perceptual processes may be universal is grounded in Bach-y-Rita's famous experiments and has important parallels with present day conceptions of the construction of meaning in neurophysiological process. TPM inspired studies of a wide range of perceptual phenomena have so far suggested basic principles that can be applied to all perceptual processes, regardless of their modality. Its new conception of the perception of spatial extent can contribute to our understanding of the visual effects that Bach-y-Rita's blind subjects experience and it may provide a useful general tool for uncovering the psychological principles behind Bach-y-Rita's findings. Because of its axiomatic approach and its focus upon universal, generative processes, TPM may also be useful in other disciplines, e.g., in providing a line between neurophysiological and psychological levels of investigation. It may ultimately serve as a general theory of how sensory experience is created. [ABSTRACT FROM AUTHOR]

The bioactive properties of multicomponent film polymeric structures, based on polyvinyl alcohol (PVA), polyvinyl pyrrolidon (PVP) and lactic acid (LA), containing heparin, trypsin and antibiotics (benzyl penicillin and kanamycin) were studied. The degree of degradation and biodegradation of multicomponent film coatings were directly regulated by the introduction of polyvinyl pyrrolidon and lactic acid, as well as by manipulating the conditions of their electroformation regime. The polymeric molecules forming the structure of the coating film do not undergo chemical changes with the breaking of the chain. [Copyright &y& Elsevier]

Simple Summary: Cytokines are molecules that help cells communicate at short range. Often, a single cytokine is measured in patient tissues to understand whether immune cells are actively clearing a tumor. We can learn whether a therapy works, even before changes in tumor burden are found. However, measuring multiple different cytokines better reflects ongoing anti-tumor activity. That is especially true for T cell-based therapies, as these cells secrete different cytokines when they eliminate tumors or not. We also need to consider that a single cytokine can perform activities that can either suppress, or support tumor growth. Taken together, we can best describe the function of T cells in a (pre) clinical setting by a palette of cytokines working together to paint a picture of ongoing immune responses to tumor cells. Cytokines are key molecules within the tumor microenvironment (TME) that can be used as biomarkers to predict the magnitude of anti-tumor immune responses. During immune monitoring, it has been customary to predict outcomes based on the abundance of a single cytokine, in particular IFN-γ or TGF-β, as a readout of ongoing anti-cancer immunity. However, individual cytokines within the TME can exhibit dual opposing roles. For example, both IFN-γ and TGF-β have been associated with pro- and anti-tumor functions. Moreover, cytokines originating from different cellular sources influence the crosstalk between CD4+ and CD8+ T cells, while the array of cytokines expressed by T cells is also instrumental in defining the mechanisms of action and efficacy of treatments. Thus, it becomes increasingly clear that a reliable readout of ongoing immunity within the TME will have to include more than the measurement of a single cytokine. This review focuses on defining a panel of cytokines that could help to reliably predict and analyze the outcomes of T cell-based anti-tumor therapies. [ABSTRACT FROM AUTHOR]

Adoptive T cell therapy has shown clinical potential for patients with cancer, though effective treatment is dependent on longevity and potency of the exploited tumor-reactive T cells. Previously, we showed that ex vivo inhibition of AKT using the research compound Akt-inhibitor VIII retained differentiation and improved functionality of minor histocompatibility antigen (MiHA)-specific CD8+ T cells. Here, we compared a panel of clinically applicable AKT-inhibitors with an allosteric or adenosine triphosphate-competitive mode of action. We analyzed phenotype, functionality, metabolism and transcriptome of AKT-inhibited CD8+ T cells using different T cell activation models. Most inhibitors facilitated T cell expansion while preserving an early memory phenotype, reflected by maintenance of CD62L, CCR7 and CXCR4 expression. Moreover, transcriptome profiling revealed that AKT-inhibited CD8+ T cells clustered closely to naturally occurring stem cell-memory CD8+ T cells, while control T cells resembled effector-memory T cells. Interestingly, AKT-inhibited CD8+ T cells showed enrichment of hypoxia-associated genes, which was consistent with enhanced glycolytic function. Notably, AKT-inhibition during MiHA-specific CD8+ T cell priming uncoupled preservation of early memory differentiation from ex vivo expansion. Furthermore, AKT-inhibited MiHA-specific CD8+ T cells showed increased polyfunctionality with co-secretion of IFN-γ and IL-2 upon antigen recall. Together, these data demonstrate that AKT-inhibitors with different modality of action promote the ex vivo generation of stem cell memory-like CD8+ T cells with a unique metabolic profile and retained polyfunctionality. Akt-inhibitor VIII and GDC-0068 outperformed other inhibitors, and are therefore promising candidates for ex vivo generation of superior tumor-reactive T cells for adoptive immunotherapy in cancer patients. [ABSTRACT FROM AUTHOR]