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1.
Nat Immunol ; 24(6): 1007-1019, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37069398

RESUMEN

Adoptive transfer of genetically engineered chimeric antigen receptor (CAR) T cells is becoming a promising treatment option for hematological malignancies. However, T cell immunotherapies have mostly failed in individuals with solid tumors. Here, with a CRISPR-Cas9 pooled library, we performed an in vivo targeted loss-of-function screen and identified ST3 ß-galactoside α-2,3-sialyltransferase 1 (ST3GAL1) as a negative regulator of the cancer-specific migration of CAR T cells. Analysis of glycosylated proteins revealed that CD18 is a major effector of ST3GAL1 in activated CD8+ T cells. ST3GAL1-mediated glycosylation induces the spontaneous nonspecific tissue sequestration of T cells by altering lymphocyte function-associated antigen-1 (LFA-1) endocytic recycling. Engineered CAR T cells with enhanced expression of ßII-spectrin, a central LFA-1-associated cytoskeleton molecule, reversed ST3GAL1-mediated nonspecific T cell migration and reduced tumor growth in mice by improving tumor-specific homing of CAR T cells. These findings identify the ST3GAL1-ßII-spectrin axis as a major cell-intrinsic program for cancer-targeting CAR T cell migration and as a promising strategy for effective T cell immunotherapy.


Asunto(s)
Receptores Quiméricos de Antígenos , Animales , Ratones , Linfocitos T CD8-positivos , Línea Celular Tumoral , Movimiento Celular , Inmunoterapia Adoptiva , Antígeno-1 Asociado a Función de Linfocito , Espectrina , Humanos , Femenino
2.
Nat Immunol ; 21(9): 1046-1057, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32747818

RESUMEN

Early recruitment of neutrophils from the blood to sites of tissue infection is a hallmark of innate immune responses. However, little is known about the mechanisms by which apoptotic neutrophils are cleared in infected tissues during resolution and the immunological consequences of in situ efferocytosis. Using intravital multiphoton microscopy, we show previously unrecognized motility patterns of interactions between neutrophils and tissue-resident phagocytes within the influenza-infected mouse airway. Newly infiltrated inflammatory monocytes become a chief pool of phagocytes and play a key role in the clearance of highly motile apoptotic neutrophils during the resolution phase. Apoptotic neutrophils further release epidermal growth factor and promote the differentiation of monocytes into tissue-resident antigen-presenting cells for activation of antiviral T cell effector functions. Collectively, these results suggest that the presence of in situ neutrophil resolution at the infected tissue is critical for optimal CD8+ T cell-mediated immune protection.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Virus de la Influenza A/fisiología , Gripe Humana/inmunología , Neutrófilos/inmunología , Infecciones por Orthomyxoviridae/inmunología , Fagocitos/inmunología , Receptores CCR2/metabolismo , Animales , Presentación de Antígeno , Apoptosis , Movimiento Celular , Células Cultivadas , Humanos , Inmunidad Innata , Microscopía Intravital , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía de Fluorescencia por Excitación Multifotónica , Receptores CCR2/genética
3.
Nat Immunol ; 20(2): 141-151, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30643265

RESUMEN

Rheumatoid arthritis is characterized by progressive joint inflammation and affects ~1% of the human population. We noted single-nucleotide polymorphisms (SNPs) in the apoptotic cell-engulfment genes ELMO1, DOCK2, and RAC1 linked to rheumatoid arthritis. As ELMO1 promotes cytoskeletal reorganization during engulfment, we hypothesized that ELMO1 loss would worsen inflammatory arthritis. Surprisingly, Elmo1-deficient mice showed reduced joint inflammation in acute and chronic arthritis models. Genetic and cell-biology studies revealed that ELMO1 associates with receptors linked to neutrophil function in arthritis and regulates activation and early neutrophil recruitment to the joints, without general inhibition of inflammatory responses. Further, neutrophils from the peripheral blood of human donors that carry the SNP in ELMO1 associated with arthritis display increased migratory capacity, whereas ELMO1 knockdown reduces human neutrophil migration to chemokines linked to arthritis. These data identify 'noncanonical' roles for ELMO1 as an important cytoplasmic regulator of specific neutrophil receptors and promoter of arthritis.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/inmunología , Artritis Experimental/inmunología , Artritis Reumatoide/inmunología , Neutrófilos/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Apoptosis/inmunología , Artritis Experimental/diagnóstico , Artritis Experimental/genética , Artritis Experimental/patología , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/genética , Artritis Reumatoide/patología , Quimiotaxis/genética , Quimiotaxis/inmunología , Colágeno/inmunología , Complemento C5a/inmunología , Complemento C5a/metabolismo , Citoplasma/inmunología , Citoplasma/metabolismo , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Voluntarios Sanos , Humanos , Microscopía Intravital , Articulaciones/citología , Articulaciones/inmunología , Leucotrieno B4/inmunología , Leucotrieno B4/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/metabolismo , Polimorfismo de Nucleótido Simple , Proteómica , Índice de Severidad de la Enfermedad , Transducción de Señal/inmunología , Imagen de Lapso de Tiempo
4.
Nature ; 628(8009): 741-745, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38658686

RESUMEN

Extensive efforts have been undertaken to combine superconductivity and the quantum Hall effect so that Cooper-pair transport between superconducting electrodes in Josephson junctions is mediated by one-dimensional edge states1-6. This interest has been motivated by prospects of finding new physics, including topologically protected quasiparticles7-9, but also extends into metrology and device applications10-13. So far it has proven challenging to achieve detectable supercurrents through quantum Hall conductors2,3,6. Here we show that domain walls in minimally twisted bilayer graphene14-18 support exceptionally robust proximity superconductivity in the quantum Hall regime, allowing Josephson junctions to operate in fields close to the upper critical field of superconducting electrodes. The critical current is found to be non-oscillatory and practically unchanging over the entire range of quantizing fields, with its value being limited by the quantum conductance of ballistic, strictly one-dimensional, electronic channels residing within the domain walls. The system described is unique in its ability to support Andreev bound states at quantizing fields and offers many interesting directions for further exploration.

5.
Immunity ; 51(2): 298-309.e6, 2019 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-31399281

RESUMEN

T-helper (Th) cell differentiation drives specialized gene programs that dictate effector T cell function at sites of infection. Here, we have shown Th cell differentiation also imposes discrete motility gene programs that shape Th1 and Th2 cell navigation of the inflamed dermis. Th1 cells scanned a smaller tissue area in a G protein-coupled receptor (GPCR) and chemokine-dependent fashion, while Th2 cells scanned a larger tissue area independent of GPCR signals. Differential chemokine reliance for interstitial migration was linked to STAT6 transcription-factor-dependent programming of integrin αVß3 expression: Th2 cell differentiation led to high αVß3 expression relative to Th1 cells. Th1 and Th2 cell modes of motility could be switched simply by manipulating the amount of αVß3 on the cell surface. Deviating motility modes from those established during differentiation impaired effector function. Thus, programmed expression of αVß3 tunes effector T cell reliance on environmental cues for optimal exploration of inflamed tissues.


Asunto(s)
Inflamación/inmunología , Células TH1/inmunología , Células Th2/inmunología , Traslado Adoptivo , Animales , Diferenciación Celular , Movimiento Celular , Células Cultivadas , Técnicas de Reprogramación Celular , Quimiocinas/metabolismo , Humanos , Integrina alfaVbeta3/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción STAT6/metabolismo
6.
Nature ; 604(7906): 502-508, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35396580

RESUMEN

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.


Asunto(s)
Estudio de Asociación del Genoma Completo , Esquizofrenia , Alelos , Predisposición Genética a la Enfermedad/genética , Genómica , Humanos , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/genética
7.
Proc Natl Acad Sci U S A ; 121(35): e2406748121, 2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39178229

RESUMEN

Chronic inflammatory milieu in the tumor microenvironment (TME) leads to the recruitment and differentiation of myeloid-derived suppressor cells (MDSCs). Polymorphonuclear (PMN)-MDSCs, which are phenotypically and morphologically defined as a subset of neutrophils, cause major immune suppression in the TME, posing a significant challenge in the development of effective immunotherapies. Despite recent advances in our understanding of PMN-MDSC functions, the mechanism that gives rise to immunosuppressive neutrophils within the TME remains elusive. Both in vivo and in vitro, newly recruited neutrophils into the tumor sites remained activated and highly motile for several days and developed immunosuppressive phenotypes, as indicated by increased arginase 1 (Arg1) and dcTrail-R1 expression and suppressed anticancer CD8 T cell cytotoxicity. The strong suppressive function was successfully recapitulated by incubating naive neutrophils with cancer cell culture supernatant in vitro. Cancer metabolite secretome analyses of the culture supernatant revealed that both murine and human cancers released lipid mediators to induce the differentiation of immunosuppressive neutrophils. Liquid chromatography-mass spectrometry (LC-MS) lipidomic analysis identified platelet-activation factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) as a common tumor-derived lipid mediator that induces neutrophil differentiation. Lysophosphatidylcholine acyltransferase 2 (LPCAT2), the PAF biosynthetic enzyme, is up-regulated in human pancreatic ductal adenocarcinoma (PDAC) and shows an unfavorable correlation with patient survival across multiple cancer types. Our study identifies PAF as a lipid-driven mechanism of MDSC differentiation in the TME, providing a potential target for cancer immunotherapy.


Asunto(s)
Diferenciación Celular , Células Supresoras de Origen Mieloide , Neutrófilos , Factor de Activación Plaquetaria , Microambiente Tumoral , Neutrófilos/inmunología , Neutrófilos/metabolismo , Humanos , Animales , Ratones , Microambiente Tumoral/inmunología , Factor de Activación Plaquetaria/metabolismo , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Línea Celular Tumoral , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ratones Endogámicos C57BL
8.
Proc Natl Acad Sci U S A ; 121(42): e2414768121, 2024 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-39388263

RESUMEN

The cotranslational misfolding of the cystic fibrosis transmembrane conductance regulator chloride channel (CFTR) plays a central role in the molecular basis of CF. The misfolding of the most common CF variant (ΔF508) remodels both the translational regulation and quality control of CFTR. Nevertheless, it is unclear how the misassembly of the nascent polypeptide may directly influence the activity of the translation machinery. In this work, we identify a structural motif within the CFTR transcript that stimulates efficient -1 ribosomal frameshifting and triggers the premature termination of translation. Though this motif does not appear to impact the interactome of wild-type CFTR, silent mutations that disrupt this RNA structure alter the association of nascent ΔF508 CFTR with numerous translation and quality control proteins. Moreover, disrupting this RNA structure enhances the functional gating of the ΔF508 CFTR channel at the plasma membrane and its pharmacological rescue by the CFTR modulators contained in the CF drug Trikafta. The effects of the RNA structure on ΔF508 CFTR appear to be attenuated in the absence of the ER membrane protein complex, which was previously found to modulate ribosome collisions during "preemptive quality control" of a misfolded CFTR homolog. Together, our results reveal that ribosomal frameshifting selectively modulates the assembly, function, and pharmacological rescue of a misfolded CFTR variant. These findings suggest that interactions between the nascent chain, quality control machinery, and ribosome may dynamically modulate ribosomal frameshifting in order to tune the processivity of translation in response to cotranslational misfolding.


Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística , Sistema de Lectura Ribosómico , Pliegue de Proteína , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Sistema de Lectura Ribosómico/genética , Humanos , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Fibrosis Quística/tratamiento farmacológico , Biosíntesis de Proteínas , Ribosomas/metabolismo , Conformación de Ácido Nucleico , Mutación
9.
Plant Cell ; 35(2): 924-941, 2023 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-36472129

RESUMEN

Heat shock protein 101 (HSP101) in plants, and bacterial and yeast orthologs, is essential for thermotolerance. To investigate thermotolerance mechanisms involving HSP101, we performed a suppressor screen in Arabidopsis thaliana of a missense HSP101 allele (hot1-4). hot1-4 plants are sensitive to acclimation heat treatments that are otherwise permissive for HSP101 null mutants, indicating that the hot1-4 protein is toxic. We report one suppressor (shot2, suppressor of hot1-4 2) has a missense mutation of a conserved residue in CLEAVAGE STIMULATION FACTOR77 (CstF77), a subunit of the polyadenylation complex critical for mRNA 3' end maturation. We performed ribosomal RNA depletion RNA-Seq and captured transcriptional readthrough with a custom bioinformatics pipeline. Acclimation heat treatment caused transcriptional readthrough in hot1-4 shot2, with more readthrough in heat-induced genes, reducing the levels of toxic hot1-4 protein and suppressing hot1-4 heat sensitivity. Although shot2 mutants develop like the wild type in the absence of stress and survive mild heat stress, reduction of heat-induced genes and decreased HSP accumulation makes shot2 in HSP101 null and wild-type backgrounds sensitive to severe heat stress. Our study reveals the critical function of CstF77 for 3' end formation of mRNA and the dominant role of HSP101 in dictating the outcome of severe heat stress.


Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Poliadenilación/genética , Calor , Respuesta al Choque Térmico/genética , Mutación/genética , Arabidopsis/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Factor de Estimulación del Desdoblamiento/genética , Factor de Estimulación del Desdoblamiento/metabolismo
10.
Circ Res ; 134(8): 970-986, 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38456277

RESUMEN

BACKGROUND: While platelets have well-studied hemostatic functions, platelets are immune cells that circulate at the interface between the vascular wall and white blood cells. The physiological implications of these constant transient interactions are poorly understood. Activated platelets induce and amplify immune responses, but platelets may also maintain immune homeostasis in healthy conditions, including maintaining vascular integrity and T helper cell differentiation, meaning that platelets are central to both immune responses and immune quiescence. Clinical data have shown an association between low platelet counts (thrombocytopenia) and immune dysfunction in patients with sepsis and extracorporeal membrane oxygenation, further implicating platelets as more holistic immune regulators, but studies of platelet immune functions in nondisease contexts have had limited study. METHODS: We used in vivo models of thrombocytopenia and in vitro models of platelet and monocyte interactions, as well as RNA-seq and ATAC-seq (assay for transposase-accessible chromatin with sequencing), to mechanistically determine how resting platelet and monocyte interactions immune program monocytes. RESULTS: Circulating platelets and monocytes interact in a CD47-dependent manner to regulate monocyte metabolism, histone methylation, and gene expression. Resting platelet-monocyte interactions limit TLR (toll-like receptor) signaling responses in healthy conditions in an innate immune training-like manner. In both human patients with sepsis and mouse sepsis models, thrombocytopenia exacerbated monocyte immune dysfunction, including increased cytokine production. CONCLUSIONS: Thrombocytopenia immune programs monocytes in a manner that may lead to immune dysfunction in the context of sepsis. This is the first demonstration that sterile, endogenous cell interactions between resting platelets and monocytes regulate monocyte metabolism and pathogen responses, demonstrating platelets to be immune rheostats in both health and disease.


Asunto(s)
Sepsis , Trombocitopenia , Ratones , Animales , Humanos , Monocitos/metabolismo , Trombocitopenia/metabolismo , Plaquetas/metabolismo , Inmunidad , Sepsis/metabolismo , Activación Plaquetaria
11.
EMBO Rep ; 2024 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-39415049

RESUMEN

Tumor-associated macrophages (TAMs) are prime therapeutic targets due to their pro-tumorigenic functions, but varying efficacy of macrophage-targeting therapies highlights our incomplete understanding of how macrophages are regulated within the tumor microenvironment (TME). The circadian clock is a key regulator of macrophage function, but how circadian rhythms of macrophages are influenced by the TME remains unknown. Here, we show that conditions associated with the TME such as polarizing stimuli, acidic pH, and lactate can alter circadian rhythms in macrophages. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate pH-driven changes in circadian rhythms are not mediated solely by cAMP signaling. Remarkably, circadian disorder of TAMs was revealed by clock correlation distance analysis. Our data suggest that heterogeneity in circadian rhythms within the TAM population level may underlie this circadian disorder. Finally, we report that circadian regulation of macrophages suppresses tumor growth in a murine model of pancreatic cancer. Our work demonstrates a novel mechanism by which the TME influences macrophage biology through modulation of circadian rhythms.

12.
Brief Bioinform ; 24(2)2023 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-36681937

RESUMEN

Single-cell RNA-seq enabled in-depth study on tissue micro-environment and immune-profiling, where a crucial step is to annotate cell identity. Immune cells play key roles in many diseases, whereas their activities are hard to track due to their diverse and highly variable nature. Existing cell-type identifiers had limited performance for this purpose. We present HiCAT, a hierarchical, marker-based cell-type identifier utilising gene set analysis for statistical scoring for given markers. It features successive identification of major-type, minor-type and subsets utilising subset markers structured in a three-level taxonomy tree. Comparison with manual annotation and pairwise match test showed HiCAT outperforms others in major- and minor-type identification. For subsets, we qualitatively evaluated the marker expression profile demonstrating that HiCAT provide the clearest immune-cell landscape. HiCAT was also used for immune-cell profiling in ulcerative colitis and discovered distinct features of the disease in macrophage and T-cell subsets that could not be identified previously.


Asunto(s)
Perfilación de la Expresión Génica , Macrófagos , ARN
13.
Nat Mater ; 23(3): 429-438, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38361041

RESUMEN

Cancer cell glycocalyx is a major line of defence against immune surveillance. However, how specific physical properties of the glycocalyx are regulated on a molecular level, contribute to immune evasion and may be overcome through immunoengineering must be resolved. Here we report how cancer-associated mucins and their glycosylation contribute to the nanoscale material thickness of the glycocalyx and consequently modulate the functional interactions with cytotoxic immune cells. Natural-killer-cell-mediated cytotoxicity is inversely correlated with the glycocalyx thickness of the target cells. Changes in glycocalyx thickness of approximately 10 nm can alter the susceptibility to immune cell attack. Enhanced stimulation of natural killer and T cells through equipment with chimeric antigen receptors can improve the cytotoxicity against mucin-bearing target cells. Alternatively, cytotoxicity can be enhanced through engineering effector cells to display glycocalyx-editing enzymes, including mucinases and sialidases. Together, our results motivate the development of immunoengineering strategies that overcome the glycocalyx armour of cancer cells.


Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Glicocálix/metabolismo , Mucinas/metabolismo , Antineoplásicos/metabolismo , Neoplasias/terapia
14.
Nat Immunol ; 14(9): 949-58, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23933892

RESUMEN

Leukocytes must traverse inflamed tissues to effectively control local infection. Although motility in dense tissues seems to be integrin independent and based on actomyosin-mediated protrusion and contraction, during inflammation, changes to the extracellular matrix (ECM) may necessitate distinct motility requirements. Indeed, we found that the interstitial motility of T cells was critically dependent on Arg-Gly-Asp (RGD)-binding integrins in the inflamed dermis. Inflammation-induced deposition of fibronectin was functionally linked to higher expression of integrin αV on effector CD4⁺ T cells. By intravital multiphoton imaging, we found that the motility of CD4⁺ T cells was dependent on αV expression. Selective blockade or knockdown of αV arrested T helper type 1 (TH1) cells in the inflamed tissue and attenuated local effector function. Our data demonstrate context-dependent specificity of lymphocyte movement in inflamed tissues that is essential for protective immunity.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Movimiento Celular/inmunología , Inflamación/inmunología , Inflamación/metabolismo , Integrina alfaV/metabolismo , Animales , Dermis/inmunología , Dermis/metabolismo , Matriz Extracelular/metabolismo , Regulación de la Expresión Génica , Inflamación/genética , Integrina alfaV/genética , Ganglios Linfáticos/inmunología , Ratones , Oligopéptidos/metabolismo , Unión Proteica , Células TH1/inmunología , Células TH1/metabolismo
15.
Immunity ; 44(4): 889-900, 2016 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-27084119

RESUMEN

Metagenomic studies show that diverse resident viruses inhabit the healthy gut; however, little is known about the role of these viruses in the maintenance of gut homeostasis. We found that mice treated with antiviral cocktail displayed more severe dextran sulfate sodium (DSS)-induced colitis compared with untreated mice. DSS-induced colitis was associated with altered enteric viral abundance and composition. When wild-type mice were reconstituted with Toll-like receptor 3 (TLR3) or TLR7 agonists or inactivated rotavirus, colitis symptoms were significantly ameliorated. Mice deficient in both TLR3 and TLR7 were more susceptible to DSS-induced experimental colitis. In humans, combined TLR3 and TLR7 genetic variations significantly influenced the severity of ulcerative colitis. Plasmacytoid dendritic cells isolated from inflamed mouse colon produced interferon-ß in a TLR3 and TLR7-dependent manner. These results imply that recognition of resident viruses by TLR3 and TLR7 is required for protective immunity during gut inflammation.


Asunto(s)
Colitis/inmunología , Tracto Gastrointestinal/virología , Interferón beta/inmunología , Glicoproteínas de Membrana/inmunología , Rotavirus/inmunología , Receptor Toll-Like 3/inmunología , Receptor Toll-Like 7/inmunología , Animales , Antivirales/farmacología , Colitis/inducido químicamente , Células Dendríticas/inmunología , Sulfato de Dextran , Microbioma Gastrointestinal , Tracto Gastrointestinal/inmunología , Humanos , Inflamación/inmunología , Interferón beta/biosíntesis , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , ARN Ribosómico 16S/genética , Receptor Toll-Like 3/genética , Receptor Toll-Like 7/genética
16.
Nature ; 566(7744): 339-343, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30760920

RESUMEN

A psychotherapeutic regimen that uses alternating bilateral sensory stimulation (ABS) has been used to treat post-traumatic stress disorder. However, the neural basis that underlies the long-lasting effect of this treatment-described as eye movement desensitization and reprocessing-has not been identified. Here we describe a neuronal pathway driven by the superior colliculus (SC) that mediates persistent attenuation of fear. We successfully induced a lasting reduction in fear in mice by pairing visual ABS with conditioned stimuli during fear extinction. Among the types of visual stimulation tested, ABS provided the strongest fear-reducing effect and yielded sustained increases in the activities of the SC and mediodorsal thalamus (MD). Optogenetic manipulation revealed that the SC-MD circuit was necessary and sufficient to prevent the return of fear. ABS suppressed the activity of fear-encoding cells and stabilized inhibitory neurotransmission in the basolateral amygdala through a feedforward inhibitory circuit from the MD. Together, these results reveal the neural circuit that underlies an effective strategy for sustainably attenuating traumatic memories.


Asunto(s)
Ansiedad/psicología , Ansiedad/terapia , Extinción Psicológica/fisiología , Miedo/fisiología , Miedo/psicología , Vías Nerviosas/fisiología , Colículos Superiores/citología , Colículos Superiores/fisiología , Animales , Ansiedad/fisiopatología , Complejo Nuclear Basolateral/citología , Complejo Nuclear Basolateral/fisiología , Condicionamiento Clásico/fisiología , Retroalimentación Fisiológica , Masculino , Núcleo Talámico Mediodorsal/citología , Núcleo Talámico Mediodorsal/fisiología , Ratones , Inhibición Neural , Optogenética , Estimulación Luminosa , Trastornos por Estrés Postraumático , Factores de Tiempo
17.
Proc Natl Acad Sci U S A ; 119(51): e2211436119, 2022 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-36512500

RESUMEN

Electric vehicles (EVs) are imposing ever-challenging standards on the lifetime and safety of lithium-ion batteries (LIBs); consequently, real-time nondestructive monitoring of battery cell degradation is highly desired. Unfortunately, high-nickel (Ni) layered oxides, the preferred LIB cathodes for EVs, undergo performance degradation originating from microcrack formation during cycling. Entropymetry is introduced as a real-time analytic tool for monitoring the evolution of microcracks in these cathodes along the state of charge. The entropy change of the layered cathode is associated with the lattice configuration and reflects the structural heterogeneity relevant to the evolution of these microcracks. The structural heterogeneity was correlated with peak broadening in in-situ X-ray diffractometry while varying the experimental conditions that affect crack formation such as the upper cutoff voltage during charging and the Ni-content of the active material. Entropymetry, proposed here as a nondestructive diagnostic tool, can contribute greatly to the safe and reliable operation of LIBs for EVs.

18.
Proc Natl Acad Sci U S A ; 119(51): e2203711119, 2022 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-36512497

RESUMEN

The selenium-binding protein 1 (SELENBP1) has been reported to be up-regulated in the prefrontal cortex (PFC) of schizophrenia patients in postmortem reports. However, no causative link between SELENBP1 and schizophrenia has yet been established. Here, we provide evidence linking the upregulation of SELENBP1 in the PFC of mice with the negative symptoms of schizophrenia. We verified the levels of SELENBP1 transcripts in postmortem PFC brain tissues from patients with schizophrenia and matched healthy controls. We also generated transgenic mice expressing human SELENBP1 (hSELENBP1 Tg) and examined their neuropathological features, intrinsic firing properties of PFC 2/3-layer pyramidal neurons, and frontal cortex (FC) electroencephalographic (EEG) responses to auditory stimuli. Schizophrenia-like behaviors in hSELENBP1 Tg mice and mice expressing Selenbp1 in the FC were assessed. SELENBP1 transcript levels were higher in the brains of patients with schizophrenia than in those of matched healthy controls. The hSELENBP1 Tg mice displayed negative endophenotype behaviors, including heterotopias- and ectopias-like anatomical deformities in upper-layer cortical neurons and social withdrawal, deficits in nesting, and anhedonia-like behavior. Additionally, hSELENBP1 Tg mice exhibited reduced excitabilities of PFC 2/3-layer pyramidal neurons and abnormalities in EEG biomarkers observed in schizophrenia. Furthermore, mice overexpressing Selenbp1 in FC showed deficits in sociability. These results suggest that upregulation of SELENBP1 in the PFC causes asociality, a negative symptom of schizophrenia.


Asunto(s)
Esquizofrenia , Humanos , Animales , Ratones , Esquizofrenia/genética , Esquizofrenia/metabolismo , Corteza Prefrontal/metabolismo , Células Piramidales/metabolismo , Encéfalo/metabolismo , Ratones Transgénicos , Proteínas de Unión al Selenio/genética , Proteínas de Unión al Selenio/metabolismo
19.
Artículo en Inglés | MEDLINE | ID: mdl-39182630

RESUMEN

BACKGROUND: Deficiency of adenosine deaminase (ADA or ADA1) has broad clinical and genetic heterogeneity. Screening techniques can identify asymptomatic infants whose phenotype and prognosis are indeterminate, and who may carry ADA variants of unknown significance. OBJECTIVE: We systematically assessed the pathogenic potential of rare ADA missense variants to better define the relationship of genotype to red blood cell (RBC) total deoxyadenosine nucleotide (dAXP) content and to phenotype. METHODS: We expressed 46 ADA missense variants in the ADA-deficient SØ3834 strain of Escherichia coli and defined genotype categories (GCs) ranked I to IV by increasing expressed ADA activity. We assessed relationships among GC rank, RBC dAXP, and phenotype in 58 reference patients with 50 different genotypes. We used our GC ranking system to benchmark AlphaMissense for predicting variant pathogenicity, and we used a minigene assay to identify exonic splicing variants in ADA exon 9. RESULTS: The 46 missense variants expressed ∼0.001% to ∼70% of wild-type ADA activity (40% had <0.05% of wild-type ADA activity and 50% expressed >1%). RBC dAXP ranged from undetectable to >75% of total adenine nucleotides and correlated well with phenotype. Both RBC dAXP and clinical severity were inversely related to total ADA activity expressed by both inherited variants. Our GC scoring system performed better than AlphaMissense in assessing variant pathogenicity, particularly for less deleterious variants. CONCLUSION: For ADA deficiency, pathogenicity is a continuum and conditional, depending on the total ADA activity contributed by both inherited variants as indicated by GC rank. However, in patients with indeterminate phenotype identified by screening, RBC dAXP measured at diagnosis may have greater prognostic value than GC rank.

20.
J Biol Chem ; 299(10): 105242, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37690692

RESUMEN

Cystic fibrosis (CF) is one of the most prevalent lethal genetic diseases with over 2000 identified mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Pharmacological chaperones such as lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445) treat mutation-induced defects by stabilizing CFTR and are called correctors. These correctors improve proper folding and thus facilitate processing and trafficking to increase the amount of functional CFTR on the cell surface. Yet, CFTR variants display differential responses to each corrector. Here, we report that variants P67L and L206W respond similarly to VX-809 but divergently to VX-445 with P67L exhibiting little rescue when treated with VX-445. We investigate the underlying cellular mechanisms of how CFTR biogenesis is altered by correctors in these variants. Affinity purification-mass spectrometry multiplexed with isobaric tandem mass tags was used to quantify CFTR protein-protein interaction changes between variants P67L and L206W. VX-445 facilitates unique proteostasis factor interactions especially in translation, folding, and degradation pathways in a CFTR variant-dependent manner. A number of these interacting proteins knocked down by siRNA, such as ribosomal subunit proteins, moderately rescued fully glycosylated P67L. Importantly, these knockdowns sensitize P67L to VX-445 and further enhance the trafficking correction of this variant. Partial inhibition of protein translation also mildly sensitizes P67L CFTR to VX-445 correction, supporting a role for translational dynamics in the rescue mechanism of VX-445. Our results provide a better understanding of VX-445 biological mechanism of action and reveal cellular targets that may sensitize nonresponsive CFTR variants to known and available correctors.


Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Variación Genética , Pirazoles , Humanos , Benzodioxoles/farmacología , Fibrosis Quística/genética , Fibrosis Quística/fisiopatología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Técnicas de Silenciamiento del Gen , Células HEK293 , Mutación , Biosíntesis de Proteínas/genética , Proteostasis/efectos de los fármacos , Pirazoles/farmacología , Proteínas Ribosómicas/genética
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