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1.
Nat Immunol ; 24(8): 1256-1264, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37400674

RESUMEN

Innate lymphoid cells (ILCs) can quickly switch from a quiescent state to an active state and rapidly produce effector molecules that provide critical early immune protection. How the post-transcriptional machinery processes different stimuli and initiates robust gene expression in ILCs is poorly understood. Here, we show that deletion of the N6-methyladenosine (m6A) writer protein METTL3 has little impact on ILC homeostasis or cytokine-induced ILC1 or ILC3 responses but significantly diminishes ILC2 proliferation, migration and effector cytokine production and results in impaired antihelminth immunity. m6A RNA modification supports an increase in cell size and transcriptional activity in activated ILC2s but not in ILC1s or ILC3s. Among other transcripts, the gene encoding the transcription factor GATA3 is highly m6A methylated in ILC2s. Targeted m6A demethylation destabilizes nascent Gata3 mRNA and abolishes the upregulation of GATA3 and ILC2 activation. Our study suggests a lineage-specific requirement of m6A for ILC2 responses.


Asunto(s)
Inmunidad Innata , Linfocitos , Citocinas/metabolismo , Homeostasis , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Linfocitos/inmunología , ARN/metabolismo , Animales , Ratones
2.
Transgenic Res ; 32(4): 279-291, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37266895

RESUMEN

Interleukin-37 is a newly discovered cytokine that plays a pivotal role in suppressing innate inflammation and acquired immunity. We have recently expressed both the mature(mat-) and pro-forms of human IL-37b in plants and demonstrated that while both forms of the plant-made hIL-37b are functional, pmat-hIL37b exhibited significantly greater activity than ppro-IL-37b. Compared to ppro-hIL-37b, on the other hand, the expression level of pmat-hIL-37b was substantially lower (100.5 µg versus 1.05 µg/g fresh leaf mass or 1% versus 0.01% TSP). Since the difference between ppro-hIL-37b and pmat-hIL-37b is that ppro-hIL-37b contains a signal sequence not cleavable by plant cells, we reasoned that this signal sequence would play a key role in stabilizing the ppro-hIL-37b protein. Here, we describe a novel approach to enhancing pmat-hIL-37b production in plants based on incorporation of a gene sequence encoding tobacco etch virus (TEV) protease between the signal peptide and the mature hIL-37b, including a TEV cleavage site at the C-termini of TEV protease. The rationale is that when expressed as a sp-TEV-matIL-37b fusion protein, the stabilizing properties of the signal peptide of pro-hIL-37b will be awarded to its fusion partners, resulting in increased yield of target proteins. The fusion protein is then expected to cleave itself in vivo to yield a mature pmat-hIL-37b. Indeed, when a sp-TEV-matIL-37b fusion gene was expressed in stable-transformed plants, a prominent band corresponding to dimeric pmat-hIL-37b was detected, with expression yields reaching 42.5 µg/g fresh leaf mass in the best expression lines. Bioassays demonstrated that plant-made mature pmat-hIL-37b is functional.


Asunto(s)
Inflamación , Señales de Clasificación de Proteína , Humanos , Plantas Modificadas Genéticamente/genética , Proteínas Recombinantes de Fusión
3.
J Immunol ; 206(8): 1776-1783, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33789982

RESUMEN

Regulatory T (Treg) cells have an essential role in maintaining immune homeostasis, in part by suppressing effector T cell functions. Phosphoinositide-dependent kinase 1 (PDK1) is a pleiotropic kinase that acts as a key effector downstream of PI3K in many cell types. In T cells, PDK1 has been shown to be critical for activation of NF-κB and AKT signaling upon TCR ligation and is therefore essential for effector T cell activation, proliferation, and cytokine production. Using Treg cell-specific conditional deletion, we now demonstrate that PDK1 is also essential for Treg cell suppressive activity in vivo. Ablation of Pdk1 specifically in Treg cells led to systemic, lethal, scurfy-like inflammation in mice. Genome-wide analysis confirmed that PDK1 is essential for the regulation of key Treg cell signature gene expression and, further, suggested that PDK1 acts primarily to control Treg cell gene expression through regulation of the canonical NF-κB pathway. Consistent with these results, the scurfy-like phenotype of mice lacking PDK1 in Treg cells was rescued by enforced activation of NF-κB downstream of PDK1. Therefore, PDK1-mediated activation of the NF-κB signaling pathway is essential for regulation of Treg cell signature gene expression and suppressor function.


Asunto(s)
Proteínas Quinasas Dependientes de 3-Fosfoinosítido/metabolismo , Trastornos Linfoproliferativos/genética , Linfocitos T Reguladores/inmunología , Proteínas Quinasas Dependientes de 3-Fosfoinosítido/genética , Animales , Antígenos CD4/metabolismo , Proliferación Celular , Células Cultivadas , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Terapia de Inmunosupresión , Activación de Linfocitos , Ratones , Ratones Noqueados , FN-kappa B/metabolismo , Transducción de Señal , Transcriptoma
4.
Proc Natl Acad Sci U S A ; 117(38): 23408-23417, 2020 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-32900942

RESUMEN

The Younger Dryas (YD), arguably the most widely studied millennial-scale extreme climate event, was characterized by diverse hydroclimate shifts globally and severe cooling at high northern latitudes that abruptly punctuated the warming trend from the last glacial to the present interglacial. To date, a precise understanding of its trigger, propagation, and termination remains elusive. Here, we present speleothem oxygen-isotope data that, in concert with other proxy records, allow us to quantify the timing of the YD onset and termination at an unprecedented subcentennial temporal precision across the North Atlantic, Asian Monsoon-Westerlies, and South American Monsoon regions. Our analysis suggests that the onsets of YD in the North Atlantic (12,870 ± 30 B.P.) and the Asian Monsoon-Westerlies region are essentially synchronous within a few decades and lead the onset in Antarctica, implying a north-to-south climate signal propagation via both atmospheric (decadal-time scale) and oceanic (centennial-time scale) processes, similar to the Dansgaard-Oeschger events during the last glacial period. In contrast, the YD termination may have started first in Antarctica at ∼11,900 B.P., or perhaps even earlier in the western tropical Pacific, followed by the North Atlantic between ∼11,700 ± 40 and 11,610 ± 40 B.P. These observations suggest that the initial YD termination might have originated in the Southern Hemisphere and/or the tropical Pacific, indicating a Southern Hemisphere/tropics to North Atlantic-Asian Monsoon-Westerlies directionality of climatic recovery.

5.
Proc Natl Acad Sci U S A ; 114(2): E142-E151, 2017 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-27956603

RESUMEN

Hematopoietic stem cells (HSCs) are able to both self-renew and differentiate. However, how individual HSC makes the decision between self-renewal and differentiation remains largely unknown. Here we report that ablation of the key epigenetic regulator Uhrf1 in the hematopoietic system depletes the HSC pool, leading to hematopoietic failure and lethality. Uhrf1-deficient HSCs display normal survival and proliferation, yet undergo erythroid-biased differentiation at the expense of self-renewal capacity. Notably, Uhrf1 is required for the establishment of DNA methylation patterns of erythroid-specific genes during HSC division. The expression of these genes is enhanced in the absence of Uhrf1, which disrupts the HSC-division modes by promoting the symmetric differentiation and suppressing the symmetric self-renewal. Moreover, overexpression of one of the up-regulated genes, Gata1, in HSCs is sufficient to phenocopy Uhrf1-deficient HSCs, which show impaired HSC symmetric self-renewal and increased differentiation commitment. Taken together, our findings suggest that Uhrf1 controls the self-renewal versus differentiation of HSC through epigenetically regulating the cell-division modes, thus providing unique insights into the relationship among Uhrf1-mediated DNA methylation, cell-division mode, and HSC fate decision.


Asunto(s)
Diferenciación Celular/fisiología , Autorrenovación de las Células/fisiología , Metilación de ADN/fisiología , Células Madre Hematopoyéticas/citología , Proteínas Nucleares/fisiología , Animales , Proteínas Potenciadoras de Unión a CCAAT , Epigénesis Genética , Ratones Transgénicos , Proteínas Nucleares/genética , Ubiquitina-Proteína Ligasas
7.
Sci Total Environ ; 918: 170507, 2024 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-38309354

RESUMEN

Conveyance and modification of carbon-isotope signals within the karst system remain difficult to constrain, due to the complexity of interactions between multiple components, including precipitation, bedrock, soil, atmosphere, and biota. Cave monitoring is thus critical to understanding both their transport in the karst system and dependence on local hydroclimatic conditions. Jiguan Cave, located in Funiu Mountain in central China, is representative of karst tourist caves with relatively thin epikarst zone. We conducted a comprehensive monitoring program of cave climate from 2018 to 2021 and measured δ13C during 2021 in monthly and heavy-rainfall samples of soil CO2, cave CO2, cave water (drip water and underground river), and underground river outlet. Our results demonstrate synchronous variations between CO2 concentration and δ13CCO2 in both soil and cave air on seasonal time scales. Cave pCO2 and carbon-isotope composition further exhibited a high sensitivity to human respiration with fluctuations of ~2000-3000 ppm within 4 days during the cave closure period in July 2021 without tourists. 13C-depleted isotopic signal of cave air in summer is the mixture of human respiration and soil CO2 which varies as a function of regional hydrological conditions of the summer monsoon during the rainy season with high temperatures and humidity. However, respired CO2 from the overlying soil was expected to be the only principal source of the cave CO2 when the anthropogenic CO2 source was removed. The high seasonal amplitude of cave air δ13CCO2 reflects ventilation dynamics, which leads to a prominent contribution from the external atmosphere during winter. Intriguingly, although the δ13C signal reflects complex vertical processes in the vertical karst profile, a heavy summer rainfall event was related to anomalously high δ13C values of cave water that can be utilized to interpret rainfall intensity and regional hydroclimate.

8.
J Exp Med ; 221(6)2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38563819

RESUMEN

The outcome of cancer and autoimmunity is often dictated by the effector functions of CD4+ conventional T cells (Tconv). Although activation of the NF-κB signaling pathway has long been implicated in Tconv biology, the cell-autonomous roles of the separate NF-κB transcription-factor subunits are unknown. Here, we dissected the contributions of the canonical NF-κB subunits RelA and c-Rel to Tconv function. RelA, rather than c-Rel, regulated Tconv activation and cytokine production at steady-state and was required for polarization toward the TH17 lineage in vitro. Accordingly, RelA-deficient mice were fully protected against neuroinflammation in a model of multiple sclerosis due to defective transition to a pathogenic TH17 gene-expression program. Conversely, Tconv-restricted ablation of c-Rel impaired their function in the microenvironment of transplanted tumors, resulting in enhanced cancer burden. Moreover, Tconv required c-Rel for the response to PD-1-blockade therapy. Our data reveal distinct roles for canonical NF-κB subunits in different disease contexts, paving the way for subunit-targeted immunotherapies.


Asunto(s)
Esclerosis Múltiple , Neoplasias , Animales , Ratones , Linfocitos T CD4-Positivos , FN-kappa B , Transducción de Señal , Microambiente Tumoral , Proteínas Proto-Oncogénicas c-rel/metabolismo
9.
Transpl Immunol ; 80: 101888, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37453584

RESUMEN

BACKGROUND: Ischemia/reperfusion (I/R) injury is a complication of liver transplantation. I/R-induced inflammatory cell death, namely, pyroptosis, that is triggered by overactive inflammasomes results in the production of proinflammatory cytokines. Hepatic I/R injury correlates with the activation of the Caspase-11-mediated pyroptosis pathway. We investigated whether ghrelin, which is a pleiotropic gut hormone, may have anti-hepatic I/R injury effects, but the mechanism by which Ghrelin ameliorates hepatic I/R -induced injury remains a mystery. METHODS: Hepatic I/R injury was induced in a mouse model by clamping the left and right lobes of the liver for 90 min followed by reperfusion for 6 h, 12 h, or 24 h. As treatment, a saline with or without ghrelin was infused via the tail vain. Hepatocytes were isolated using a two-step collagenase liver perfusion method. RESULTS: In our study, treatment with ghrelin protected against hepatic I/R injury as shown by decreased alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels (p < 0.001) and reduced the histological injury in liver tissues compared with untreated controls. The LDH level of primary hepatocytes was increased by hypoxia/reoxygenation (H/R), and it was then restored to normal levels by ghrelin-treatment (p < 0.05). Western blotting analysis showed that ghrelin significantly inhibited the expression of pyroptosis-related proteins, including Caspase-11, GSDMD-N, NLRP3 and HMGB1, both in vivo and in vitro (all p < 0.05) compared with the untreated controls. Immunofluorescence showed that the expression of Gasdamin D (GSDMD) in hepatocytes was increased after I/R or H/R, whereas GSDMD expression was reduced by ghrelin treatment (p < 0.05). CONCLUSIONS: Our findings suggest that ghrelin ameliorated I/R-induced hepatic injury by inhibiting Caspase-11-mediated pyroptosis. Ghrelin may be a potential therapeutic option to prevent hepatic I/R injury after liver transplantation.


Asunto(s)
Piroptosis , Daño por Reperfusión , Animales , Ratones , Caspasas/metabolismo , Ghrelina/metabolismo , Isquemia/complicaciones , Isquemia/metabolismo , Isquemia/patología , Hígado/patología , Reperfusión , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo
10.
Transpl Immunol ; 73: 101597, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35385777

RESUMEN

BACKGROUND & AIMS: Ghrelin, a gut hormone with pleiotropic effects, may act as a protective signal in parenchymal cells. Hepatic ischemia-reperfusion injury (HIRI) causes acute-on-chronic liver failure and induces transformation of acute to chronic injury. HIRI model of mice was established by a semi-hepatic blocking method and treated with Ghrelin. This process is involved in inflammation, oxidative stress damage and apoptosis, and is associated with the expansion and activation of fibrotic haematopoietic stem cells (HSCs) which express and secrete high levels of collagen that induces liver fibrosis. Therefore, we investigated the effects of Ghrelin during transformation of HIRI to liver fibrosis, and explored the molecular mechanism of Ghrelin's action based on Smad and ERK pathways. METHODS: Hepatic injury was detected by plasma ALT levels. The hepatic histology and collagen were elucidated by HE staining and Masson staining, respectively. Liver inflammation levels and inflammatory cell counts were assessed by MPO and HE staining, respectively. The antioxidant capacity of plasma was evaluated based on the levels of SOD, MDA, and XOD. The mRNA or protein expression levels of genes related to apoptosis, fibrosis, Smad, and ERK pathways were assessed by real-time quantitative PCR (RT-qPCR), ELISA, or western blotting. RESULTS: The HIRI model was established to investigate the effects of the liver injury transformed to liver fibrosis. Ghrelin exhibited good hepatic protection by ameliorating liver histological changes and decreasing plasma ALT levels. Ghrelin significantly decreased the expression of MPO than that in model group, suggesting that Ghrelin blocked the inflammatory response in the HIRI liver tissue; this supports the anti-inflammatory effects of Ghrelin. Ghrelin significantly decreased apoptosis (enhanced Bcl-2 expression, and down-regulated Bax and Caspase 3). Ghrelin exhibited anti-oxidative effects as it inhibited plasma MDA levels, and promoted plasma SOD and XOD levels. Moreover, Ghrelin inhibited activation of hepatic stellate cells, blocked traditional fibrotic Smad and ERK signalling pathways, and reduced hepatic fibrosis by stimulating degradation of extracellular matrices (ECMs; such as collagen I, collagen III, HA, and LN). CONCLUSIONS: This study demonstrates that Ghrelin delays the transformation of HIRI to liver fibrosis process which is correlated to its anti-apoptotic, anti-inflammatory, and anti-oxidative effects. Moreover, Ghrelin alleviates HIRI-mediated liver fibrosis, inhibits activation of HSCs, and reduces accumulation of ECM via inhibition of Smad and ERK signalling pathways.


Asunto(s)
Sistema de Señalización de MAP Quinasas , Daño por Reperfusión , Animales , Antiinflamatorios/uso terapéutico , Colágeno Tipo I/metabolismo , Ghrelina/metabolismo , Ghrelina/farmacología , Ghrelina/uso terapéutico , Inflamación/metabolismo , Hígado/patología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Ratones , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/farmacología , Superóxido Dismutasa/uso terapéutico
11.
Metabol Open ; 13: 100166, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35198946

RESUMEN

The NLRP3 inflammasome, as an important component of the innate immune system, plays vital roles in various metabolic disorders. It has been reported that the NLRP3 inflammasome can be activated by a broad range of distinct stimuli, such as K+ efflux, mitochondrial dysfunction, lysosomal disruption and trans-Golgi disassembly, etc. However, there has been no well-established model for NLRP3 inflammasome activation so far, especially the underlying mechanisms for mitochondria in NLRP3 inflammasome activation remain elusive. Given that K+ efflux is a widely accepted nexus for triggering activation of NLRP3 inflammasome in most previous studies, we sought to elucidate the role of mitochondria in K+ efflux-induced NLRP3 inflammasome activation. Here, we demonstrated that inflammation activation by LPS evoked the expression of genes that involved in mitochondrial biogenesis and mitophagy, subsequently mitochondrial mass and mitochondrial membrane potential were also elevated, suggesting the contribution of mitochondria in inflammatory responses. Moreover, we inhibited mitochondrial biogenesis by silencing Tfam and genetic ablation of Tfam abolished the NLRP3 inflammasome activation induced by K+ efflux via release of mitochondrial DNA (mtDNA), as deprivation of cellular mtDNA by EtBr treatment could reverse inflammasome activation induced by K+ efflux. Collectively, we reveal that mtDNA release induced by K+ efflux in macrophages activates NLRP3 inflammasome, and propose that mitochondria may serve as a potential therapeutic target for NLRP3 inflammasome-related diseases.

12.
Innovation (Camb) ; 3(6): 100338, 2022 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-36353675

RESUMEN

The widely accepted "Milankovitch theory" explains insolation-induced waxing and waning of the ice sheets and their effect on the global climate on orbital timescales. In the past half century, however, the theory has often come under scrutiny, especially regarding its "100-ka problem." Another drawback, but the one that has received less attention, is the "monsoon problem," which pertains to the exclusion of monsoon dynamics in classic Milankovitch theory even though the monsoon prevails over the vast low-latitude (∼30° N to ∼30° S) region that covers half of the Earth's surface and receives the bulk of solar radiation. In this review, we discuss the major issues with the current form of Milankovitch theory and the progress made at the research forefront. We suggest shifting the emphasis from the ultimate outcomes of the ice volume to the causal relationship between changes in northern high-latitude insolation and ice age termination events (or ice sheet melting rate) to help reconcile the classic "100-ka problem." We discuss the discrepancies associated with the characterization of monsoon dynamics, particularly the so-called "sea-land precession-phase paradox" and the "Chinese 100-ka problem." We suggest that many of these discrepancies are superficial and can be resolved by applying a holistic "monsoon system science" approach. Finally, we propose blending the conventional Kutzbach orbital monsoon hypothesis, which calls for summer insolation forcing of monsoons, with Milankovitch theory to formulate a combined "Milankovitch-Kutzbach hypothesis" that can potentially explain the dual nature of orbital hydrodynamics of the ice sheet and monsoon systems, as well as their interplays and respective relationships with the northern high-latitude insolation and inter-tropical insolation differential.

13.
Nat Commun ; 13(1): 5867, 2022 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-36195764

RESUMEN

Our understanding of climate dynamics during millennial-scale events is incomplete, partially due to the lack of their precise phase analyses under various boundary conditions. Here we present nine speleothem oxygen-isotope records from mid-to-low-latitude monsoon regimes with sub-centennial age precision and multi-annual resolution, spanning the Heinrich Stadial 2 (HS2) - a millennial-scale event that occurred at the Last Glacial Maximum. Our data suggests that the Greenland and Antarctic ice-core chronologies require +320- and +400-year adjustments, respectively, supported by extant volcanic evidence and radiocarbon ages. Our chronological framework shows a synchronous HS2 onset globally. Our records precisely characterize a centennial-scale abrupt "tropical atmospheric seesaw" superimposed on the conventional "bipolar seesaw" at the beginning of HS2, implying a unique response/feedback from low-latitude hydroclimate. Together with our observation of an early South American monsoon shift at the HS2 termination, we suggest a more active role of low-latitude hydroclimate dynamics underlying millennial events than previously thought.

14.
Cell Res ; 32(12): 1105-1123, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36302855

RESUMEN

Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Further knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, our study reveals the mechanisms for altered epigenetic programs in AML and provides a promising targeted therapeutic strategy against AML.


Asunto(s)
Leucemia Mieloide Aguda , Humanos , Carcinogénesis , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Histona Desacetilasas , Leucemia Mieloide Aguda/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
15.
Sci Adv ; 7(48): eabi9275, 2021 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-34826247

RESUMEN

The Liangzhu culture in the Yangtze River Delta (YRD) was among the world's most advanced Neolithic cultures. Archeological evidence suggests that the Liangzhu ancient city was abandoned, and the culture collapsed at ~4300 years ago. Here, we present speleothem records from southeastern China in conjunction with other paleoclimatic and archeological data to show that the Liangzhu culture collapsed within a short and anomalously wet period between 4345 ± 32 and 4324 ± 30 years ago, supporting the hypothesis that the city was abandoned after large-scale flooding and inundation. We further show that the demise of Neolithic cultures in the YRD occurred within an extended period of aridity that started at ~4000 ± 45 years ago. We suggest that the major hydroclimatic changes between 4300 and 3000 years ago may have resulted from an increasing frequency of the El Niño­Southern Oscillation in the context of weakened Northern Hemisphere summer insolation.

16.
Sci Rep ; 10(1): 14519, 2020 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-32884074

RESUMEN

With the discovery of magnetoreceptor mechanisms in animals, it materialized the novel applications of controlling cell and animal behaviors using magnetic fields. T cells have shown to be sensitive to magnetic fields. Here, we reported that exposure to moderate SMFs (static magnetic fields) led to increased granule and cytokine secretion as well as ATP production and mitochondrial respiration from CD8+ T cells. These effects were inhibited by knocking down the Uqcrb and Ndufs6 genes of mitochondrial respiratory chain, whose transcriptions were regulated by candidate magnetoreceptor genes Isca1 and Cry1/Cry2. SMF exposure also promoted CD8+ T cell granule and cytokine secretion and repressed tumor growth in vivo. SMFs enhanced CD8+ T cell cytotoxicity, and the adoptive transfer into tumor-bearing mice resulted in enhanced antitumor effects. Collectively, our study suggests that moderate SMFs enhance CD8+ T cell cytotoxicity by promoting mitochondrial respiration and promoted the antitumor function of CD8+ T cells.


Asunto(s)
Linfocitos T CD8-positivos/metabolismo , Campos Magnéticos , Mitocondrias/metabolismo , Inmunidad Adaptativa/fisiología , Adenosina Trifosfato/metabolismo , Animales , Línea Celular , Ratones , Ratones Endogámicos C57BL
17.
Sci Adv ; 6(42)2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33067226

RESUMEN

Madagascar and the Mascarene Islands of Mauritius and Rodrigues underwent catastrophic ecological and landscape transformations, which virtually eliminated their entire endemic vertebrate megafauna during the past millennium. These ecosystem changes have been alternately attributed to either human activities, climate change, or both, but parsing their relative importance, particularly in the case of Madagascar, has proven difficult. Here, we present a multimillennial (approximately the past 8000 years) reconstruction of the southwest Indian Ocean hydroclimate variability using speleothems from the island of Rodrigues, located ∼1600 km east of Madagascar. The record shows a recurring pattern of hydroclimate variability characterized by submillennial-scale drying trends, which were punctuated by decadal-to-multidecadal megadroughts, including during the late Holocene. Our data imply that the megafauna of the Mascarenes and Madagascar were resilient, enduring repeated past episodes of severe climate stress, but collapsed when a major increase in human activity occurred in the context of a prominent drying trend.

18.
Nat Commun ; 9(1): 3746, 2018 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-30218073

RESUMEN

In response to myeloablative stresses, HSCs are rapidly activated to replenish myeloid progenitors, while maintaining full potential of self-renewal to ensure life-long hematopoiesis. However, the key factors that orchestrate HSC activities during physiological stresses remain largely unknown. Here we report that Med23 controls the myeloid potential of activated HSCs. Ablation of Med23 in hematopoietic system leads to lymphocytopenia. Med23-deficient HSCs undergo myeloid-biased differentiation and lose the self-renewal capacity. Interestingly, Med23-deficient HSCs are much easier to be activated in response to physiological stresses. Mechanistically, Med23 plays essential roles in maintaining stemness genes expression and suppressing myeloid lineage genes expression. Med23 is downregulated in HSCs and Med23 deletion results in better survival under myeloablative stress. Altogether, our findings identify Med23 as a gatekeeper of myeloid potential of HSCs, thus providing unique insights into the relationship among Med23-mediated transcriptional regulations, the myeloid potential of HSCs and HSC activation upon stresses.


Asunto(s)
Diferenciación Celular/genética , Autorrenovación de las Células/genética , Células Madre Hematopoyéticas/citología , Complejo Mediador/genética , Células Mieloides/citología , Estrés Fisiológico/genética , Animales , Trasplante de Médula Ósea , Regulación de la Expresión Génica , Técnicas de Inactivación de Genes , Hematopoyesis , Células Madre Hematopoyéticas/metabolismo , Ratones , Células Mieloides/metabolismo , Células Progenitoras Mieloides/citología , Células Progenitoras Mieloides/metabolismo
19.
Sci Rep ; 8(1): 12344, 2018 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-30120280

RESUMEN

In southeastern China (SEC), the precipitation amount produced by the East Asian summer monsoon (EASM) is almost equivalent to that during the non-summer monsoon (NSM) period, both of them significantly affecting agriculture and socioeconomy. Here, we present a seasonally-resolved stalagmite δ18O record (δ18Os) for the interval 1810-2009 AD from E'mei cave, Jiangxi Province, SEC. The comparison between δ18Os and instrumental data indicates that the δ18Os variability is primarily controlled by the precipitation seasonality (i.e., the ratio of EASM/NSM precipitation) modulated by the El Niño/Southern Oscillation (ENSO) on interannual to interdecadal timescales. Higher (lower) δ18Os values thereby correspond to lower (higher) EASM/NSM ratios associated with El Niño (La Niña) events. Significant correlations with ENSO and the Pacific Decadal Oscillation (PDO) indicate that the precipitation seasonality in SEC is remarkably influenced by ocean-atmosphere interactions, with lower (higher) EASM/NSM ratios during warm (cold) phases of ENSO/PDO. The progressive increase in δ18Os since 2005 AD may reflect a strengthening of the central Pacific El Niño under continued anthropogenic global warming. The relationship between seasonal precipitation and δ18Os with ENSO/PDO requires further studies.

20.
Huan Jing Ke Xue ; 36(5): 1582-9, 2015 May.
Artículo en Zh | MEDLINE | ID: mdl-26314103

RESUMEN

Geochemical dynamics of cave water were monitored to unveil its variation and controlling factors from October 2009 to December 2013 in Jiguan Cave,west of Henan province,southeastern coast of the loess plateau. The results showed that: (1) the hydrochemical types of the cave water are HCO(3-)-Ca(2+)-Mg2+ and HCO(3-)-Mg(2+)-Ca2+. HCO(3-) are over 80% of the anions, Ca2+ and Mg2+ are the dominate cations, and ground river keeping in erosion and pool water drips in deposition all the year. (2) Dripping water and pool water in Ji guan cave can respond perfectly to the change of external climate environment, which geochemistry indexes possess the extraordinary seasonal effects. (3) The concentration changes of the Ca2+, Mg2+ , SO4(2-) responded sensitively to annual precipitation change. Ca2+, Mg2+, SO4(2-) rise in waterlogging year and fall in drought year. Because HCO(3-) controlled by CO2 concentration. HCO(3-) concentration showed a unconspicuous response to the change of external climate environment. (4) The concentration changes of Ca2+, Mg2+, SO4(2-) have no obvious seasonal variation and showed a unconspicuous response to the change of external climate environment.


Asunto(s)
Cuevas , Agua Subterránea/química , Tiempo (Meteorología) , China , Monitoreo del Ambiente , Ríos , Estaciones del Año
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