RESUMEN
Phytoplankton and sea ice algae are traditionally considered to be the main primary producers in the Arctic Ocean. In this Perspective, we explore the importance of benthic primary producers (BPPs) encompassing microalgae, macroalgae, and seagrasses, which represent a poorly quantified source of Arctic marine primary production. Despite scarce observations, models predict that BPPs are widespread, colonizing ~3 million km2 of the extensive Arctic coastal and shelf seas. Using a synthesis of published data and a novel model, we estimate that BPPs currently contribute ~77 Tg C y-1 of primary production to the Arctic, equivalent to ~20 to 35% of annual phytoplankton production. Macroalgae contribute ~43 Tg C y-1, seagrasses contribute ~23 Tg C y-1, and microalgae-dominated shelf habitats contribute ~11 to 16 Tg C y-1. Since 2003, the Arctic seafloor area exposed to sunlight has increased by ~47,000 km2 y-1, expanding the realm of BPPs in a warming Arctic. Increased macrophyte abundance and productivity is expected along Arctic coastlines with continued ocean warming and sea ice loss. However, microalgal benthic primary production has increased in only a few shelf regions despite substantial sea ice loss over the past 20 y, as higher solar irradiance in the ice-free ocean is counterbalanced by reduced water transparency. This suggests complex impacts of climate change on Arctic light availability and marine primary production. Despite significant knowledge gaps on Arctic BPPs, their widespread presence and obvious contribution to coastal and shelf ecosystem production call for further investigation and for their inclusion in Arctic ecosystem models and carbon budgets.
Asunto(s)
Microalgas , Algas Marinas , Ecosistema , Presupuestos , Carbono , Cambio Climático , Cubierta de Hielo , FitoplanctonRESUMEN
The photochemical degradation of chromophoric dissolved organic matter (CDOM) upon solar exposure, known as photobleaching, can significantly alter the optical properties of the surface ocean. By leading to the breakdown of UV- and visible-radiation-absorbing moieties within dissolved organic matter, photobleaching regulates solar heating, the vertical distribution of photochemical processes, and UV exposure and light availability to the biota in surface waters. Despite its biogeochemical and ecological relevance, this sink of CDOM remains poorly quantified. Efforts to quantify photobleaching globally have long been hampered by the inherent challenge of determining representative apparent quantum yields (AQYs) for this process, and by the resulting lack of understanding of their variability in natural waters. Measuring photobleaching AQY is made challenging by the need to determine AQY matrices (AQY-M) that capture the dual spectral dependency of this process (i.e., magnitude varies with both excitation wavelength and response wavelength). A new experimental approach now greatly facilitates the quantification of AQY-M for natural waters, and can help address this problem. Here, we conducted controlled photochemical experiments and applied this new approach to determine the AQY-M of 27 contrasting water samples collected globally along the land-ocean aquatic continuum (i.e., rivers, estuaries, coastal ocean, and open ocean). The experiments and analyses revealed considerable variability in the magnitude and spectral characteristics of the AQY-M among samples, with strong dependencies on CDOM composition/origin (as indicated by the CDOM 275-295-nm spectral slope coefficient, S275-295), solar exposure duration, and water temperature. The experimental data facilitated the development and validation of a statistical model capable of accurately predicting the AQY-M from three simple predictor variables: 1) S275-295, 2) water temperature, and 3) a standardized measure of solar exposure. The model will help constrain the variability of the AQY-M when modeling photobleaching rates on regional and global scales.
RESUMEN
In hydrological optics, "optical closure" means consistency between the apparent optical properties (AOPs) determined from radiometric measurements and those derived from radiative transfer modelling based on concurrently measured inherent optical properties (IOPs) and boundary conditions (sea and sky states). Good optical closure not only provides confidence in the data quality but also informs on the adequacy of the radiative transfer parameterization. Achieving optical closure in highly absorptive coastal waters is challenging due to the low signal-to-noise ratio of radiometric measurements and uncertainties in the measurements of IOPs, namely the spectral absorption and backscattering coefficients. Here, we present an optical closure assessment using a comprehensive set of in situ IOPs acquired in highly absorptive coastal waters optically dominated by chromophoric dissolved organic matter (CDOM). The spectral remote sensing reflectance, Rrs(λ), was modeled using the software HydroLight (HL) with measured IOPs and observed boundary conditions. Corresponding in-water in situ Rrs(λ) was derived from radiometric measurements made with a Compact Optical Profiling System (C-OPS; Biospherical). The assessment revealed that the inclusion of inelastic scattering processes in the model, specifically sun-induced CDOM fluorescence (fDOM) and sun-induced chlorophyll fluorescence (SICF) from Chlorophyll-a ([chl]), significantly improved the optical closure and led to good agreement between measured and modeled Rrs (i.e., for 440 ≤ λ ≤ 710 nm with no inelastic processes: R2=0.90, slope=0.64; with inelastic processes: R2=0.96, slope=0.90). The analysis also indicated that fDOM and SICF contributed a substantial fraction of the green-red wavelength Rrs in these waters. Specifically, fDOM contributed â¼18% of the modeled Rrs in the green region and SICF accounted for â¼20% of the modeled Rrs in the red region. Overall, this study points out the importance of accounting for fDOM in remote sensing applications in CDOM-dominated waters.
RESUMEN
T follicular helper (TFH) cells are essential for developing protective Ab responses following vaccination. Greater understanding of the genetic program leading to TFH differentiation is needed. Chromatin modifications are central in the control of gene expression. However, detailed knowledge of how chromatin regulators (CRs) regulate differentiation of TFH cells is limited. We screened a large short hairpin RNA library targeting all known CRs in mice and identified the histone methyltransferase mixed lineage leukemia 1 (Mll1) as a positive regulator of TFH differentiation. Loss of Mll1 expression reduced formation of TFH cells following acute viral infection or protein immunization. In addition, expression of the TFH lineage-defining transcription factor Bcl6 was reduced in the absence of Mll1. Transcriptomics analysis identified Lef1 and Tcf7 as genes dependent on Mll1 for their expression, which provides one mechanism for the regulation of TFH differentiation by Mll1. Taken together, CRs such as Mll1 substantially influence TFH differentiation.
Asunto(s)
Cromatina , Células T Auxiliares Foliculares , Animales , Ratones , Diferenciación Celular , Cromatina/metabolismo , Regulación de la Expresión Génica , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Células T Auxiliares Foliculares/metabolismo , Linfocitos T Colaboradores-InductoresRESUMEN
CD8 + T cells with stem cell-like properties (T SCM ) sustain adaptive immunity to intracellular pathogens and tumors. However, the developmental origins and chromatin regulatory factors (CRFs) that establish their differentiation are unclear. Using an RNA interference screen of all CRFs we discovered the histone methylase Mll1 was required during T cell receptor (TCR) stimulation for development of a T SCM precursor state and mature memory (T MEM ) cells, but not short-lived or transitory effector cell-like states, in response to viral infections and tumors. Mll1 was essential for widespread de novo deposition of histone H3 lysine 4 trimethylation (H3K4me3) upon TCR stimulation, which accounted for 70% of all activation-induced sites in mature T MEM cells. Mll1 promoted both H3K4me3 deposition and reduced TCR-induced Pol II pausing at genes whose single-cell transcriptional dynamics explained trajectories into nascent T SCM precursor states during viral infection. Our results suggest Mll1-dependent control of Pol II elongation and H3K4me3 establishes and maintains differentiation of CD8 + T SCM cell states.
RESUMEN
T follicular helper (TFH) cells are a specialized subset of CD4 T cells that deliver critical help signals to B cells for the production of high-affinity Abs. Understanding the genetic program regulating TFH differentiation is critical if one wants to manipulate TFH cells during vaccination. A large number of transcription factor (TFs) involved in the regulation of TFH differentiation have been characterized. However, there are likely additional unknown TFs required for this process. To identify new TFs, we screened a large short hairpin RNA library targeting 353 TFs in mice using an in vivo RNA interference screen. Yin Yang 1 (YY-1) was identified as a novel positive regulator of TFH differentiation. Ablation of YY-1 severely impaired TFH differentiation following acute viral infection and protein immunization. We found that the zinc fingers of YY-1 are critical to support TFH differentiation. Thus, we discovered a novel TF involved in the regulation of TFH cells.
Asunto(s)
Centro Germinal , Linfocitos T Colaboradores-Inductores , Factores de Transcripción/metabolismo , Animales , Diferenciación Celular , Activación de Linfocitos , Ratones , ARN Interferente Pequeño/metabolismo , Células T Auxiliares FolicularesRESUMEN
Water quality deterioration is expected to worsen the light conditions in shallow coastal waters with increasing human activities. Temperate seagrasses are known to tolerate a highly fluctuating light environment. However, depending on their ability to adjust to some decline in light conditions, decreases in daily light quantity and quality could affect seagrass physiology, productivity, and, eventually, survival if the Minimum Quantum Requirements (MQR) are not reached. To better understand if, how, and to what extent photosynthetic adjustments contribute to light acclimation, eelgrass (Zostera marina L.) shoots from the cold temperate St. Lawrence marine estuary (Rimouski, QC, Canada) were exposed to seven light intensity treatments (6, 36, 74, 133, 355, 503, and 860 µmol photons m-2 s-1, 14:10 light:dark photoperiod). Photosynthetic capacity and efficiency were quantified after five and 25 days of light exposure by Pulse Amplitude Modulated (PAM) fluorometry to assess the rapid response of the photosynthetic apparatus and its acclimation potential. Photoacclimation was also studied through physiological responses of leaves and shoots (gross and net primary production, pigment content, and light absorption). Shoots showed proof of photosynthetic adjustments at irradiances below 200 µmol photons m-2 s-1, which was identified as the threshold between limiting and saturating irradiances. Rapid Light Curves (RLC) and net primary production (NPP) rates revealed sustained maximal photosynthetic rates from the highest light treatments down to 74 µmol photons m-2 s-1, while a compensation point (NPP = 0) of 13.7 µmol photons m-2 s-1 was identified. In addition, an important package effect was observed, since an almost three-fold increase in chlorophyll content in the lowest compared to the highest light treatment did not change the leaves' light absorption. These results shed new light on photosynthetic and physiological processes, triggering light acclimation in cold temperate eelgrass. Our study documents an MQR value for eelgrass in the St. Lawrence estuary, which is highly pertinent in the context of conservation and restoration of eelgrass meadows.
RESUMEN
Many girls believe they have little natural ability in computer science and girls' perception of self-efficacy beliefs for programming is generally low. Offering engaging hands-on programming activities could be a beneficial strategy to increase girls' self-efficacy beliefs for programming since it has the potential to offer them exposure to mastery experiences. However, a programming workshop in a museum might not offer ideal settings to promote girls' mastery experiences in programming because of its short duration and how gender stereotypes may impact the participation in hands-on activities. In the research presented here, we explore how a science museum's introductory programming workshop focused on robotics can impact pupils' self-efficacy beliefs for programming related to mastery experiences, with a specific focus on girls. H1-Prior to the programming workshop, it is expected that girls' self-efficacy beliefs will be lower than boys'. H2-Boys generally have more positive experiences with STEM activities than girls, irrespective of experimental condition. Thus, following the workshop, we predict that girls' and boys' self-efficacy for programming will have increased, but that boy's self-efficacy beliefs will remain higher than girls'. In total, 172 pupils (94 girls) aged 10-14 years completed a Mastery Experiences in Programming questionnaire before and after taking part in a programming workshop. Our results show that after a 2-h programming workshop in a science museum, gender differences in self-efficacy for programming initially observed narrowed and even disappeared.
De nombreuses filles estiment posséder peu d'aptitudes naturelles en informatique et leur sentiment d'efficacité personnelle en ce qui a trait à la programmation demeure généralement faible. Le fait de proposer des activités de programmation captivantes et pratiques peut s'avérer une stratégie efficace pour augmenter le sentiment d'efficacité personnelle des filles quant à la programmation parce que ces activités possèdent le potentiel de leur procurer de précieuses expériences de réussite. Cependant, les ateliers de programmation organisés dans les musées n'offrent pas nécessairement les meilleures conditions pour favoriser les expériences de réussite en programmation pour les filles, en raison de leur courte durée et parce que les stéréotypes liés au genre peuvent avoir des effets sur la participation aux activités pratiques. Dans cette étude, nous explorons comment un atelier d'initiation à la programmation axée sur la robotique, offert dans un musée de sciences, peut modifier le sentiment d'efficacité personnelle des élèves à l'égard de la programmation en ce qui a trait aux expériences de réussite, et ce particulièrement chez les filles. H1 Avant la tenue de l'atelier de programmation, il est attendu que le sentiment d'efficacité personnelle des filles sera plus faible que celui des garçons. H2Ces derniers vivent généralement plus d'expériences positives dans les STIM que les filles, peu importe la condition expérimentale en cause. Ainsi, nous prédisons qu'après la tenue de l'atelier, le niveau d'efficacité personnelle à l'égard de la programmation des filles et des garçons aura augmenté, mais que celui des garçons demeurera plus élevé que celui des filles. Le nombre d'élèves âgés de 10 à 14 ans qui ont rempli un questionnaire portant sur les expériences de réussite en programmation avant et après la tenue de l'atelier est de 172, dont 94 sont des filles. Les résultats indiquent qu'après un atelier de programmation d'une durée de deux heures, tenu dans un musée de sciences, les différences entre les genres initialement observées quant à l'efficacité personnelle à l'égard de la programmation se sont amenuisées et ont même disparu.
RESUMEN
Limited knowledge is available on the relationship between antigen-specific immune responses and COVID-19 disease severity. We completed a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects. SARS-CoV-2-specific CD4+ and CD8+ T cells were each associated with milder disease. Coordinated SARS-CoV-2-specific adaptive immune responses were associated with milder disease, suggesting roles for both CD4+ and CD8+ T cells in protective immunity in COVID-19. Notably, coordination of SARS-CoV-2 antigen-specific responses was disrupted in individuals ≥ 65 years old. Scarcity of naive T cells was also associated with aging and poor disease outcomes. A parsimonious explanation is that coordinated CD4+ T cell, CD8+ T cell, and antibody responses are protective, but uncoordinated responses frequently fail to control disease, with a connection between aging and impaired adaptive immune responses to SARS-CoV-2.
Asunto(s)
Inmunidad Adaptativa , Antígenos Virales/inmunología , Infecciones por Coronavirus/patología , Neumonía Viral/patología , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Betacoronavirus/inmunología , Betacoronavirus/aislamiento & purificación , Betacoronavirus/metabolismo , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , COVID-19 , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Citocinas/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/virología , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Climate changes in the Arctic may weaken the currently tight pelagic-benthic coupling. In response to decreasing sea ice cover, arctic marine systems are expected to shift from a 'sea-ice algae-benthos' to a 'phytoplankton-zooplankton' dominance. We used mollusc shells as bioarchives and fatty acid trophic markers to estimate the effects of the reduction of sea ice cover on the food exported to the seafloor. Bathyal bivalve Astarte moerchi living at 600 m depth in northern Baffin Bay reveals a clear shift in growth variations and Ba/Ca ratios since the late 1970s, which we relate to a change in food availability. Tissue fatty acid compositions show that this species feeds mainly on microalgae exported from the euphotic zone to the seabed. We, therefore, suggest that changes in pelagic-benthic coupling are likely due either to local changes in sea ice dynamics, mediated through bottom-up regulation exerted by sea ice on phytoplankton production, or to a mismatch between phytoplankton bloom and zooplankton grazing due to phenological change. Both possibilities allow a more regular and increased transfer of food to the seabed. This article is part of the theme issue 'The changing Arctic Ocean: consequences for biological communities, biogeochemical processes and ecosystem functioning'.
Asunto(s)
Exoesqueleto/anatomía & histología , Bivalvos/anatomía & histología , Ecosistema , Exoesqueleto/química , Exoesqueleto/crecimiento & desarrollo , Animales , Regiones Árticas , Bario/análisis , Bivalvos/química , Bivalvos/crecimiento & desarrollo , Calcio/análisis , Cambio Climático/historia , Ácidos Grasos/análisis , Cadena Alimentaria , Historia del Siglo XX , Historia del Siglo XXI , Cubierta de Hielo , Fitoplancton/crecimiento & desarrollo , Datación Radiométrica , Estaciones del Año , Zooplancton/crecimiento & desarrolloRESUMEN
T follicular helper (TFH) cells are a distinct type of CD4+ T cells that are essential for most antibody and B lymphocyte responses. TFH cell regulation and dysregulation is involved in a range of diseases. Bcl-6 is the lineage-defining transcription factor of TFH cells and its activity is essential for TFH cell differentiation and function. However, how Bcl-6 controls TFH biology has largely remained unclear, at least in part due to the intrinsic challenges of connecting repressors to gene upregulation in complex cell types with multiple possible differentiation fates. Multiple competing models were tested here by a series of experimental approaches to determine that Bcl-6 exhibits negative autoregulation and controls pleiotropic attributes of TFH differentiation and function, including migration, costimulation, inhibitory receptors and cytokines, via multiple repressor-of-repressor gene circuits.
Asunto(s)
Regulación de la Expresión Génica/inmunología , Centro Germinal/inmunología , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Proteínas Represoras/genética , Linfocitos T Colaboradores-Inductores/inmunología , Traslado Adoptivo , Animales , Sistemas CRISPR-Cas/genética , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Línea Celular , Movimiento Celular/genética , Movimiento Celular/inmunología , Secuenciación de Inmunoprecipitación de Cromatina , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Redes Reguladoras de Genes , Centro Germinal/citología , Humanos , Masculino , Ratones , Mutación , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , RNA-Seq , Proteínas Represoras/metabolismo , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
The distribution and quality of water resources vary dramatically across Canada, and human impacts such as land-use and climate changes are exacerbating uncertainties in water supply and security. At the national level, Canada has no enforceable standards for safe drinking water and no comprehensive water-monitoring program to provide detailed, timely reporting on the state of water resources. To provide Canada's first national assessment of lake health, the NSERC Canadian Lake Pulse Network was launched in 2016 as an academic-government research partnership. LakePulse uses traditional approaches for limnological monitoring as well as state-of-the-art methods in the fields of genomics, emerging contaminants, greenhouse gases, invasive pathogens, paleolimnology, spatial modelling, statistical analysis, and remote sensing. A coordinated sampling program of about 680 lakes together with historical archives and a geomatics analysis of over 80,000 lake watersheds are used to examine the extent to which lakes are being altered now and in the future, and how this impacts aquatic ecosystem services of societal importance. Herein we review the network context, objectives and methods.
RESUMEN
In this study, we report on the performance of satellite-based photosynthetically available radiation (PAR) algorithms used in published oceanic primary production models. The performance of these algorithms was evaluated using buoy observations under clear and cloudy skies, and for the particular case of low sun angles typically encountered at high latitudes or at moderate latitudes in winter. The PAR models consisted of (i) the standard one from the NASA-Ocean Biology Processing Group (OBPG), (ii) the Gregg and Carder (GC) semi-analytical clear-sky model, and (iii) look-up-tables based on the Santa Barbara DISORT atmospheric radiative transfer (SBDART) model. Various combinations of atmospheric inputs, empirical cloud corrections, and semi-analytical irradiance models yielded a total of 13 (11 + 2 developed in this study) different PAR products, which were compared with in situ measurements collected at high frequency (15 min) at a buoy site in the Mediterranean Sea (the "BOUée pour l'acquiSition d'une Série Optique à Long termE," or, "BOUSSOLE" site). An objective ranking method applied to the algorithm results indicated that seven PAR products out of 13 were well in agreement with the in situ measurements. Specifically, the OBPG method showed the best overall performance with a root mean square difference (RMSD) (bias) of 19.7% (6.6%) and 10% (6.3%) followed by the look-up-table method with a RMSD (bias) of 25.5% (6.8%) and 9.6% (2.6%) at daily and monthly scales, respectively. Among the four methods based on clear-sky PAR empirically corrected for cloud cover, the Dobson and Smith method consistently underestimated daily PAR while the Budyko formulation overestimated daily PAR. Empirically cloud-corrected methods using cloud fraction (CF) performed better under quasi-clear skies (CF<0.3) with an RMSD (bias) of 9.7%-14.8% (3.6%-11.3%) than under partially clear to cloudy skies (0.3
Asunto(s)
Citocinas , Interleucina-4 , Linfocitos B , Humanos , Interleucinas , Linfocitos T Colaboradores-InductoresRESUMEN
The differentiation of helper T cells into effector subsets is critical to host protection. Transcription factors of the E-protein and Id families are important arbiters of T cell development, but their role in the differentiation of the TH1 and TFH subsets of helper T cells is not well understood. Here, TH1 cells showed more robust Id2 expression than that of TFH cells, and depletion of Id2 via RNA-mediated interference increased the frequency of TFH cells. Furthermore, TH1 differentiation was blocked by Id2 deficiency, which led to E-protein-dependent accumulation of effector cells with mixed characteristics during viral infection and severely impaired the generation of TH1 cells following infection with Toxoplasma gondii. The TFH cell-defining transcriptional repressor Bcl6 bound the Id2 locus, which provides a mechanism for the bimodal Id2 expression and reciprocal development of TH1 cells and TFH cells.
Asunto(s)
Infecciones por Arenaviridae/inmunología , Diferenciación Celular , Proteína 2 Inhibidora de la Diferenciación/metabolismo , Virus de la Coriomeningitis Linfocítica/inmunología , Células TH1/fisiología , Toxoplasma/inmunología , Toxoplasmosis/inmunología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Células Cultivadas , Femenino , Centro Germinal/inmunología , Proteína 2 Inhibidora de la Diferenciación/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Unión Proteica , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , ARN Interferente Pequeño/genética , Células TH1/parasitología , Células TH1/virologíaRESUMEN
Significantly higher levels of plasma CXCL13 [chemokine (C-X-C motif) ligand 13] were associated with the generation of broadly neutralizing antibodies (bnAbs) against HIV in a large longitudinal cohort of HIV-infected individuals. Germinal centers (GCs) perform the remarkable task of optimizing B-cell Ab responses. GCs are required for almost all B-cell receptor affinity maturation and will be a critical parameter to monitor if HIV bnAbs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4(+) T follicular helper (GC Tfh) cells problematic. The CXCL13-CXCR5 [chemokine (C-X-C motif) receptor 5] chemokine axis plays a central role in organizing both B-cell follicles and GCs. Because GC Tfh cells can produce CXCL13, we explored the potential use of CXCL13 as a blood biomarker to indicate GC activity. In a series of studies, we found that plasma CXCL13 levels correlated with GC activity in draining lymph nodes of immunized mice, immunized macaques, and HIV-infected humans. Furthermore, plasma CXCL13 levels in immunized humans correlated with the magnitude of Ab responses and the frequency of ICOS(+) (inducible T-cell costimulator) Tfh-like cells in blood. Together, these findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings.
Asunto(s)
Biomarcadores/sangre , Quimiocina CXCL13/sangre , Quimiocina CXCL13/inmunología , Centro Germinal/inmunología , Animales , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Infecciones por VIH/sangre , Infecciones por VIH/inmunología , Humanos , Ganglios Linfáticos/inmunología , Macaca , Ratones Endogámicos C57BL , VacunaciónRESUMEN
T follicular helper (Tfh) cells are essential providers of help to B cells. The transcription factor B-cell CLL/lymphoma 6 (Bcl6) is a lineage-defining regulator of Tfh cells and germinal center B cells. In B cells, Bcl6 has the potential to recruit distinct transcriptional corepressors through its BTB domain or its poorly characterized middle domain (also known as RDII), but in Tfh cells the roles of the Bcl6 middle domain have yet to be clarified. Mimicked acetylation of the Bcl6 middle domain (K379Q) in CD4 T cells results in significant reductions in Tfh differentiation in vivo. Blimp1 (Prdm1) is a potent inhibitor of Tfh cell differentiation. Although Bcl6 K379Q still bound to the Prdm1 cis-regulatory elements in Tfh cells, Prdm1 expression was derepressed. This was a result of the failure of Bcl6 K379Q to recruit metastasis-associated protein 3 (MTA3). The loss of Bcl6 function in Bcl6 K379Q-expressing CD4 T cells could be partially rescued by abrogating Prdm1 expression. In addition to Prdm1, we found that Bcl6 recruits MTA3 to multiple genes involved in Tfh cell biology, including genes important for cell migration, cell survival, and alternative differentiation pathways. Thus, Bcl6 middle domain mediated repression is a major mechanism of action by which Bcl6 controls CD4 T-cell fate and function.
Asunto(s)
Diferenciación Celular/inmunología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Proteínas de Neoplasias/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Inmunoprecipitación de Cromatina , Clonación Molecular , Cartilla de ADN/genética , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutagénesis Sitio-Dirigida , Proteínas de Neoplasias/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-bcl-6 , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Represoras/inmunología , Factores de Transcripción/metabolismoRESUMEN
The FANC-BRCA DNA repair pathway is activated in response to interstrand crosslinks formed in DNA. A homozygous mutation in 1 of the 17 Fanconi anemia (FA) genes results in malfunctions of this pathway and development of FA syndrome. The integrity of this protein network is essential for good maintenance of DNA repair process and genome stability. Following the identification of an alternatively splice isoform of FANCE (Fanconi anemia complementation group E) significantly expressed in breast cancer individuals from high-risk non-BRCA1/2 families, we studied the impact of this FANCE splice isoform (FANCEΔ4) on DNA repair processes. We have demonstrated that FANCEΔ4 mRNA was efficiently translated into a functional protein and expressed in normal and breast cancer cell lines. Following treatment with the crosslinking agent mitomycin C, EUFA130 (FANCE-deficient) cells infected with FANCEΔ4 were blocked into G2/M phase, while cell survival was significantly reduced compared with FANCE-infected EUFA130 cells. In addition, FANCEΔ4 did not allow FANCD2 and FANCI monoubiquitination, which represents a crucial step of the FANC-BRCA functional pathway. As observed for FANCE wild-type protein, localization of FANCEΔ4 protein was confined to the nucleus following mitomycin C treatment. Although FANCEΔ4 protein showed interaction with FANCE, FANCEΔ4 did not support normal function of FANCE protein in this pathway and could have deleterious effects on FANCE protein activity. We have demonstrated that FANCEΔ4 seems to act as a regulator of FANCD2 protein expression level by promoting its degradation. This study highlights the importance of an efficient regulation of alternative splicing expression of FA genes for proper DNA repair.
Asunto(s)
Empalme Alternativo , Reparación del ADN , Proteína del Grupo de Complementación E de la Anemia de Fanconi/genética , Anemia de Fanconi/genética , Secuencia de Aminoácidos , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Supervivencia Celular , Anemia de Fanconi/metabolismo , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/genética , Proteína del Grupo de Complementación E de la Anemia de Fanconi/química , Proteína del Grupo de Complementación E de la Anemia de Fanconi/metabolismo , Proteínas del Grupo de Complementación de la Anemia de Fanconi/metabolismo , Regulación de la Expresión Génica , Células HEK293 , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estructura Terciaria de Proteína , Alineación de SecuenciaRESUMEN
T follicular helper (Tfh) cells are essential for germinal centers (GCs) and most long-term humoral immunity. Differentiation of Tfh cells depends on the transcriptional repressor B cell CLL/lymphoma 6 (Bcl6). Bcl6 mediates gene repression via the recruitment of corepressors. Currently, it is unknown how Bcl6 recruits corepressors to regulate gene expression of Tfh cells. In this article, we demonstrate, using a mutant form of Bcl6 with two BTB (bric-a-brac, tramtrack, broad-complex) mutations that abrogate corepressor binding, that the Bcl6 BTB domain is required for proper differentiation of Tfh and GC-Tfh cells in vivo. Importantly, we also observe a significant defect in GC B cell development. These results are consistent in multiple contexts, including a novel lymphocytic choriomeningitis virus nucleoprotein-specific TCR-transgenic mouse model. Taken together, these data suggest that the Bcl6 BTB domain is a key mediator of the differentiation of Tfh cells.
Asunto(s)
Diferenciación Celular , Centro Germinal/inmunología , Centro Germinal/metabolismo , Dominios y Motivos de Interacción de Proteínas , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/metabolismo , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Diferenciación Celular/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Transgénicos , Unión Proteica , Proteínas Proto-Oncogénicas c-bcl-6/química , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
Intense regional warming was observed in the western Antarctic Peninsula (WAP) over the last 50 years. Here, we investigate the impact of climate change on primary production (PP) in this highly productive region. This study is based on temporal data series of ozone thickness (1972-2010), sea ice concentration (1978-2010), sea-surface temperature (1990-2010), incident irradiance (1988-2010) and satellite-derived chlorophyll a concentration (Chl-a, 1997-2010) for the coastal WAP. In addition, we apply a photosynthesis/photoinhibition spectral model to satellite-derived data (1997-2010) to compute PP and examine the separate impacts of environmental forcings. Since 1978, sea ice retreat has been occurring earlier in the season (in March in 1978 and in late October during the 2000s) while the ozone hole is present in early spring (i.e. August to November) since the early 1990s, increasing the intensity of ultraviolet-B radiation (UVBR, 280-320 nm). The WAP waters have also warmed over 1990-2010. The modelled PP rates are in the lower range of previously reported PP rates in the WAP. The annual open water PP in the study area increased from 1997 to 2010 (from 0.73 to 1.03 Tg C yr(-1) ) concomitantly with the increase in the production season length. The coincidence between the earlier sea ice retreat and the presence of the ozone hole increased the exposure to incoming radiation (UVBR, UVAR and PAR) and, thus, increased photoinhibition during austral spring (September to November) in the study area (from 0.014 to 0.025 Tg C yr(-1) ). This increase in photoinhibition was minor compared to the overall increase in PP, however. Climate change hence had an overall positive impact on PP in the WAP waters.