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1.
Cancer Immunol Res ; 12(6): 663-672, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38489753

RESUMEN

The DNA exonuclease three-prime repair exonuclease 1 (TREX1) is critical for preventing autoimmunity in mice and humans by degrading endogenous cytosolic DNA, which otherwise triggers activation of the innate cGAS/STING pathway leading to the production of type I IFNs. As tumor cells are prone to aberrant cytosolic DNA accumulation, we hypothesized that they are critically dependent on TREX1 activity to limit their immunogenicity. Here, we show that in tumor cells, TREX1 restricts spontaneous activation of the cGAS/STING pathway, and the subsequent induction of a type I IFN response. As a result, TREX1 deficiency compromised in vivo tumor growth in mice. This delay in tumor growth depended on a functional immune system, systemic type I IFN signaling, and tumor-intrinsic cGAS expression. Mechanistically, we show that tumor TREX1 loss drove activation of CD8+ T cells and NK cells, prevented CD8+ T-cell exhaustion, and remodeled an immunosuppressive myeloid compartment. Consequently, TREX1 deficiency combined with T-cell-directed immune checkpoint blockade. Collectively, we conclude that TREX1 is essential to limit tumor immunogenicity, and that targeting this innate immune checkpoint remodels the tumor microenvironment and enhances antitumor immunity by itself and in combination with T-cell-targeted therapies. See related article by Toufektchan et al., p. 673.


Asunto(s)
Exodesoxirribonucleasas , Inmunidad Innata , Proteínas de la Membrana , Nucleotidiltransferasas , Fosfoproteínas , Exodesoxirribonucleasas/genética , Exodesoxirribonucleasas/metabolismo , Animales , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Ratones , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Humanos , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/genética , Interferón Tipo I/metabolismo , Ratones Noqueados , Ratones Endogámicos C57BL , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Transducción de Señal , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico
2.
J Chem Educ ; 101(2): 337-343, 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38370575

RESUMEN

Topics associated with the chemical sciences form a significant part of the curriculum in science at the primary school level in the U.K. In this methodology paper, we demonstrate how a wide range of research articles associated with the chemical sciences can be disseminated to an elementary school audience and how children can carry out investigations associated with cutting-edge research in the classroom. We discuss how the Primary Science Teaching Trust's (PSTT's) "I bet you did not know" (IBYDK) articles and their accompanying Teacher Guides benefit children, primary (elementary) school teachers, and other stakeholders including the researchers themselves. We define three types of research articles; ones describing how children can reproduce the research themselves without much adaptation, others where children can mirror the research using similar methods, and some where an analogy can be used to explain the research. We provide exemplars of each type and some preliminary feedback on articles written.

3.
J Clin Immunol ; 44(2): 44, 2024 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-38231408

RESUMEN

Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.


Asunto(s)
Artritis , Síndrome de Behçet , Productos Biológicos , Enfermedades Inflamatorias del Intestino , Masculino , Humanos , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/genética , Artralgia , Proteínas de Unión al ADN , Factores de Transcripción/genética
4.
Stroke Vasc Neurol ; 7(5): 367-374, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35443984

RESUMEN

INTRODUCTION: Current guidelines recommend blood pressure (BP) lowering in patients after acute intracerebral haemorrhage (ICH) without guidance on initial choice of antihypertensive class. This study sought to determine if initial antihypertensive class differentially effects acute BP lowering in a large multiethnic ICH cohort. METHODS: Subjects enrolled in the Ethnic/Racial Variations in ICH study between August 2010 and August 2017 with elevated admission BP and who received labetalol, nicardipine or hydralazine monotherapy as initial antihypertensive were analysed. Primary outcomes were systolic and diastolic BP changes from baseline to first BP measurement after initial antihypertensive treatment. Secondary outcomes included haematoma expansion (HE), hospital length of stay (LOS) and modified Rankin Score (mRS) up to 12 months after ICH. Exploratory outcomes assessed effects of race/ethnicity. Linear and logistic regression analyses, adjusted for relevant covariates, were performed to determine associations of antihypertensive class with outcomes. RESULTS: In total, 1156 cases were used in analyses. Antihypertensive class was associated with diastolic BP change (p=0.003), but not systolic BP change (p=0.419). Initial dosing with nicardipine lowered acute diastolic BP than labetalol (least square mean difference (labetalol-nicardipine)=5.47 (2.37, 8.57), p<0.001). Initial antihypertensive class was also found to be associated with LOS (p=0.028), but not with HE (p=0.406), mortality (p=0.118), discharge disposition (p=0.083) or mRS score at discharge, 3, 6 and 12 months follow-up (p=0.262, 0.276, 0.152 and 0.36, respectively). Race/ethnicity variably affected multivariable models. CONCLUSION: In this large acute ICH cohort, initial antihypertensive class was associated with acute diastolic, but not systolic, BP-lowering suggesting differential effects of antihypertensive agents. TRIAL REGISTRATION NUMBER: NCT01202864.


Asunto(s)
Hipertensión , Labetalol , Humanos , Antihipertensivos/efectos adversos , Presión Sanguínea , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/tratamiento farmacológico , Hidralazina/farmacología , Hipertensión/diagnóstico , Hipertensión/tratamiento farmacológico , Hipertensión/complicaciones , Labetalol/farmacología , Nicardipino/efectos adversos
5.
Nat Immunol ; 22(9): 1118-1126, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34326534

RESUMEN

Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli. In mouse macrophages, Elf4 both sustained the expression of anti-inflammatory genes, such as Il1rn, and limited the upregulation of inflammation amplifiers, including S100A8, Lcn2, Trem1 and neutrophil chemoattractants. Blockade of Trem1 reversed inflammation and intestine pathology after in vivo lipopolysaccharide challenge in mice carrying patient-derived variants in Elf4. Thus, ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD.


Asunto(s)
Proteínas de Unión al ADN/genética , Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades Inflamatorias del Intestino/genética , Macrófagos/inmunología , Factores de Transcripción/genética , Animales , Calgranulina A/metabolismo , Femenino , Regulación de la Expresión Génica/genética , Enfermedades Autoinflamatorias Hereditarias/inmunología , Enfermedades Autoinflamatorias Hereditarias/patología , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Proteína Antagonista del Receptor de Interleucina 1/inmunología , Lipocalina 2/metabolismo , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Th17/inmunología , Transcripción Genética/genética , Receptor Activador Expresado en Células Mieloides 1/antagonistas & inhibidores , Receptor Activador Expresado en Células Mieloides 1/metabolismo
6.
R Soc Open Sci ; 6(11): 191501, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31827872

RESUMEN

Faunal assemblages at hydrothermal vents associated with island-arc volcanism are less well known than those at vents on mid-ocean ridges and back-arc spreading centres. This study characterizes chemosynthetic biotopes at active hydrothermal vents discovered at the Kemp Caldera in the South Sandwich Arc. The caldera hosts sulfur and anhydrite vent chimneys in 1375-1487 m depth, which emit sulfide-rich fluids with temperatures up to 212°C, and the microbial community of water samples in the buoyant plume rising from the vents was dominated by sulfur-oxidizing Gammaproteobacteria. A total of 12 macro- and megafaunal taxa depending on hydrothermal activity were collected in these biotopes, of which seven species were known from the East Scotia Ridge (ESR) vents and three species from vents outside the Southern Ocean. Faunal assemblages were dominated by large vesicomyid clams, actinostolid anemones, Sericosura sea spiders and lepetodrilid and cocculinid limpets, but several taxa abundant at nearby ESR hydrothermal vents were rare such as the stalked barnacle Neolepas scotiaensis. Multivariate analysis of fauna at Kemp Caldera and vents in neighbouring areas indicated that the Kemp Caldera is most similar to vent fields in the previously established Southern Ocean vent biogeographic province, showing that the species composition at island-arc hydrothermal vents can be distinct from nearby seafloor-spreading systems. δ 13C and δ 15N isotope values of megafaunal species analysed from the Kemp Caldera were similar to those of the same or related species at other vent fields, but none of the fauna sampled at Kemp Caldera had δ 13C values, indicating nutritional dependence on Epsilonproteobacteria, unlike fauna at other island-arc hydrothermal vents.

7.
Nat Commun ; 10(1): 4364, 2019 09 25.
Artículo en Inglés | MEDLINE | ID: mdl-31554793

RESUMEN

Phosphatidylinositol 3-kinase-gamma (PI3Kγ) is highly expressed in leukocytes and is an attractive drug target for immune modulation. Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3Kγ. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ. She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic pneumonitis and colitis, with reduced peripheral blood memory B, memory CD8+ T, and regulatory T cells and increased CXCR3+ tissue-homing CD4 T cells. PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3α/ß-dependent manner upon TLR stimulation. Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice. Together, our results emphasize the physiological importance of PI3Kγ in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice.


Asunto(s)
Inmunidad Adaptativa/inmunología , Fosfatidilinositol 3-Quinasa Clase Ib/inmunología , Síndromes de Inmunodeficiencia/inmunología , Inflamación/inmunología , Microbiota/inmunología , Inmunidad Adaptativa/genética , Animales , Células Cultivadas , Fosfatidilinositol 3-Quinasa Clase Ib/deficiencia , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Modelos Animales de Enfermedad , Femenino , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/metabolismo , Inflamación/genética , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
8.
PLoS One ; 14(12): e0218904, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31891586

RESUMEN

Video and image data are regularly used in the field of benthic ecology to document biodiversity. However, their use is subject to a number of challenges, principally the identification of taxa within the images without associated physical specimens. The challenge of applying traditional taxonomic keys to the identification of fauna from images has led to the development of personal, group, or institution level reference image catalogues of operational taxonomic units (OTUs) or morphospecies. Lack of standardisation among these reference catalogues has led to problems with observer bias and the inability to combine datasets across studies. In addition, lack of a common reference standard is stifling efforts in the application of artificial intelligence to taxon identification. Using the North Atlantic deep sea as a case study, we propose a database structure to facilitate standardisation of morphospecies image catalogues between research groups and support future use in multiple front-end applications. We also propose a framework for coordination of international efforts to develop reference guides for the identification of marine species from images. The proposed structure maps to the Darwin Core standard to allow integration with existing databases. We suggest a management framework where high-level taxonomic groups are curated by a regional team, consisting of both end users and taxonomic experts. We identify a mechanism by which overall quality of data within a common reference guide could be raised over the next decade. Finally, we discuss the role of a common reference standard in advancing marine ecology and supporting sustainable use of this ecosystem.


Asunto(s)
Clasificación/métodos , Procesamiento de Imagen Asistido por Computador/normas , Biología Marina/normas , Animales , Inteligencia Artificial , Biodiversidad , Curaduría de Datos/métodos , Curaduría de Datos/normas , Bases de Datos Factuales , Ecología , Ecosistema , Procesamiento de Imagen Asistido por Computador/métodos , Biología Marina/clasificación
9.
Cancer Immunol Res ; 6(12): 1524-1536, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30352798

RESUMEN

T-cell priming occurs when a naïve T cell recognizes cognate peptide-MHC complexes on an activated antigen-presenting cell. The circumstances of this initial priming have ramifications on the fate of the newly primed T cell. Newly primed CD8+ T cells can embark onto different trajectories, with some becoming short-lived effector cells and others adopting a tissue resident or memory cell fate. To determine whether T-cell priming influences the quality of the effector T-cell response to tumors, we used transnuclear CD8+ T cells that recognize the melanoma antigen TRP1 using TRP1high or TRP1low TCRs that differ in both affinity and fine specificity. From a series of altered peptide ligands, we identified a point mutation (K8) in a nonanchor residue that, when analyzed crystallographically and biophysically, destabilized the peptide interaction with the MHC binding groove. In vitro, the K8 peptide induced robust proliferation of both TRP1high and TRP1low CD8+ T cells but did not induce expression of PD-1. Cytokine production from K8-stimulated TRP1 cells was minimal, whereas cytotoxicity was increased. Upon transfer into B16 tumor-bearing mice, the reference peptide (TRP1-M9)- and K8-stimulated TRP1 cells were equally effective at controlling tumor growth but accomplished this through different mechanisms. TRP1-M9-stimulated cells produced more IFNγ, whereas K8-stimulated cells accumulated to higher numbers and were more cytotoxic. We, therefore, conclude that TCR recognition of weakly binding peptides during priming can skew the effector function of tumor-specific CD8+ T cells.


Asunto(s)
Antígenos de Neoplasias/metabolismo , Linfocitos T CD8-positivos/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Melanoma Experimental/inmunología , Animales , Linfocitos T CD8-positivos/metabolismo , Melanoma Experimental/patología , Ratones Endogámicos C57BL , Ratones Transgénicos , Oligopéptidos/química , Oligopéptidos/genética , Oligopéptidos/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo
10.
Cancer Immunol Res ; 6(4): 389-401, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29459478

RESUMEN

Cytokine-based therapies for cancer have not achieved widespread clinical success because of inherent toxicities. Treatment for pancreatic cancer is limited by the dense stroma that surrounds tumors and by an immunosuppressive tumor microenvironment. To overcome these barriers, we developed constructs of single-domain antibodies (VHHs) against PD-L1 fused with IL-2 and IFNγ. Targeting cytokine delivery in this manner reduced pancreatic tumor burden by 50%, whereas cytokines fused to an irrelevant VHH, or blockade of PD-L1 alone, showed little effect. Targeted delivery of IL-2 increased the number of intratumoral CD8+ T cells, whereas IFNγ reduced the number of CD11b+ cells and skewed intratumoral macrophages toward the display of M1-like characteristics. Imaging of fluorescent VHH-IFNγ constructs, as well as transcriptional profiling, demonstrated targeting of IFNγ to the tumor microenvironment. Many tumors and tumor-infiltrating myeloid cells express PD-L1, rendering them potentially susceptible to this form of targeted immunotherapy. Cancer Immunol Res; 6(4); 389-401. ©2018 AACR.


Asunto(s)
Antígeno B7-H1/metabolismo , Citocinas/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Anticuerpos de Dominio Único/farmacología , Microambiente Tumoral , Animales , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citocinas/antagonistas & inhibidores , Citocinas/genética , Modelos Animales de Enfermedad , Humanos , Melanoma Experimental , Ratones , Terapia Molecular Dirigida , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Anticuerpos de Dominio Único/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología
11.
J Immunol ; 199(1): 159-171, 2017 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-28576977

RESUMEN

Invariant NKT (iNKT) cell functional subsets are defined by key transcription factors and output of cytokines, such as IL-4, IFN-γ, IL-17, and IL-10. To examine how TCR specificity determines iNKT function, we used somatic cell nuclear transfer to generate three lines of mice cloned from iNKT nuclei. Each line uses the invariant Vα14Jα18 TCRα paired with unique Vß7 or Vß8.2 subunits. We examined tissue homing, expression of PLZF, T-bet, and RORγt, and cytokine profiles and found that, although monoclonal iNKT cells differentiated into all functional subsets, the NKT17 lineage was reduced or expanded depending on the TCR expressed. We examined iNKT thymic development in limited-dilution bone marrow chimeras and show that higher TCR avidity correlates with higher PLZF and reduced T-bet expression. iNKT functional subsets showed distinct tissue distribution patterns. Although each individual monoclonal TCR showed an inherent subset distribution preference that was evident across all tissues examined, the iNKT cytokine profile differed more by tissue of origin than by TCR specificity.


Asunto(s)
Diferenciación Celular , Células T Asesinas Naturales/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Subgrupos de Linfocitos T/inmunología , Animales , Linfocitos B/inmunología , Linfocitos B/fisiología , Citocinas/genética , Citocinas/inmunología , Citotoxicidad Inmunológica/inmunología , Interleucina-10/inmunología , Interleucina-10/metabolismo , Interleucina-17/inmunología , Interleucina-17/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Ratones , Ratones Endogámicos C57BL , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Técnicas de Transferencia Nuclear , Especificidad de Órganos , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo
12.
PLoS One ; 12(5): e0177825, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28542616

RESUMEN

The CrbS/R two-component signal transduction system is a conserved regulatory mechanism through which specific Gram-negative bacteria control acetate flux into primary metabolic pathways. CrbS/R governs expression of acetyl-CoA synthase (acsA), an enzyme that converts acetate to acetyl-CoA, a metabolite at the nexus of the cell's most important energy-harvesting and biosynthetic reactions. During infection, bacteria can utilize this system to hijack host acetate metabolism and alter the course of colonization and pathogenesis. In toxigenic strains of Vibrio cholerae, CrbS/R-dependent expression of acsA is required for virulence in an arthropod model. Here, we investigate the function of the CrbS/R system in Pseudomonas aeruginosa, Pseudomonas entomophila, and non-toxigenic V. cholerae strains. We demonstrate that its role in acetate metabolism is conserved; this system regulates expression of the acsA gene and is required for growth on acetate as a sole carbon source. As a first step towards describing the mechanism of signaling through this pathway, we identify residues and domains that may be critical for phosphotransfer. We further demonstrate that although CrbS, the putative hybrid sensor kinase, carries both a histidine kinase domain and a receiver domain, the latter is not required for acsA transcription. In order to determine whether our findings are relevant to pathogenesis, we tested our strains in a Drosophila model of oral infection previously employed for the study of acetate-dependent virulence by V. cholerae. We show that non-toxigenic V. cholerae strains lacking CrbS or CrbR are significantly less virulent than are wild-type strains, while P. aeruginosa and P. entomophila lacking CrbS or CrbR are fully pathogenic. Together, the data suggest that the CrbS/R system plays a central role in acetate metabolism in V. cholerae, P. aeruginosa, and P. entomophila. However, each microbe's unique environmental adaptations and pathogenesis strategies may dictate conditions under which CrbS/R-mediated acs expression is most critical.


Asunto(s)
Acetato CoA Ligasa/genética , Proteínas Bacterianas/metabolismo , Ambiente , Variación Genética , Transcripción Genética , Acetatos/metabolismo , Animales , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Secuencia Conservada , Regulación Bacteriana de la Expresión Génica , Proteínas Hemolisinas/metabolismo , Dominios Proteicos , Pseudomonas aeruginosa/citología , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/patogenicidad , Eliminación de Secuencia , Homología de Secuencia de Ácido Nucleico , Transducción de Señal , Vibrio cholerae/citología , Vibrio cholerae/genética , Vibrio cholerae/metabolismo , Vibrio cholerae/patogenicidad , Virulencia
13.
Mol Cancer Ther ; 16(3): 428-439, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28148714

RESUMEN

Selinexor (KPT-330) is a first-in-class nuclear transport inhibitor currently in clinical trials as an anticancer agent. To determine how selinexor might affect antitumor immunity, we analyzed immune homeostasis in mice treated with selinexor and found disruptions in T-cell development, a progressive loss of CD8 T cells, and increases in inflammatory monocytes. Antibody production in response to immunization was mostly normal. Precursor populations in bone marrow and thymus were unaffected by selinexor, suggesting that normal immune homeostasis could recover. We found that a high dose of selinexor given once per week preserved nearly normal immune functioning, whereas a lower dose given 3 times per week did not restore immune homeostasis. Both naïve and effector CD8 T cells cultured in vitro showed impaired activation in the presence of selinexor. These experiments suggest that nuclear exportins are required for T-cell development and function. We determined the minimum concentration of selinexor required to block T-cell activation and showed that T-cell-inhibitory effects of selinexor occur at levels above 100 nmol/L, corresponding to the first 24 hours post-oral dosing. In a model of implantable melanoma, selinexor treatment at 10 mg/kg with a 4-day drug holiday led to intratumoral IFNγ+, granzyme B+ cytotoxic CD8 T cells that were comparable with vehicle-treated mice. Overall, selinexor treatment leads to transient inhibition of T-cell activation, but clinically relevant once and twice weekly dosing schedules that incorporate sufficient drug holidays allow for normal CD8 T-cell functioning and development of antitumor immunity. Mol Cancer Ther; 16(3); 428-39. ©2017 AACRSee related article by Farren et al., p. 417.


Asunto(s)
Antineoplásicos/administración & dosificación , Homeostasis/efectos de los fármacos , Homeostasis/inmunología , Hidrazinas/administración & dosificación , Inmunidad/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Triazoles/administración & dosificación , Animales , Formación de Anticuerpos/efectos de los fármacos , Formación de Anticuerpos/inmunología , Biomarcadores , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunomodulación/efectos de los fármacos , Inmunoterapia , Melanoma Experimental , Ratones , Ratones Noqueados , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Linfocitos T/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
14.
J Anim Ecol ; 84(4): 898-913, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25732205

RESUMEN

Few species of reptant decapod crustaceans thrive in the cold-stenothermal waters of the Southern Ocean. However, abundant populations of a new species of anomuran crab, Kiwa tyleri, occur at hydrothermal vent fields on the East Scotia Ridge. As a result of local thermal conditions at the vents, these crabs are not restricted by the physiological limits that otherwise exclude reptant decapods south of the polar front. We reveal the adult life history of this species by piecing together variation in microdistribution, body size frequency, sex ratio, and ovarian and embryonic development, which indicates a pattern in the distribution of female Kiwaidae in relation to their reproductive development. High-density 'Kiwa' assemblages observed in close proximity to sources of vent fluids are constrained by the thermal limit of elevated temperatures and the availability of resources for chemosynthetic nutrition. Although adult Kiwaidae depend on epibiotic chemosynthetic bacteria for nutrition, females move offsite after extrusion of their eggs to protect brooding embryos from the chemically harsh, thermally fluctuating vent environment. Consequently, brooding females in the periphery of the vent field are in turn restricted by low-temperature physiological boundaries of the deep-water Southern Ocean environment. Females have a high reproductive investment in few, large, yolky eggs, facilitating full lecithotrophy, with the release of larvae prolonged, and asynchronous. After embryos are released, larvae are reliant on locating isolated active areas of hydrothermal flow in order to settle and survive as chemosynthetic adults. Where the cold water restricts the ability of all adult stages to migrate over long distances, these low temperatures may facilitate the larvae in the location of vent sites by extending the larval development period through hypometabolism. These differential life-history adaptations to contrasting thermal environments lead to a disjunct life history among males and females of K. tyleri, which is key to their success in the Southern Ocean vent environment. We highlight the complexity in understanding the importance of life-history biology, in combination with environmental, ecological and physiological factors contributing to the overall global distribution of vent-endemic species.


Asunto(s)
Decápodos/fisiología , Respiraderos Hidrotermales , Temperatura , Adaptación Fisiológica , Animales , Decápodos/embriología , Decápodos/crecimiento & desarrollo , Embrión no Mamífero/fisiología , Femenino , Larva/fisiología , Estadios del Ciclo de Vida/fisiología , Masculino , Reproducción/fisiología
15.
Trends Ecol Evol ; 29(8): 465-75, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25001598

RESUMEN

Deep-sea ecosystems represent Earth's major ecological research frontier. Focusing on seafloor ecosystems, we demonstrate how new technologies underpin discoveries that challenge major ecological hypotheses and paradigms, illuminating new deep-sea geosphere-biosphere interactions. We now recognize greater habitat complexity, new ecological interactions and the importance of 'dark energy', and chemosynthetic production in fuelling biodiversity. We also acknowledge functional hotspots that contradict a food-poor, metabolically inactive, and minor component of global carbon cycles. Symbioses appear widespread, revealing novel adaptations. Populations show complex spatial structure and evolutionary histories. These new findings redefine deep-sea ecology and the role of Earth's largest biome in global biosphere functioning. Indeed, deep-sea exploration can open new perspectives in ecological research to help mitigate exploitation impacts.


Asunto(s)
Organismos Acuáticos/fisiología , Ecosistema , Biología Marina , Animales , Biodiversidad , Simbiosis/fisiología
16.
PLoS One ; 9(4): e95839, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24788771

RESUMEN

Anthropogenic litter is present in all marine habitats, from beaches to the most remote points in the oceans. On the seafloor, marine litter, particularly plastic, can accumulate in high densities with deleterious consequences for its inhabitants. Yet, because of the high cost involved with sampling the seafloor, no large-scale assessment of distribution patterns was available to date. Here, we present data on litter distribution and density collected during 588 video and trawl surveys across 32 sites in European waters. We found litter to be present in the deepest areas and at locations as remote from land as the Charlie-Gibbs Fracture Zone across the Mid-Atlantic Ridge. The highest litter density occurs in submarine canyons, whilst the lowest density can be found on continental shelves and on ocean ridges. Plastic was the most prevalent litter item found on the seafloor. Litter from fishing activities (derelict fishing lines and nets) was particularly common on seamounts, banks, mounds and ocean ridges. Our results highlight the extent of the problem and the need for action to prevent increasing accumulation of litter in marine environments.


Asunto(s)
Agua de Mar , Contaminantes del Agua , Europa (Continente)
17.
Oecologia ; 174(1): 45-54, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24036933

RESUMEN

Metabolic rate is a key component of energy budgets that scales with body size and varies with large-scale environmental geographical patterns. Here we conduct an analysis of standard metabolic rates (SMR) of marine ectotherms across a 70° latitudinal gradient in both hemispheres that spanned collection temperatures of 0-30 °C. To account for latitudinal differences in the size and skeletal composition between species, SMR was mass normalized to that of a standard-sized (223 mg) ash-free dry mass individual. SMR was measured for 17 species of calcified invertebrates (bivalves, gastropods, urchins and brachiopods), using a single consistent methodology, including 11 species whose SMR was described for the first time. SMR of 15 out of 17 species had a mass-scaling exponent between 2/3 and 1, with no greater support for a 3/4 rather than a 2/3 scaling exponent. After accounting for taxonomy and variability in parameter estimates among species using variance-weighted linear mixed effects modelling, temperature sensitivity of SMR had an activation energy (Ea) of 0.16 for both Northern and Southern Hemisphere species which was lower than predicted under the metabolic theory of ecology (Ea 0.2-1.2 eV). Northern Hemisphere species, however, had a higher SMR at each habitat temperature, but a lower mass-scaling exponent relative to SMR. Evolutionary trade-offs that may be driving differences in metabolic rate (such as metabolic cold adaptation of Northern Hemisphere species) will have important impacts on species abilities to respond to changing environments.


Asunto(s)
Adaptación Fisiológica , Metabolismo Energético , Invertebrados/metabolismo , Temperatura , Animales , Evolución Biológica , Tamaño Corporal , Ecosistema , Modelos Lineales
18.
Mol Phylogenet Evol ; 69(3): 610-8, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23906600

RESUMEN

Molecular methods have been used for the first time to determine the phylogeny of families, genera and species within the Pennatulacea (sea pens). Variation in ND2 and mtMutS mitochondrial protein-coding genes proved adequate to resolve phylogenetic relationships among pennatulacean families. The gene mtMutS is more variable than ND2 and differentiates all genera, and many pennatulacean species. A molecular phylogeny based on a Bayesian analysis reveals that suborder Sessiliflorae is paraphyletic and Subselliflorae is polyphyletic. Many families of pennatulaceans do not represent monophyletic groups including Umbellulidae, Pteroeididae, and Kophobelemnidae. The high frequency of morphological homoplasy in pennatulaceans has led to many misinterpretations in the systematics of the group. The traditional classification scheme for pennatulaceans requires revision.


Asunto(s)
Antozoos/clasificación , Evolución Molecular , Filogenia , Animales , Antozoos/genética , Teorema de Bayes , Genes Mitocondriales , Proteínas Mitocondriales/genética , Análisis de Secuencia de ADN
19.
PLoS One ; 8(3): e60319, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23555955

RESUMEN

The dynamics and microdistribution of faunal assemblages at hydrothermal vents often reflect the fine-scale spatial and temporal heterogeneity of the vent environment. This study examined the reproductive development and population structure of the caridean shrimp Rimicaris hybisae at the Beebe and Von Damm Vent Fields (Mid-Cayman Spreading Centre, Caribbean) using spatially discrete samples collected in January 2012. Rimicaris hybisae is gonochoric and exhibits iteroparous reproduction. Oocyte size-frequency distributions (21-823 µm feret diameters) varied significantly among samples. Embryo development was asynchronous among females, which may result in asynchronous larval release for the populations. Specimens of R. hybisae from the Von Damm Vent Field (2294 m) were significantly larger than specimens from the Beebe Vent Field. Brooding females at Von Damm exhibited greater size-specific fecundity, possibly as a consequence of a non-linear relationship between fecundity and body size that was consistent across both vent fields. Samples collected from several locations at the Beebe Vent Field (4944-4972 m) revealed spatial variability in the sex ratios, population structure, size, and development of oocytes and embryos of this mobile species. Samples from the Von Damm Vent Field and sample J2-613-24 from Beebe Woods exhibited the highest frequencies of ovigerous females and significantly female-biased sex ratios. Environmental variables within shrimp aggregations may influence the distribution of ovigerous females, resulting in a spatially heterogeneous pattern of reproductive development in R. hybisae, as found in other vent taxa.


Asunto(s)
Decápodos/fisiología , Animales , Decápodos/embriología , Embrión no Mamífero/embriología , Embrión no Mamífero/fisiología , Femenino , Larva/fisiología , Masculino , Dinámica Poblacional , Reproducción
20.
PLoS One ; 8(1): e54686, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23359806

RESUMEN

In the austral summer of 2011 we undertook an investigation of three volcanic highs in the Central Bransfield Basin, Antarctica, in search of hydrothermal activity and associated fauna to assess changes since previous surveys and to evaluate the extent of hydrothermalism in this basin. At Hook Ridge, a submarine volcanic edifice at the eastern end of the basin, anomalies in water column redox potential (E(h)) were detected close to the seafloor, unaccompanied by temperature or turbidity anomalies, indicating low-temperature hydrothermal discharge. Seepage was manifested as shimmering water emanating from the sediment and from mineralised structures on the seafloor; recognisable vent endemic fauna were not observed. Pore fluids extracted from Hook Ridge sediment were depleted in chloride, sulfate and magnesium by up to 8% relative to seawater, enriched in lithium, boron and calcium, and had a distinct strontium isotope composition ((87)Sr/(86)Sr = 0.708776 at core base) compared with modern seawater ((87)Sr/(86)Sr ≈ 0.70918), indicating advection of hydrothermal fluid through sediment at this site. Biogeochemical zonation of redox active species implies significant moderation of the hydrothermal fluid with in situ diagenetic processes. At Middle Sister, the central ridge of the Three Sisters complex located about 100 km southwest of Hook Ridge, small water column E(h) anomalies were detected but visual observations of the seafloor and pore fluid profiles provided no evidence of active hydrothermal circulation. At The Axe, located about 50 km southwest of Three Sisters, no water column anomalies in E(h), temperature or turbidity were detected. These observations demonstrate that the temperature anomalies observed in previous surveys are episodic features, and suggest that hydrothermal circulation in the Bransfield Strait is ephemeral in nature and therefore may not support vent biota.


Asunto(s)
Sedimentos Geológicos , Respiraderos Hidrotermales , Regiones Antárticas , Modelos Teóricos , Oxidación-Reducción
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