RESUMO
Urban flooding poses a significant challenge to the rapidly growing Indian cities. Low-impact development strategies such as green roofs have shown the potential to reduce urban flooding. However, their performance assessment significantly varies across different studies. Therefore, the study's primary objective is to evaluate green roofs in the Indian context. For this evaluation, the green roofs are assessed based on building-level implementation scenarios for a high-density urban area in India for 25%,50%, and 75% application rates and different rainfall intensities (2,3 and 4-h duration and 2,5,10 and 25-year frequencies). Secondly, to probe the variations in the green roof performance across studies, uncertainty contributions to the runoff reduction from different parameters are quantified. The results show that green roofs can reduce up to 62% of flood volume and 24% of runoff. However, they are reasonably effective only beyond 25% application rates. Further, rainfall intensity contributes the most to the uncertainty of runoff reduction from green roofs. This uncertainty assessment implies that localized evaluation of green roofs depending on local rainfall conditions is required for city-wide policy planning. The study has a significant contribution to building confidence in the ability of green roofs to reduce urban floods in the context of developing countries like India.
Assuntos
Cidades , Inundações , Índia , Incerteza , Chuva , Conservação dos Recursos Naturais/métodosRESUMO
The intensity of eddy diffusivity and the spatial average of water velocity at the depths of the water column in oceans and lakes play a fundamental role in phytoplankton production and phytoplankton and zooplankton biomass, and community composition. The critical depth and intensity of turbulent mixing within the water column profoundly affect phytoplankton biomass, which depends on the sinking characteristic of planktonic algal species. We propose an Nutrient-Phytoplankton-Zooplankton (NPZ) model in 3D space with light and nutrient-limited growth in a micro-scale ecological study. To incorporate micro-scale observation of phytoplankton intermittency in bloom mechanism in stationary as well as oceanic turbulent flows, a moment closure method has been applied in this study. Experimental observations imply that an increase in turbulence is sometimes ecologically advantageous for non-motile planktonic algae. How do we ensure whether there will be a bloom cycle or whether there can be any bloom at all when the existing phytoplankton group is buoyant, heavier, motile, or non-motile? To address these questions, we have explored the effects of critical depth, the intensity of eddy diffusivity, spatial average of water velocity, on the concentration as well as horizontal and vertical distribution of phytoplankton and zooplankton biomass using a mathematical model and moment closure technique. We quantify a critical threshold value of eddy diffusivity and the spatial average of water velocity and observe the corresponding changes in the phytoplankton bloom dynamics. Our results highlight the importance of eddy diffusivity and the spatial average of water velocity on seasonal bloom dynamics and also mimic different real-life bloom scenarios in Mikawa Bay (Japan), Tokyo Bay (Japan), Arakawa River (Japan), the Baltic Sea, the North Atlantic Ocean, Gulf Alaska, the North Arabian Sea, the Cantabrian Sea, Lake Nieuwe Meer (Netherlands) and several shallower lakes.
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Fitoplâncton , Plâncton , Animais , Estações do Ano , Biomassa , Zooplâncton , Água , LagosRESUMO
In parallel with the genetic and epigenetic changes that accumulate in tumor cells, chronic tumor-promoting inflammation establishes a local microenvironment that fosters the development of malignancy. While knowledge of the specific factors that distinguish tumor-promoting from non-tumor-promoting inflammation remains inchoate, nevertheless, as highlighted in this series on the 'Hallmarks of Cancer', it is clear that tumor-promoting inflammation is essential to neoplasia and metastatic progression making identification of specific factors critical. Studies of immunometabolism and inflamometabolism have revealed a role for the tryptophan catabolizing enzyme IDO1 as a core element in tumor-promoting inflammation. At one level, IDO1 expression promotes immune tolerance to tumor antigens, thereby helping tumors evade adaptive immune control. Additionally, recent findings indicate that IDO1 also promotes tumor neovascularization by subverting local innate immunity. This newly recognized function for IDO1 is mediated by a unique myeloid cell population termed IDVCs (IDO1-dependent vascularizing cells). Initially identified in metastatic lesions, IDVCs may exert broader effects on pathologic neovascularization in various disease settings. Mechanistically, induction of IDO1 expression in IDVCs by the inflammatory cytokine IFNγ blocks the antagonistic effect of IFNγ on neovascularization by stimulating the expression of IL6, a powerful pro-angiogenic cytokine. By contributing to vascular access, this newly ascribed function for IDO1 aligns with its involvement in other cancer hallmark functionalities, (tumor-promoting inflammation, immune escape, altered cellular metabolism, metastasis), which may stem from an underlying role in normal physiological functions such as wound healing and pregnancy. Understanding the nuances of how IDO1 involvement in these cancer hallmark functionalities varies between different tumor settings will be crucial to the future development of successful IDO1-directed therapies.
RESUMO
The general circulation models (GCMs) and emission scenarios (RCP 4.5 and 8.5) have proven to be significantly functional in evaluating the impacts of climate change (CC) on hydrology, although their performance and accuracy varies on a regional scale. The objective of the present study is to evaluate the performance of five CMIP5 GCMs (CanESM2, BNU-ESM, CNRM-CM5, MPI-ESM-LR and MPI-ESM-MR) on a regional scale in the West Flowing River Basins-2 (WFRB-2) in India to model the impact of CC and its scenario uncertainty using reliability ensemble average (REA) method. For quantifying the results, the upper, middle and lower regions of WFRB-2 are separately analysed. The MPIMR and MPILR GCM model shows highest reliability factor range (0.3-0.6) in predicting the annual mean and annual maximum rainfall for most of the grids in the region. The GCM-simulated runoff using VIC (variable infiltration capacity) model is evaluated using statistical parameters such as root mean square error (RMSE), percentage bias (Pbias) and standard deviation (Std). The annual mean (maximum) runoff obtained using REA ensemble shows least RMSE, Pbias and Std values, i.e. 21.08%, 9.10 mm and 8.9 mm (6%, 39.1 mm, 39.1 mm), respectively for the middle region, which demonstrates higher reliability of GCM outputs in the flood-prone regions of WFRB-2. Furthermore, the future projection of annual maximum rainfall/runoff shows an increase of 50 mm/15 mm in the near future (2011-2040) for lower and 20 mm/6 mm for middle regions, which may cause flooding activities in the lower and middle region of WFRB-2.
Assuntos
Monitoramento Ambiental , Mudança Climática , Monitoramento Ambiental/métodos , Índia , Reprodutibilidade dos Testes , IncertezaRESUMO
Hot extremes are anticipated to be more frequent and more intense under climate change, making the Indo-Gangetic Plain of India, with a 400 million population, vulnerable to heat stress. Recent studies suggest that irrigation has significant cooling and moistening effects over this region. While large-scale irrigation is prevalent in the Indo-Gangetic Plain during the two major cropping seasons, Kharif (Jun-Sep) and Rabi (Nov-Feb), hot extremes are reported in the pre-monsoon months (Apr-May) when irrigation activities are minimal. Here, using observed irrigation data and regional climate model simulations, we show that irrigation effects on heat stress during pre-monsoon are 4.9 times overestimated with model-simulated irrigation as prescribed in previous studies. We find that irrigation increases relative humidity by only 2.5%, indicating that irrigation is a non-crucial factor enhancing the moist heat stress. On the other hand, we detect causal effects of aerosol abundance on the daytime land surface temperature. Our study highlights the need to consider actual irrigation data in testing model-driven hypotheses related to the land-atmosphere feedback driven by human water management.
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Poluentes Atmosféricos , Aerossóis/análise , Poluentes Atmosféricos/análise , Atmosfera , Monitoramento Ambiental , Resposta ao Choque Térmico , Humanos , Índia , Estações do AnoRESUMO
A microscale ecological study using the closure approach to understand the impact of productivity controlled by geographical and seasonal variations on the intermittency of phytoplankton is done in this paper. Using this approach for a nutrient-phytoplankton model with Holling type III functional response, it has been shown how the dynamics of the system can be affected by the environmental fluctuations triggered by the impact of light, temperature, and salinity, which fluctuate with regional and seasonal variations. Reynold's averaging method in space, which results in expressing the original components in terms of its mean (average value) and perturbation (fluctuation) has been used to determine the impact of growth fluctuation in phytoplankton distribution and in the intermittency of phytoplankton spreading (variance). Parameters are estimated from the nature of productivity and spread of phytoplankton density during field observation done at four different locations of Tokyo Bay. The model validation shows that our results are in good agreement with the field observation and succeeded in explaining the intermittent phytoplankton distribution at different locations of Tokyo Bay, Japan, and its neighboring coastal regions.
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Fitoplâncton , Salinidade , Monitoramento Ambiental , Japão , Estações do Ano , TemperaturaRESUMO
Long term drought management requires proper assessment and characterization of drought hazard, vulnerability and risk. This is particularly important for an agriculture-dependent, highly-populated, developing country such as India. However, the regulation of drought vulnerability and drought risk assessment in the country is mostly region-specific and ad-hoc, considering only a limited number of vulnerability indicators. In this study, a comprehensive, fine-resolution, country-wide drought risk assessment is carried out considering drought hazard in a multivariate framework, and using reliable drought vulnerability indicators that account for exposure, sensitivity and adaptive capacity. Further, multiple aggregation techniques including subjective, objective and comprehensive methods are employed for vulnerability assessment, and their performance assessed and compared. The Analytic Hierarchy Process (AHP)+Entropy and TOPSIS methods, which are comprehensive aggregation techniques are found to be better performing, TOPSIS being the most robust method. A bivariate choropleth map based on the TOPSIS-derived drought vulnerability shows regions of Punjab, Haryana, Uttar Pradesh and Tamil Nadu subjected to drought hazard-driven risk, while risk in other regions such as Rajasthan, parts of Central India, Orissa and parts of Maharashtra are driven more by drought vulnerability. Parts of Western Rajasthan, Vidharbha, North-East India, Chattisgarh, Tamil Nadu and Karnataka are under severe drought risk resulting from an interplay of hazard and vulnerability. Irrigation index, water body fraction, and groundwater availability are found to be the most significant indicators for assessing drought vulnerability in India. The above findings can aid decision makers and government bodies to plan region-specific line of action for building drought resilience.
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Secas , Água Subterrânea , Agricultura , Índia , Medição de RiscoRESUMO
OBJECTIVE: The route of termination of pregnancy in eclampsia is not clearly established. This study aims to compare the fetomaternal outcome between planned vaginal delivery and planned cesarean section in women with eclampsia after 34 weeks of gestation. METHODS: This prospective observational study was conducted in the department of Obstetrics and Gynecology, Midnapore Medical College, West Bengal, India. 182 women with eclampsia carrying 34 weeks or more gestation were allocated to either cesarean(CD) or vaginal delivery (VD) group. The primary measure of outcome was severe maternal outcome. Secondary measures of outcome were perinatal mortality and morbidity. RESULTS: Of the 62 women allocated in vaginal delivery (VD) group, 60 women (32.97%) had vaginal delivery and 122 (67.03%) had undergone cesarean delivery (CD). Severe maternal outcome was more common in VD group in comparison with CD group (72.5% vs 27.5%, P < 0.00001 RR 2.64 OR 6.98). Perinatal outcome in relation to Apgar score at 5 min, still birth was better in CD group than VD group. Perinatal death was higher in VD group when compared with CD group (25.8%; vs. 8.33%; P = 0.002, RR 3.1 OR 3.83). CONCLUSION: There is increasing trend of delivering the eclampsia mother at > 34 weeks of gestation by cesarean section instead of inducing labor and delivering vaginally. Cesarean section when chosen as method of delivery does not increase morbidity or mortality.
RESUMO
Immune checkpoint inhibitors demonstrate clinical activity in many tumor types, however, only a fraction of patients benefit. Combining CD137 agonists with these inhibitors increases anti-tumor activity preclinically, but attempts to translate these observations to the clinic have been hampered by systemic toxicity. Here we describe a human CD137xPD-L1 bispecific antibody, MCLA-145, identified through functional screening of agonist- and immune checkpoint inhibitor arm combinations. MCLA-145 potently activates T cells at sub-nanomolar concentrations, even under suppressive conditions, and enhances T cell priming, differentiation and memory recall responses. In vivo, MCLA-145 anti-tumor activity is superior to immune checkpoint inhibitor comparators and linked to recruitment and intra-tumor expansion of CD8 + T cells. No graft-versus-host-disease is observed in contrast to other antibodies inhibiting the PD-1 and PD-L1 pathway. Non-human primates treated with 100 mg/kg/week of MCLA-145 show no adverse effects. The conditional activation of CD137 signaling by MCLA-145, triggered by neighboring cells expressing >5000 copies of PD-L1, may provide both safety and potency advantages.
Assuntos
Ligante 4-1BB/agonistas , Anticorpos Biespecíficos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Ligante 4-1BB/imunologia , Animais , Anticorpos Biespecíficos/imunologia , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Tolerância Imunológica/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Imunoterapia , Ativação Linfocitária/efeitos dos fármacosRESUMO
In addition to immunosuppression, it is generally accepted that myeloid-derived suppressor cells (MDSC) also support tumor angiogenesis. The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1) has been implicated in promoting neovascularization through its positioning as a key regulatory node between the inflammatory cytokines IFNγ and IL6. Here, we report that within the heterogeneous expanse of Gr-1+ MDSCs, both IDO1 expression and the ability to elicit neovascularization in vivo were associated with a minor subset of autofluorescent, CD11blo cells. IDO1 expression was further restricted to a discrete, CD11c and asialo-GM1 double-positive subpopulation of these cells, designated here as IDVCs (IDO1-dependent vascularizing cells), due to the dominant role that IDO1 activity in these cells was found to play in promoting neovascularization. Mechanistically, the induction of IDO1 in IDVCs provided a negative-feedback constraint on the antiangiogenic effect of host IFNγ by intrinsically signaling for the production of IL6 through general control nonderepressible 2 (GCN2)-mediated activation of the integrated stress response. These findings reveal fundamental molecular and cellular insights into how IDO1 interfaces with the inflammatory milieu to promote neovascularization.
Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação/metabolismo , Interferon gama/metabolismo , Interleucina-6/metabolismo , Neovascularização Patológica/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Inflamação/patologia , Interferon gama/genética , Interleucina-6/genética , Camundongos Endogâmicos BALB C , Camundongos Knockout , Metástase Neoplásica , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/genética , Proteínas Serina-Treonina Quinases/genética , Transdução de SinaisRESUMO
BACKGROUND: The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which subverts T-cell immunity at multiple levels, is itself subject to inherent T-cell reactivity. This intriguing deviation from central tolerance has been interpreted as counterbalancing IDO1-mediated immunosuppression. Based on this hypothesis, clinical studies employing an IDO1 peptide-based vaccine approach for cancer treatment have been initiated, but there remains a pressing need to further investigate the immunological ramifications of stimulating the anti-IDO1 T-cell response in this manner. METHODS: CT26 colon carcinoma tumors were evaluated for expression of IDO1 protein by western blot analysis, immunofluorescence microscopy and flow cytometry. Mouse IDO1-derived peptides, predicted to bind either major histocompatibility complex (MHC) class I or II of the H2d BALB/c strain, were emulsified in 50% Montanide for prophylactic or therapeutic vaccine treatment of CT26 tumor-bearing mice initiated either 7 days prior to or following tumor cell injection, respectively. In some therapeutic treatment experiments, administration of programmed cell death protein 1-binding antibody (anti-PD1 antibody) or epacadostat was concurrently initiated. Tumor size was determined by caliper measurements and comparative tumor growth suppression was assessed by longitudinal analyses of tumor growth data. For adoptive transfer, T cells from complete responder animals were isolated using paramagnetic beads and fluorescence-activated cell sorting. RESULTS: This study identifies mouse MHC class I-directed and II-directed, IDO1-derived peptides capable of eliciting antitumor responses, despite finding IDO1 expressed exclusively in tumor-infiltrating immune cells. Treatment of established tumors with anti-PD1 antibody and class I-directed but not class II-directed IDO1 peptide vaccines produced an enhanced antitumor response. Likewise, class I-directed and II-directed IDO1 peptides elicited an enhanced combinatorial response, suggesting distinct mechanisms of action. Consistent with this interpretation, adoptive transfer of isolated CD8+ T cells from class I and CD4+ T cells from class II peptide-vaccinated responder mice delayed tumor growth. The class II-directed response was completely IDO1-dependent while the class I-directed response included an IDO1-independent component consistent with antigen spread. CONCLUSIONS: The in vivo antitumor effects demonstrated with IDO1-based vaccines via targeting of the tumor microenvironment highlight the utility of mouse models for further exploration and refinement of this novel vaccine-based approach to IDO1-directed cancer therapy and its potential to improve patient response rates to anti-PD1 therapy.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/uso terapêutico , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Vacinas de Subunidades Antigênicas/uso terapêutico , Animais , Vacinas Anticâncer/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Vacinas de Subunidades Antigênicas/farmacologiaRESUMO
The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase-1 (IDO1) has attracted enormous attention in driving cancer immunosuppression, neovascularization, and metastasis. IDO1 suppresses local CD8+ T effector cells and natural killer cells and induces CD4+ T regulatory cells (iTreg) and myeloid-derived suppressor cells (MDSC). The structurally distinct enzyme tryptophan dioxygenase (TDO) also has been implicated recently in immune escape and metastatic progression. Lastly, emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated iTreg and contribute to B-cell inflammed states in certain cancers. IDO1 and TDO are upregulated widely in neoplastic cells but also variably in stromal, endothelial, and innate immune cells of the tumor microenviroment and in tumor-draining lymph nodes. Pharmacological and genetic proofs in preclinical models of cancer have validated IDO1 as a cancer therapeutic target. IDO1 inhibitors have limited activity on their own but greatly enhance "immunogenic" chemotherapy or immune checkpoint drugs. IDO/TDO function is rooted in inflammatory programming, thereby influencing tumor neovascularization, MDSC generation, and metastasis beyond effects on adaptive immune tolerance. Discovery and development of two small molecule enzyme inhibitors of IDO1 have advanced furthest to date in Phase II/III human trials (epacadostat and navoximod, respectively). Indoximod, a tryptophan mimetic compound with a different mechanism of action in the IDO pathway has also advanced in multiple Phase II trials. Second generation combined IDO/TDO inhibitors may broaden impact in cancer treatment, for example, in addressing IDO1 bypass (inherent resistance) or acquired resistance to IDO1 inhibitors. This review surveys knowledge about IDO1 function and how IDO1 inhibitors reprogram inflammation to heighten therapeutic responses in cancer.
Assuntos
Inibidores Enzimáticos/farmacologia , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Inflamação/terapia , Neoplasias/terapia , Animais , Inibidores Enzimáticos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
We discuss how small-molecule inhibitors of the tryptophan (Trp) catabolic enzyme indoleamine 2,3-dioxygenase (IDO) represent a vanguard of new immunometabolic adjuvants to safely enhance the efficacy of cancer immunotherapy, radiotherapy, or 'immunogenic' chemotherapy by leveraging responses to tumor neoantigens. IDO inhibitors re-program inflammatory processes to help clear tumors by blunting tumor neovascularization and restoring immunosurveillance. Studies of regulatory and effector pathways illuminate IDO as an inflammatory modifier. Recent work suggests that coordinate targeting of the Trp catabolic enzymes tryptophan 2,3-dioxygenase (TDO) and IDO2 may also safely broaden efficacy. Understanding IDO inhibitors as adjuvants to turn immunologically 'cold' tumors 'hot' can seed new concepts in how to improve the efficacy of cancer therapy while limiting collateral damage.
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Reprogramação Celular/genética , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Neoplasias/terapia , Reprogramação Celular/imunologia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Inflamação/imunologia , Inflamação/patologia , Neoplasias/genética , Neoplasias/imunologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Triptofano/metabolismo , Triptofano Oxigenase/antagonistas & inibidores , Triptofano Oxigenase/imunologiaRESUMO
The immune tolerogenic effects of IDO1 (indoleamine 2,3-dioxygenase 1) have been well documented and genetic studies in mice have clearly established the significance of IDO1 in tumor promotion. Dichotomously, the primary inducer of IDO1, the inflammatory cytokine IFNγ (interferon-γ), is a key mediator of immune-based tumor suppression. One means by which IFNγ can exert an anti-cancer effect is by decreasing tumor neovascularization. We speculated that IDO1 might contribute to cancer promotion by countering this anti-neovascular effect of IFNγ, possibly through IDO1-potentiated elevation of the pro-tumorigenic inflammatory cytokine IL6 (interleukin-6). In this study, we investigated how genetic loss of IDO1 affects neovascularization in mouse models of oxygen-induced retinopathy and lung metastasis. Neovascularization in both models was significantly reduced in mice lacking IDO1, was similarly reduced with loss of IL6, and was restored in both cases by concomitant loss of IFNγ. Likewise, the lack of IDO1 or IL6 resulted in reduced metastatic tumor burden and increased survival, which the concomitant loss of IFNγ abrogated. This insight into IDO1's involvement in pro-tumorigenic inflammatory neovascularization may have important ramifications for IDO1 inhibitor development, not only in cancer where clinical trials are currently ongoing, but in other disease indications associated with neovascularization as well.
Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Neovascularização Patológica/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Inflamação/complicações , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Knockout , Metástase Neoplásica , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/genéticaRESUMO
The importance of follicular T helper (TFH) cells and the germinal center (GC) reaction in the humoral immune response has become clear in recent years, however the role of TFH cells and the GC in an HIV vaccine strategy remains unclear. In this study, we primed mice with gp120-encoding DNA and boosted with gp120 protein, a regimen previously shown to induce high titers of high affinity and cross-reactive anti-gp120 Abs. Priming with gp120 DNA caused increased TFH cell differentiation, GC B cells, and antigen-specific antibody titers, compared with priming with gp120 protein. Priming with DNA also caused more activated CD4(+) T cells to become TFH cells and more GC B cells to become memory cells. Deletion of BCL6 midway through the vaccine regimen resulted in loss of TFH cells and GCs, and, unexpectedly, increased anti-gp120 IgG titers and avidity. Our data suggests vaccination with gp120-encoding DNA elicits a stronger and more rapid TFH and GC response than gp120 protein. Furthermore, we demonstrate that the GC reaction may actually limit antigen-specific IgG secretion in the context of repeated immunizations.
Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos B/imunologia , Centro Germinativo/citologia , Proteína gp120 do Envelope de HIV/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinas de DNA/imunologia , Vacinas contra a AIDS/administração & dosagem , Animais , Proteínas de Ligação a DNA/metabolismo , Feminino , Anticorpos Anti-HIV/sangue , Proteína gp120 do Envelope de HIV/administração & dosagem , Proteína gp120 do Envelope de HIV/genética , Imunoglobulina G/sangue , Masculino , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-6 , Vacinação/métodos , Vacinas de DNA/administração & dosagem , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
Low-moisture foods have been responsible for a number of salmonellosis outbreaks worldwide over the last few decades, with cross contamination from contaminated equipment being the most predominant source. To date, actions have been focused on stringent hygienic practices prior to production, namely periodical sanitization of the processing equipment and lines. Not only does optimum sanitization require in-depth knowledge on the type and source of contaminants, but also the heat resistance of microorganisms is unique and often dependent on the heat transfer characteristics of the low-moisture foods. Rheological properties, including viscosity, degree of turbulence, and flow characteristics (for example, Newtonian or non-Newtonian) of both liquid and semisolid foods are critical factors impacting the flow behavior that consequently interferes heat transfer and related control elements. The demand for progressively more accurate prediction of complex fluid phenomena has called for the employment of computational fluid dynamics (CFD) to model mass and heat transfer during processing of various food products, ranging from drying to baking. With the aim of improving the quality and safety of low-moisture foods, this article critically reviewed the published literature concerning microbial survival in semisolid low-moisture foods, including chocolate, honey, and peanut butter. Critical rheological properties and state-of-the-art CFD application relevant to quality production of those products were also addressed. It is anticipated that adequate prediction of specific transport properties during optimum sanitization through CFD could be used to solve current and future food safety challenges.
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Análise de Alimentos , Microbiologia de Alimentos , Qualidade dos Alimentos , Salmonella/fisiologia , Água/química , Salmonella/isolamento & purificaçãoRESUMO
The transcriptional repressor Bcl6 controls development of the follicular Th cell (T(FH)) lineage, but the precise mechanisms by which Bcl6 regulates this process are unclear. A model has been proposed whereby Bcl6 represses the differentiation of T cells into alternative effector lineages, thus favoring T(FH) cell differentiation. Analysis of T cell differentiation using Bcl6-deficient mice has been complicated by the strong proinflammatory phenotype of Bcl6-deficient myeloid cells. In this study, we report data from a novel mouse model where Bcl6 is conditionally deleted in T cells (Bcl6(fl/fl)Cre(CD4) mice). After immunization, programmed death -1 (PD-1)(high) T(FH) cells in Bcl6(fl/fl)Cre(CD4) mice are decreased >90% compared with control mice, and Ag-specific IgG is sharply reduced. Residual PD-1(high)CXCR5(+) T(FH) cells in Bcl6(fl/fl)Cre(CD4) mice show a significantly higher rate of apoptosis than do PD-1(high)CXCR5(+) T(FH) cells in control mice. Immunization of Bcl6(fl/fl)Cre(CD4) mice did not reveal enhanced differentiation into Th1, Th2, or Th17 lineages, although IL-10 expression by CD4 T cells was markedly elevated. Thus, T cell-extrinsic factors appear to promote the increased Th1, Th2, and Th17 responses in germline Bcl6-deficient mice. Furthermore, IL-10 may be a key target gene for Bcl6 in CD4 T cells, which enables Bcl6 to promote the T(FH) cell phenotype. Finally, our data reveal a novel mechanism for the role of Bcl6 in promoting T(FH) cell survival.
Assuntos
Proteínas de Ligação a DNA/genética , Mutação , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Proteínas de Ligação a DNA/metabolismo , Expressão Gênica , Técnicas de Inativação de Genes , Ordem dos Genes , Marcação de Genes , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-6 , Linfócitos T Auxiliares-Indutores/citologiaRESUMO
The transcriptional repressor protein BCL6 regulates T cell differentiation by repressing Th2 responses and promoting follicular Th cell responses. However, little is known about the role of BCL6 in Th17 responses. We found that memory T cells from BCL6-deficient mice had increased IL-17 production. Additionally, BCL6 expression is upregulated in CD4 T cells cultured under Th17 conditions. T cells from BCL6-deficient mice showed defective Th17 differentiation and enhanced IL-4 production in vitro; however, normal Th17 differentiation was obtained with BCL6-deficient T cells under culture conditions when highly pure naive CD4 T cells were used, when IL-4 production was inhibited, or when TGF-beta levels were increased. Retrovirus-mediated expression of BCL6 in CD4 T cells repressed IL-4 and augmented basal IL-17 mRNA expression. These data support the idea that BCL6 promotes Th17 differentiation through suppression of Th2 differentiation. BCL6-deficient T cells transplanted into Rag1(-/-) mice produced wild-type levels of IL-17, indicating that, in vivo, BCL6-deficient T cells develop relatively normal Th17 responses. Macrophages from BCL6-deficient mice showed strikingly increased expression of the Th17-promoting cytokines IL-6, IL-23, and TGF-beta, and conditioned media from BCL6-deficient macrophages promoted augmented IL-17 expression by T cells. We propose that the increased Th17 activity in BCL6-deficient mice is due, in part, to BCL6-deficient macrophages promoting increased Th17 differentiation in vivo. T cells may require BCL6 for optimal Th17 differentiation; however, BCL6 function in macrophages critically regulates Th17 differentiation in vivo. We hypothesize that increased Th17 differentiation aggravates the severe Th2-type inflammatory disease in BCL6-deficient mice.