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In the version of this article initially published, some identification of the supplementary information was incorrect. The items originally called Supplementary Tables 1, 2, 3, 4 and 5 should be Source Data Figures 1, 2, 4, 5 and 7, respectively; those originally called Supplementary Tables 6, 7 and 8 should be Supplementary Tables 1, 2 and 3, respectively; and those originally called Source Data Figures 1, 2, 4, 5 and 7 should be Supplementary Tables 4, 5, 6, 7 and 8, respectively. The errors have been corrected in the HTML version of the article.
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Deletion of master regulators of the B cell lineage reprograms B cells into T cells. Here we found that the transcription factor Hoxb5, which is expressed in uncommitted hematopoietic progenitor cells but is not present in cells committed to the B cell or T cell lineage, was able to reprogram pro-pre-B cells into functional early T cell lineage progenitors. This reprogramming started in the bone marrow and was completed in the thymus and gave rise to T lymphocytes with transcriptomes, hierarchical differentiation, tissue distribution and immunological functions that closely resembled those of their natural counterparts. Hoxb5 repressed B cell 'master genes', activated regulators of T cells and regulated crucial chromatin modifiers in pro-pre-B cells and ultimately drove the B cell fate-to-T cell fate conversion. Our results provide a de novo paradigm for the generation of functional T cells through reprogramming in vivo.
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Linfocitos B/citología , Linaje de la Célula/inmunología , Reprogramación Celular/inmunología , Proteínas de Homeodominio/inmunología , Linfocitos T/citología , Animales , Diferenciación Celular , Linaje de la Célula/genética , Reprogramación Celular/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Células Precursoras de Linfocitos B/citologíaRESUMEN
BACKGROUND: Microglia is the major contributor of post-stroke neuroinflammation cascade and the crucial cellular target for the treatment of ischemic stroke. Currently, the endogenous mechanism underlying microglial activation following ischemic stroke remains elusive. Serglycin (SRGN) is a proteoglycan expressed in immune cells. Up to now, the role of SRGN on microglial activation and ischemic stroke is largely unexplored. METHODS: Srgn knockout (KO), Cd44-KO and wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAO) to mimic ischemic stroke. Exogenous SRGN supplementation was achieved by stereotactic injection of recombinant mouse SRGN (rSRGN). Cerebral infarction was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Neurological functions were evaluated by the modified neurological severity score (mNSS) and grip strength. Microglial activation was detected by Iba1 immunostaining, morphological analysis and cytokines' production. Neuronal death was examined by MAP2 immunostaining and FJB staining. RESULTS: The expression of SRGN and its receptor CD44 was significantly elevated in the ischemic mouse brains, especially in microglia. In addition, lipopolysaccharide (LPS) induced SRGN upregulation in microglia in vitro. rSRGN worsened ischemic brain injury in mice and amplified post-stroke neuroinflammation, while gene knockout of Srgn exerted reverse impacts. rSRGN promoted microglial proinflammatory activation both in vivo and in vitro, whereas Srgn-deficiency alleviated microglia-mediated inflammatory response. Moreover, the genetic deletion of Cd44 partially rescued rSRGN-induced excessed neuroinflammation and ischemic brain injury in mice. Mechanistically, SRGN boosted the activation of NF-κB signal, and increased glycolysis in microglia. CONCLUSION: SRGN acts as a novel therapeutic target in microglia-boosted proinflammatory response following ischemic stroke.
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Lesiones Encefálicas , Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Proteínas de Transporte Vesicular , Animales , Ratones , Microglía/metabolismo , Isquemia Encefálica/metabolismo , Enfermedades Neuroinflamatorias , Accidente Cerebrovascular/metabolismo , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/metabolismo , Proteoglicanos/metabolismo , Accidente Cerebrovascular Isquémico/metabolismo , Lesiones Encefálicas/metabolismoRESUMEN
N-type Mg3 Sb2 -based thermoelectric materials show great promise in power generation due to their mechanical robustness, low cost of Mg, and high figure of merit (ZT) over a wide range of temperatures. However, their poor thermal stability hinders their practical applications. Here, MgB2 is introduced to improve the thermal stability of n-type Mg3 Sb2 . Enabled by MgB2 decomposition, extra Mg can be released into the matrix for Mg compensation thermodynamically, and secondary phases of MgâB compounds can kinetically prevent Mg diffusion along grain boundaries. These synergetic effects inhibit the formation of Mg vacancies at elevated temperatures, thereby enhancing the thermal stability of n-type Mg3 Sb2 . Consequently, the Mg3.05 (Sb0.75 Bi0.25 )1.99 Te0.01 (MgB2 )0.03 sample exhibits negligible variation in thermoelectric performance during the 120-hour continuous measurement at 673 K. Moreover, the ZT of n-type Mg3 Sb2 can be maintained by adding MgB2 , reaching a high average ZT of ≈1.1 within 300-723 K. An eight-pair Mg3 Sb2 -GeTe-based thermoelectric device is also fabricated, achieving an energy conversion efficiency of ≈5.7% at a temperature difference of 438 K with good thermal stability. This work paves a new way to enhance the long-term thermal stability of n-type Mg3 Sb2 -based alloys and other thermoelectrics for practical applications.
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TDP-43 proteinopathy is linked to neurodegenerative diseases that feature synaptic loss in the cortex and hippocampus, although it remains unclear how TDP-43 regulates mature synapses. We report that, in adult mouse hippocampus, TDP-43 knockdown, but not overexpression, induces robust structural and functional damage to excitatory synapses, supporting a role for TDP-43 in maintaining mature synapses. Dendritic spine loss induced by TDP-43 knockdown is rescued by wild-type TDP-43, but not ALS/FTLD-associated mutants, suggesting a common TDP-43 functional deficiency in neurodegenerative diseases. Interestingly, M337V and A90V mutants also display dominant negative activities against WT TDP-43, partially explaining why M337V transgenic mice develop hippocampal degeneration similar to that in excitatory neuronal TDP-43 knockout mice, and why A90V mutation is associated with Alzheimer's disease. Further analyses reveal that a TDP-43 knockdown-induced reduction in GluN2A contributes to synaptic loss. Our results show that loss of TDP-43 function underlies hippocampal and cortical synaptic degeneration in TDP-43 proteinopathies.
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Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Proteinopatías TDP-43 , Ratones , Animales , Proteinopatías TDP-43/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Ratones Transgénicos , Hipocampo/metabolismo , Ratones Noqueados , Esclerosis Amiotrófica Lateral/genéticaRESUMEN
Climate change may diminish biodiversity; thus, it is urgent to predict how species' ranges may shift in the future by integrating multiple factors involving more taxa. Bats are particularly sensitive to climate change due to their high surface-to-volume ratio. However, few studies have considered geographic variables associated with roost availability and even fewer have linked the distributions of bats to their thermoregulation and energy regulation traits. We used species distribution models to predict the potential distributions of 12 bat species in China under current and future greenhouse gas emission scenarios (SSP1-2.6 and SSP5-8.5) and examined factors that could affect species' range shifts, including climatic, geographic, habitat, and human activity variables and wing surface-to-mass ratio (S-MR). The results suggest that Ia io, Rhinolophus ferrumequinum, and Rhinolophus rex should be given the highest priority for conservation in future climate conservation strategies. Most species were predicted to move northward, except for I. io and R. rex, which moved southward. Temperature seasonality, distance to forest, and distance to karst or cave were the main environmental factors affecting the potential distributions of bats. We found significant relationships between S-MR and geographic distribution, current potential distribution, and future potential distribution in the 2050s. Our work highlights the importance of analyzing range shifts of species with multifactorial approaches, especially for species traits related to thermoregulation and energy regulation, to provide targeted conservation strategies.
Patrones y correlaciones de los cambios potenciales en la distribución de las especies de murciélago de China en el contexto del cambio climático Resumen El cambio climático puede disminuir la biodiversidad, por lo que es urgente pronosticar cómo puede cambiar en el futuro la distribución de las especies mediante la integración de múltiples factores que involucren a más taxones. Los murciélagos son particularmente sensibles al cambio climático debido a que tienen una gran proporción superficievolumen. Sin embargo, hay pocos estudios que han considerado las variables asociadas con la disponibilidad de nidos y son todavía menos los que han conectado la distribución de los murciélagos con sus rasgos de termorregulación y regulación de energía. Usamos modelos de distribución de especies para pronosticar la distribución potencial de doce especies de murciélago en China bajo escenarios actuales y futuros de emisión de gases de efecto invernadero (SSP12.6 y SSP58.5) y analizamos los factores que podrían afectar el cambio en la distribución de las especies, incluyendo las variables climáticas, geográficas, de hábitat y de actividad humana y la proporción entre la superficie del ala y la masa (P SM). Los resultados sugieren que Ia io, Rhinolophus ferrumequinum y R. rex deberían ser la mayor prioridad de conservación para las estrategias de conservación climáticas en el futuro. Pronosticamos que la mayoría de las especies se desplazarían al norte, a excepción de I. io y R. rex, que se desplazarían hacia el sur. Los principales factores que afectaron la distribución potencial de los murciélagos fueron la estacionalidad de la temperatura, la distancia al bosque y la distancia a la cueva o al karst. Encontramos una relación significativa entre la P SM y la distribución geográfica, la distribución potencial actual y la distribución potencial para la década de 2050. Nuestra investigación destaca la importancia del análisis de los cambios de distribución de las especies con enfoques multifactoriales, especialmente para los rasgos de especie relacionados con la termorregulación y la regulación de energía, para proporcionar estrategias de conservación focalizadas.
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Necroptosis is a form of regulated necrosis mediated by the formation of the necrosome, composed of the RIPK1/RIPK3/MLKL complex. Here, we developed a proximity ligation assay (PLA) that allows in situ visualization of necrosomes in necroptotic cells and in vivo. Using PLA assay, we show that necrosomes can be found in close proximity to the endoplasmic reticulum (ER). Furthermore, we show that necroptosis activates ER stress sensors, PERK, IRE1α, and ATF6 in a RIPK1-RIPK3-MLKL axis-dependent manner. Activated MLKL can be translocated to the ER membrane to directly initiate the activation of ER stress signaling. The activation of IRE1α in necroptosis promotes the splicing of XBP1, and the subsequent incorporation of spliced XBP1 messenger RNA (mRNA) into extracellular vesicles (EVs). Finally, we show that unlike that of a conventional ER stress response, necroptosis promotes the activation of unfolded protein response (UPR) sensors without affecting their binding of GRP78. Our study reveals a signaling pathway that links MLKL activation in necroptosis to an unconventional ER stress response.
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Endorribonucleasas/metabolismo , Proteínas de Choque Térmico/metabolismo , Necroptosis , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Respuesta de Proteína Desplegada , eIF-2 Quinasa/metabolismo , Apoptosis , Retículo Endoplásmico , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Endorribonucleasas/genética , Células HT29 , Proteínas de Choque Térmico/genética , Humanos , Proteínas Serina-Treonina Quinasas/genética , Empalme del ARN , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína 1 de Unión a la X-Box/genética , eIF-2 Quinasa/genéticaRESUMEN
BACKGROUND: It is inevitable to change the function or expression of genes during the environmental adaption of species. Both the giant panda (Ailuropoda melanoleuca) and red panda (Ailurus fulgens) belong to Carnivora and have developed similar adaptations to the same dietary switch to bamboos at the morphological and genomic levels. However, the genetic adaptation at the gene expression level is unclear. Therefore, we aimed to examine the gene expression patterns of giant and red panda convergent specialized bamboo-diets. We examined differences in liver and pancreas transcriptomes between the two panda species and other non-herbivorous species. RESULTS: The clustering and PCA plots suggested that the specialized bamboo diet may drive similar expression shifts in these two species of pandas. Therefore, we focused on shared liver and pancreas DEGs (differentially expressed genes) in the giant and red panda relative to other non-herbivorous species. Genetic convergence occurred at multiple levels spanning carbohydrate metabolism, lipid metabolism, and lysine degradation. The shared adaptive convergence DEGs in both organs probably be an evolutionary response to the high carbohydrate, low lipid and lysine bamboo diet. Convergent expression of those nutrient metabolism-related genes in both pandas was an intricate process and subjected to multi-level regulation, including DNA methylation and transcription factor. A large number of lysine degradation and lipid metabolism related genes were hypermethylated in promoter regions in the red panda. Most genes related to carbohydrate metabolism had reduced DNA methylation with increased mRNA expression in giant pandas. Unlike the red panda, the core gene of the lysine degradation pathway (AASS) doesn't exhibit hypermethylation modification in the giant panda, and dual-luciferase reporter assay showed that transcription factor, NR3C1, functions as a transcriptional activator in AASS transcription through the binding to AASS promoter region. CONCLUSIONS: Our results revealed the adaptive expressions and regulations of the metabolism-related genes responding to the unique nutrients in bamboo food and provided data accumulation and research hints for the future revelation of complex mechanism of two pandas underlying convergent adaptation to a specialized bamboo diet.
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Ailuridae , Dieta , Ursidae , Animales , Dieta/veterinaria , Expresión Génica , Lisina/metabolismo , Ursidae/genética , Ursidae/metabolismo , Ailuridae/genética , Ailuridae/metabolismoRESUMEN
N-type Mg3 (Bi, Sb)2 -based thermoelectric (TE) alloys show great promise for solid-state power generation and refrigeration, owing to their excellent figure-of-merit (ZT) and using cheap Mg. However, their rigorous preparation conditions and poor thermal stability limit their large-scale applications. Here, this work develops an Mg compensating strategy to realize n-type Mg3 (Bi, Sb)2 by a facile melting-sintering approach. "2D roadmaps" of TE parameters versus sintering temperature and time are plotted to understand the Mg-vacancy-formation and Mg-diffusion mechanisms. Under this guidance, high weight mobility of 347 cm2 V-1 s-1 and power factor of 34 µW cm-1 K-2 can be obtained for Mg3.05 Bi1.99 Te0.01 , and a peak ZT≈1.55 at 723 K and average ZT≈1.25 within 323-723 K can be obtained for Mg3.05 (Sb0.75 Bi0.25 )1.99 Te0.01 . Moreover, this Mg compensating strategy can also improve the interfacial connecting and thermal stability of corresponding Mg3 (Bi, Sb)2 /Fe TE legs. As a consequence, this work fabricates an 8-pair Mg3 Sb2 -GeTe-based power-generation device reaching an energy conversion efficiency of ≈5.0% at a temperature difference of 439 K, and a one-pair Mg3 Sb2 -Bi2 Te3 -based cooling device reaching -10.7 °C at the cold side. This work paves a facile way to obtain Mg3 Sb2 -based TE devices at low cost and also provides a guide to optimize the off-stoichiometric defects in other TE materials.
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The progression of several cancers, including lung cancer, has been linked to long non-coding RNAs (lncRNAs) (LC). The current research concentrated on elucidating the effects of MALAT1 on the course of LC and investigating potential pathways. The qPCR and in situ hybridization (ISH) assays were used to measure MALAT1 expression in LC tissues. Additionally, the overall survival (OS), a percentage of LC patients with various MALAT1 levels was examined. Additionally, it was determined whether MALAT1 was expressed in LC cells through qPCR analysis. LC cells' proliferation, apoptosis, and metastasis were all examined concerning MALAT1 utilizing the following techniques: EdU, CCK-8, western blot and flow cytometry. This study predicted and verified the correlation between MALAT1, microRNA (miR)-338-3p as well as pyrroline-5-carboxylate reductase 2 using bioinformatics and dual-luciferase reporters (PYCR2). On the activity and function of MALAT1/miR-338-3p/PYCR2 in LC cell activities, more study was conducted. The amount of MALAT1 was raised in LC tissues and cells. Low OS was seen in patients with elevated MALAT1 expression. By inhibiting MALAT1, LC cells saw decreased migration, invasion, and proliferation as well as an increase in apoptosis. Additionally, PYCR2 appeared as an objective of miR-338-3p, while MALAT1 was a target of miR-338-3p. Additionally, the over-expression of miR-338-3p had effects that were comparable to those of MALAT1 down-regulation. The function of miR-338-3p inhibitor on the functional activities of LC cells co-transfected with sh-MALAT1 was partially recovered by PYCR2 inhibition. MALAT1/miR-338-3p/PYCR2 maybe the novel target for LC therapy.
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Carcinoma , Neoplasias Pulmonares , MicroARNs , Pirrolina Carboxilato Reductasas , ARN Largo no Codificante , Humanos , Carcinoma/genética , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Pirrolina Carboxilato Reductasas/genética , ARN Largo no Codificante/genética , Neoplasias Pulmonares/genéticaRESUMEN
Circ_LRP6 is participated in the occurrence and development of numerous tumors. Nevertheless, its roles and mechanism in osteosarcoma (OS) is unknown. This study aims to illustrate this point. With the use of qRT-PCR, the level of circ_LRP6, miR-122-5p, miR-204-5p and HMGB1 was identified. To observe cell proliferation, migration and invasion, we adopted CCK-8 and Transwell assays in the present study. Besides, to prove the existing interaction, bioinformatics analysis and dual luciferase reporting assays were employed. The influence of circ_LRP6 on osteosarcoma in vivo was evaluated by subcutaneous tumor formation model in nude mice. In osteosarcoma tissues, circ_LRP6 and HMGB1 are strongly denoted, whereas miR-122-5p and miR-204-5p are under-expressed. Circ_LRP6 knockdown could significantly hinder the proliferation, migration and invasion of osteosarcoma cells. Circ_LRP6 hindered the proliferation of osteosarcoma in vivo. Bioinformatics predicted that miR-122-5p and miR-204-5p functioned as direct targets of circ_LRP6, and HMGB1 were possible target genes of miR-122-5p and miR-204-5p. The findings indicated that the low level of miR-122-5p and miR-204-5p and the overexpression of HMGB1 could partially restore and reduce the inhibitory impact of circ_LRP6 on the proliferation, migration and invasion of osteosarcoma cells. Circ_LRP6 affects osteosarcoma progression via the miR-122-5p/miR-204-5p/HMGB1 axis, and is shown to be a molecular biomarker.
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Neoplasias Óseas , Proteína HMGB1 , MicroARNs , Osteosarcoma , Animales , Ratones , Proteína HMGB1/genética , Ratones Desnudos , Osteosarcoma/genética , Proliferación Celular/genética , Neoplasias Óseas/genética , MicroARNs/genética , Línea Celular TumoralRESUMEN
Hematopoietic stem cells (HSCs) are dominantly quiescent under homeostasis, which is a key mechanism of maintaining the HSC pool for life-long hematopoiesis. Dormant HSCs poise to be immediately activated on urgent conditions and can return to quiescence after regaining homeostasis. To date, the molecular networks of regulating the threshold of HSC dormancy, if exist, remain largely unknown. Here, we unveiled that deletion of Nupr1, a gene preferentially expressed in HSCs, activated the quiescence HSCs under homeostatic status, which conferred engraftment competitive advantage on HSCs without compromising their stemness and multi-lineage differentiation abilities in serial transplantation settings. Following an expansion protocol, the Nupr1-/- HSCs proliferate more robustly than their wild type counterparts in vitro. Nupr1 inhibits the expression of p53 and the rescue of which offsets the engraftment advantage. Our data unveil the de novo role of Nupr1 as an HSC quiescence-regulator, which provides insights into accelerating the engraftment efficacy of HSC transplantation by targeting the HSC quiescence-controlling network.
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Proteínas de Unión al ADN/genética , Células Madre Hematopoyéticas , Proteínas de Neoplasias/genética , Proteína p53 Supresora de Tumor , Animales , Diferenciación Celular , Hematopoyesis/genética , Homeostasis , Ratones , Ratones Endogámicos C57BL , Proteína p53 Supresora de Tumor/genéticaRESUMEN
An original and facile method for the generation of ß-naphtha-1-thioquinones using DAST and 2-naphthols has been developed. A series of dehydro-2-naphthol-1-sulphides or naphtha-oxathiane derivatives were synthesized by in situ Diels-Alder cycloaddition reactions of ß-naphtha-1-thioquinone with itself or various alkenes.
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Naftoles , Alcanos , Reacción de Cicloadición , Dietilaminas , Flúor , Solventes , EstereoisomerismoRESUMEN
A photoexcited sulfenylation of C(sp3)-H bonds in amides is developed for the synthesis of sulfenyl amides using thiosulfonates as a sulfur source. In the presence of easily available and inexpensive Na2-eosin Y, TBHP and K2CO3, various sulfenyl amides can be obtained under the irradiation of blue light at room temperature.
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Amidas , Azufre , Amidas/química , Azufre/químicaRESUMEN
Canine distemper virus (CDV) is a highly fatal virus to the giant panda (Ailuropoda melanoleuca). Although vaccination is a key preventative measure in captive giant pandas, the immune response of giant pandas after vaccination remains unclear. Therefore, this study focuses on differential alternative splicing (DAS) events of giant pandas before and after vaccination to investigate the role of alternative splicing in the immune response of giant pandas after CDV vaccination. In this study, we identified 1113 DAS genes, which had 1288 DAS events. The KEGG functional enrichment analysis of DAS genes showed enrichment of some DNA damage repair and immune-related pathways. In the combined analysis of DAS and differentially expressed genes (from our previous research), we identified 66 differentially expressed genes with a DAS event, and found that some important immune-related genes, such as IL15, IL18, IL18RAP, CHUK, IFI44, CD40, and CD46 underwent DAS events and were involved in the immune response of giant pandas after CDV vaccination. We describe here the alternative splicing events of giant pandas after CDV vaccination for the first time and show that the results indicated that alternative splicing has an important role in regulating the immune response of giant pandas after vaccination.
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Virus del Moquillo Canino , Moquillo , Enfermedades de los Perros , Ursidae , Vacunas , Empalme Alternativo , Animales , Moquillo/genética , Moquillo/prevención & control , Virus del Moquillo Canino/genética , Perros , Perfilación de la Expresión Génica , Ursidae/genéticaRESUMEN
Necroptosis and ferroptosis are two distinct necrotic cell death modalities with no known common molecular mechanisms. Necroptosis is activated by ligands of death receptors such as tumor necrosis factor-α (TNF-α) under caspase-deficient conditions, whereas ferroptosis is mediated by the accumulation of lipid peroxides upon the depletion/or inhibition of glutathione peroxidase 4 (GPX4). The molecular mechanism that mediates the execution of ferroptosis remains unclear. In this study, we identified 2-amino-5-chloro-N,3-dimethylbenzamide (CDDO), a compound known to inhibit heat shock protein 90 (HSP90), as an inhibitor of necroptosis that could also inhibit ferroptosis. We found that HSP90 defined a common regulatory nodal between necroptosis and ferroptosis. We showed that inhibition of HSP90 by CDDO blocked necroptosis by inhibiting the activation of RIPK1 kinase. Furthermore, we showed that the activation of ferroptosis by erastin increased the levels of lysosome-associated membrane protein 2a to promote chaperone-mediated autophagy (CMA), which, in turn, promoted the degradation of GPX4. Importantly, inhibition of CMA stabilized GPX4 and reduced ferroptosis. Our results suggest that activation of CMA is involved in the execution of ferroptosis.
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Autofagia/genética , Glutatión Peroxidasa/genética , Proteína 2 de la Membrana Asociada a los Lisosomas/genética , Chaperonas Moleculares/genética , Necrosis/genética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Autofagia/efectos de los fármacos , Caspasas/genética , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/genética , Humanos , Hierro/metabolismo , Ligandos , Peróxidos Lipídicos/genética , Peróxidos Lipídicos/metabolismo , Chaperonas Moleculares/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Piperazinas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. FXS is caused by loss of expression of fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates translation of numerous mRNA targets, some of which are present at synapses. While protein synthesis deficits have long been postulated as an etiology of FXS, how FMRP loss affects distributions of newly synthesized proteins is unknown. Here we investigated the role of FMRP in regulating expression of new copies of the synaptic protein PSD95 in an in vitro model of synaptic plasticity. We find that local BDNF application promotes persistent accumulation of new PSD95 at stimulated synapses and dendrites of cultured neurons, and that this accumulation is absent in FMRP-deficient mouse neurons. New PSD95 accumulation at sites of BDNF stimulation does not require known mechanisms regulating FMRP-mRNA interactions but instead requires the PI3K-mTORC1-S6K1 pathway. Surprisingly, in FMRP-deficient neurons, BDNF induction of new PSD95 accumulation can be restored by mTORC1-S6K1 blockade, suggesting that constitutively high mTORC1-S6K1 activity occludes PSD95 regulation by BDNF and that alternative pathways exist to mediate induction when mTORC1-S6K1 is inhibited. This study provides direct evidence for deficits in local protein synthesis and accumulation of newly synthesized protein in response to local stimulation in FXS, and supports mTORC1-S6K1 pathway inhibition as a potential therapeutic approach for FXS.
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Homólogo 4 de la Proteína Discs Large/metabolismo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Neuronas/metabolismo , Animales , Dendritas/metabolismo , Síndrome del Cromosoma X Frágil/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/fisiología , Ratas , Transducción de Señal/fisiología , Sinapsis/metabolismoRESUMEN
BACKGROUND AND AIM: Lung cancer is a common malignancy. Non-small cell lung cancer (NSCLC) is divided into lung squamous cancer (LUSC), large cell carcinoma, and adenocarcinoma. More than 85% of lung cancer cases are NSCLC patients. Further exploration of the pathogenesis of lung cancer is of great significance. In this study, functions of far upstream element-binding protein 1 (FUBP1) on the proliferation and tumor immunity of LUSC cells were evaluated. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA) database, Western blot analysis, and immunohistochemistry (IHC) analysis were used to examine the overexpression levels of FUBP1 in LUSC and paracancerous tissues, LUSC cell line, and human normal lung cell line. Then, Western blot assay was employed to validate the transfection efficiency of FUBP1 knockdown in SK-MES-1 cells. Cell counting kit-8 and colony formation assays were used to detect the viability and proliferation of SK-MES-1 cells. Transwell assay was used to examine the migrative and invasive abilities of SK-MES-1 cells. Finally, the xenograft tumor mice model was applied to explore the role of FUBP1 in vivo. IHC assay was used to determine the expression levels FUBP1, PD-L1, and Ki-67. Flow cytometry technology was employed to detect the proportion of CD4+ and CD8+ cells in short sequence negative control (sh-NC) and sh-FUBP1 groups. RESULTS: Collectively, the results first indicated that FUBP1 was up-regulated in LUSC tissues and cells. It was also demonstrated that knockdown of FUBP1 suppressed cell migration, invasion, and proliferation in lung squamous carcinoma cells. Finally, knockdown of FUBP1 regulated tumor immunity in vivo. CONCLUSION: This research suggested that FUBP1 promotes the proliferation of LUSC cells and regulates tumor immunity through programmed death-ligand 1 (PD-L1).
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Proteínas de Unión al ADN/metabolismo , Neoplasias Pulmonares , Proteínas de Unión al ARN/metabolismo , Animales , Antígeno B7-H1/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Proliferación Celular , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Pulmón/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Proteínas de Unión al ARN/genéticaRESUMEN
Previous studies implied that elevated exposure to amphenicol antibiotics may induce increased oxidative stress. However, the effects of amphenicol antibiotics exposure on oxidative stress damage in human have not been well studied. This study examined the associations between amphenicol antibiotics exposure and oxidative damage biomarkers in school children. Three major amphenicols including chloramphenicol (CAP), thiamphenicol (TAP), florfenicol (FF) and two biomarkers of 8-hydroxydeoxyguanosine (8-OHdG) for oxidative DNA damage and 8-oxo-7,8- dihydroguanosine (8-OHG) for oxidative RNA damage were measured in 414 morning urine samples collected from 70 school children in Shanghai, China. School children were exposed to CAP, TAP, and FF with median concentrations of 1.37, 0.36, and 0.06 µg/g Cre, respectively. Linear mixed models revealed that an interquartile range (IQR) increase of urinary TAP was positively associated with 7.75%(95% CI: 4.40%, 11.1%) increase of 8-OHdG and 7.48%(95% CI: 2.49%, 15.6%) increase of 8-OHG, respectively; in addition, CAP was associated with elevated 8-OHdG. Although FF was not found to be significantly associated with either 8-OHdG or 8-OHG, it is warranted to further investigate FF and its metabolites levels in relation to oxidative stress in future study. Our findings provide new evidence for the effects of exposure to TAP and CAP on nucleic acid oxidative damage in Children.
Asunto(s)
Antibacterianos , Cloranfenicol , Biomarcadores/metabolismo , Niño , China , Cloranfenicol/análisis , ADN , Daño del ADN , Humanos , Estrés Oxidativo , ARN/metabolismoRESUMEN
Molybdenum disulfide (MoS2 ) is a promising alternative to Pt-based catalysts for electrocatalytic hydrogen evolution reaction (HER) in an acidic environment. However, alkaline HER activity for molybdenum disulfide is limited by its slow water dissociation kinetics. Interface engineering is an effective strategy for the design of alkaline HER catalysts. However, the restricted heterointerfaces of current catalysts have significantly limited their alkaline HER performance. Herein, a novel assembly of cobalt-doped interface- and defect-rich MoS2 /Ni3 S2 hetero-nanosheet anchoring on hierarchical carbon framework for alkaline HER is reported by directly vulcanizing NiMoO4 nanosheets. In the heterostructure nanosheet, Ni3 S2 acts as a water dissociation promoter and MoS2 acts as a hydrogen acceptor. Density functional theory calculations find that redistribution of charges at the heterointerface can reduce hydrogen adsorption Gibbs free energy (∆GH* ) and water decomposition energy barrier. The resulting hierarchical electrode with the synergistic effect of both hybrid components shows a low overpotential of 89 mV at -10 mA cm-2 in 1 m KOH, a Tafel slope as low as 62 mV dec-1 , and can run at -100 mA cm-2 for at least 50 h without obvious voltage change. This study provides a potentially feasible strategy for the design of heterostructure-based electrocatalysts with abundant active interfaces.