RESUMEN
Chiral amines are commonly used in the pharmaceutical and agrochemical industries1. The strong demand for unnatural chiral amines has driven the development of catalytic asymmetric methods1,2. Although the N-alkylation of aliphatic amines with alkyl halides has been widely adopted for over 100 years, catalyst poisoning and unfettered reactivity have been preventing the development of a catalyst-controlled enantioselective version3-5. Here we report the use of chiral tridentate anionic ligands to enable the copper-catalysed chemoselective and enantioconvergent N-alkylation of aliphatic amines with α-carbonyl alkyl chlorides. This method can directly convert feedstock chemicals, including ammonia and pharmaceutically relevant amines, into unnatural chiral α-amino amides under mild and robust conditions. Excellent enantioselectivity and functional-group tolerance were observed. The power of the method is demonstrated in a number of complex settings, including late-stage functionalization and in the expedited synthesis of diverse amine drug molecules. The current method indicates that multidentate anionic ligands are a general solution for overcoming transition-metal-catalyst poisoning.
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Alquilación , Aminas , Catálisis , Cobre , Amidas/química , Aminas/química , Cobre/química , Ligandos , Preparaciones Farmacéuticas/químicaRESUMEN
Mitophagy is essential for cellular homeostasis, but how mitophagy is regulated is largely unknown. Here we found that the kinase Jnk2 was required for stress-induced mitophagy. Jnk2 promoted ubiquitination and proteasomal degradation of the small mitochondrial form of the tumor suppressor ARF (smARF). Loss of Jnk2 led to the accumulation of smARF, which induced excessive autophagy that resulted in lysosomal degradation of the mitophagy adaptor p62 at steady state. Depletion of p62 prevented Jnk2-deficient cells from mounting mitophagy upon stress. Jnk2-deficient mice displayed defective mitophagy, which resulted in tissue damage under hypoxic stress, as well as hyperactivation of inflammasomes and increased mortality in sepsis. Our findings define a unique mechanism of maintaining immunological homeostasis that protects the host from tissue damage and mortality.
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Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Hipoxia/inmunología , Proteína Quinasa 9 Activada por Mitógenos/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Sepsis/inmunología , Animales , Células Cultivadas , Daño del ADN/fisiología , Femenino , Inflamasomas/metabolismo , Lipopolisacáridos/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Quinasa 9 Activada por Mitógenos/genética , Mitofagia/genética , Proteolisis , Proteínas Proto-Oncogénicas c-myc/metabolismo , Sepsis/inducido químicamente , UbiquitinaciónRESUMEN
The molecular mechanism of tumor metastasis, especially how metastatic tumor cells colonize in a distant site, remains poorly understood. Here we reported that ARHGAP15, a Rho GTPase activating protein, enhanced gastric cancer (GC) metastatic colonization, which was quite different from its reported role as a tumor suppressor gene in other cancers. It was upregulated in metastatic lymph nodes and significantly associated with a poor prognosis. Ectopic expression of ARHGAP15 promoted metastatic colonization of gastric cancer cells in murine lungs and lymph nodes in vivo or protected cells from oxidative-related death in vitro. However, genetic downregulation of ARHGAP15 had the opposite effect. Mechanistically, ARHGAP15 inactivated RAC1 and then decreased intracellular accumulation of reactive oxygen species (ROS), thus enhancing the antioxidant capacity of colonizing tumor cells under oxidative stress. This phenotype could be phenocopied by inhibition of RAC1 or rescued by the introduction of constitutively active RAC1 into cells. Taken together, these findings suggested a novel role of ARHGAP15 in promoting gastric cancer metastasis by quenching ROS through inhibiting RAC1 and its potential value for prognosis estimation and targeted therapy.
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Neoplasias Gástricas , Ratones , Animales , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Gástricas/genética , Regulación hacia Abajo , Estrés Oxidativo , Proteína de Unión al GTP rac1/genética , Línea Celular TumoralRESUMEN
Cancer-associated fibroblasts (CAFs) play vital roles in establishing a suitable tumor microenvironment. In this study, RNA sequencing data revealed that CAFs could promote cell proliferation, angiogenesis, and ECM reconstitution by binding to integrin families and activating PI3K/AKT pathways in esophageal squamous cell carcinoma (ESCC). The secretions of CAFs play an important role in regulating these biological activities. Among these secretions, we found that MFGE8 is specifically secreted by CAFs in ESCC. Additionally, the secreted MFGE8 protein is essential in CAF-regulated vascularization, tumor proliferation, drug resistance, and metastasis. By binding to Integrin αVß3/αVß5 receptors, MFGE8 promotes tumor progression by activating both the PI3K/AKT and ERK/AKT pathways. Interestingly, the biological function of MFGE8 secreted by CAFs fully demonstrated the major role of CAFs in ESCC and its mode of mechanism, showing that MFGE8 could be a driver factor of CAFs in remodeling the tumor environment. In vivo treatment targeting CAFs-secreting MFGE8 or its receptor produced significant inhibitory effects on ESCC growth and metastasis, which provides an approach for the treatment of ESCC.
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Fibroblastos Asociados al Cáncer , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/patología , Fibroblastos Asociados al Cáncer/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Línea Celular Tumoral , Proliferación Celular , Fibroblastos/metabolismo , Microambiente Tumoral , Antígenos de Superficie/metabolismo , Proteínas de la Leche/metabolismoRESUMEN
BACKGROUND AND AIMS: Deregulation of adenosine-to-inosine editing by adenosine deaminase acting on RNA 1 (ADAR1) leads to tumor-specific transcriptome diversity with prognostic values for HCC. However, ADAR1 editase-dependent mechanisms governing liver cancer stem cell (LCSC) generation and maintenance have remained elusive. APPROACH AND RESULTS: RNA-seq profiling identified ADAR1-responsive recoding editing events in HCC and showed editing frequency of GLI1 , rather than transcript abundance was clinically relevant. Functional differences in LCSC self-renewal and tumor aggressiveness between wild-type (GLI1 wt ) and edited GLI1 (GLI1 edit ) were elucidated. We showed that overediting of GLI1 induced an arginine-to-glycine (R701G) substitution, augmenting tumor-initiating potential and exhibiting a more aggressive phenotype. GLI1 R701G harbored weak affinity to SUFU, which in turn, promoted its cytoplasmic-to-nuclear translocation to support LCSC self-renewal by increased pluripotency gene expression. Moreover, editing predisposed to stabilize GLI1 by abrogating ß-TrCP-GLI1 interaction. Integrative analysis of single-cell transcriptome further revealed hyperactivated mitophagy in ADAR1-enriched LCSCs. GLI1 editing promoted a metabolic switch to oxidative phosphorylation to control stress and stem-like state through PINK1-Parkin-mediated mitophagy in HCC, thereby conferring exclusive metastatic and sorafenib-resistant capacities. CONCLUSIONS: Our findings demonstrate a novel role of ADAR1 as an active regulator for LCSCs properties through editing GLI1 in the highly heterogeneous HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/patología , Proteína con Dedos de Zinc GLI1/metabolismo , Proteínas de Unión al ARN/metabolismo , Mitofagia , Células Madre Neoplásicas/metabolismoRESUMEN
The essential role of plastid translation in embryogenesis has been established in many plants, but a retrograde signal triggered by defective plastid translation machinery that may leads to embryogenesis arrest remains unknown. In this study, we characterized an embryo defective27 (emb27) mutant in maize (Zea mays), and cloning indicates that Emb27 encodes the plastid ribosomal protein S13. The null mutant emb27-1 conditions an emb phenotype with arrested embryogenesis; however, the leaky mutant emb27-2 exhibits normal embryogenesis but an albino seedling-lethal phenotype. The emb27-1/emb27-2 trans-heterozygotes display varying phenotypes from emb to normal seeds but albino seedlings. Analysis of the Emb27 transcription levels in these mutants revealed that the Emb27 expression level in the embryo corresponds with the phenotypic expression of the emb27 mutants. In the W22 genetic background, an Emb27 transcription level higher than 6% of the wild-type level renders normal embryogenesis, whereas lower than that arrests embryogenesis. Mutation of Emb27 reduces the level of plastid 16S rRNA and the accumulation of the plastid-encoded proteins. As a secondary effect, splicing of several plastid introns was impaired in emb27-1 and 2 other plastid translation-defective mutants, emb15 and emb16, suggesting that plastome-encoded factors are required for the splicing of these introns, such as Maturase K (MatK). Our results indicate that EMB27 is essential for plastid protein translation, embryogenesis, and seedling development in maize and reveal an expression threshold of Emb27 for maize embryogenesis.
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Regulación de la Expresión Génica de las Plantas , Mutación , Proteínas de Plantas , Plastidios , Plantones , Semillas , Zea mays , Zea mays/genética , Zea mays/embriología , Plantones/genética , Plantones/crecimiento & desarrollo , Semillas/genética , Semillas/crecimiento & desarrollo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Mutación/genética , Plastidios/genética , Plastidios/metabolismo , Fenotipo , Empalme del ARN/genética , Intrones/genética , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismoRESUMEN
Identifying the PPR-E+-NUWA-DYW2 editosome improves our understanding of the C-to-U RNA editing in plant organelles. However, the mechanism of RNA editing remains to be elucidated. Here, we report that GLUTAMINE-RICH PROTEIN23 (GRP23), a previously identified nuclear transcription regulator, plays an essential role in mitochondrial RNA editing through interacting with MORF (multiple organellar RNA-editing factor) proteins and atypical DYW-type pentatricopeptide repeat (PPR) proteins. GRP23 is targeted to mitochondria, plastids, and nuclei. Analysis of the grp23 mutants rescued by embryo-specific complementation shows decreased editing efficiency at 352 sites in mitochondria and 6 sites in plastids, with a predominant specificity for sites edited by the PPR-E and PPR-DYW proteins. GRP23 interacts with atypical PPR-DYW proteins (MEF8, MEF8S, DYW2, and DYW4) and MORF proteins (MORF1 and MORF8), whereas the four PPR-DYWs interact with the two MORFs. These interactions may increase the stability of the GRP23-MORF-atypical PPR-DYW complex. Furthermore, analysis of mef8Nâ³64aamef8s double mutants shows that MEF8/MEF8S are required for the editing of the PPR-E protein-targeted sites in mitochondria. GRP23 could enhance the interaction between PPR-E and MEF8/MEF8S and form a homodimer or heterodimer with NUWA. Genetic complementation analysis shows that the C-terminal domains of GRP23 and NUWA possess a similar function, probably in the interaction with the MORFs. NUWA also interacts with atypical PPR-DYWs in yeast. Both GRP23 and NUWA interact with the atypical PPR-DYWs, suggesting that the PPR-E proteins recruit MEF8/MEF8S, whereas the PPR-E+ proteins specifically recruit DYW2 as the trans deaminase, and then GRP23, NUWA, and MORFs facilitate and/or stabilize the E or E+-type editosome formation.
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Proteínas de Arabidopsis , Arabidopsis , Edición de ARN , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Mitocondrias/metabolismo , Edición de ARN/genética , ARN Mitocondrial/metabolismo , Factores de Transcripción/metabolismoRESUMEN
The 3d transition metal-catalyzed enantioconvergent radical cross-coupling provides a powerful tool for chiral molecule synthesis. In the classic mechanism, the bond formation relies on the interaction between nucleophile-sequestered metal complexes and radicals, limiting the nucleophile scope to sterically uncongested ones. The coupling of sterically congested nucleophiles poses a significant challenge due to difficulties in transmetalation, restricting the reaction generality. Here, we describe a probable outer-sphere nucleophilic attack mechanism that circumvents the challenging transmetalation associated with sterically congested nucleophiles. This strategy enables a general copper-catalyzed enantioconvergent radical N-alkylation of aromatic amines with secondary/tertiary alkyl halides and exhibits catalyst-controlled stereoselectivity. It accommodates diverse aromatic amines, especially bulky secondary and primary ones to deliver value-added chiral amines (>110 examples). It is expected to inspire the coupling of more nucleophiles, particularly challenging sterically congested ones, and accelerate reaction generality.
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Blood-based biomarkers of immune checkpoint inhibitors (ICIs) response in patients with nasopharyngeal carcinoma (NPC) are lacking, so it is necessary to identify biomarkers to select NPC patients who will benefit most or least from ICIs. The absolute values of lymphocyte subpopulations, biochemical indexes, and blood routine tests were determined before ICIs-based treatments in the training cohort (n = 130). Then, the least absolute shrinkage and selection operator (Lasso) Cox regression analysis was developed to construct a prediction model. The performances of the prediction model were compared to TNM stage, treatment, and Epstein-Barr virus (EBV) DNA using the concordance index (C-index). Progression-free survival (PFS) was estimated by Kaplan-Meier (K-M) survival curve. Other 63 patients were used for validation cohort. The novel model composed of histologic subtypes, CD19+ B cells, natural killer (NK) cells, regulatory T cells, red blood cells (RBC), AST/ALT ratio (SLR), apolipoprotein B (Apo B), and lactic dehydrogenase (LDH). The C-index of this model was 0.784 in the training cohort and 0.735 in the validation cohort. K-M survival curve showed patients with high-risk scores had shorter PFS compared to the low-risk groups. For predicting immune therapy responses, the receiver operating characteristic (ROC), decision curve analysis (DCA), net reclassifcation improvement index (NRI) and integrated discrimination improvement index (IDI) of this model showed better predictive ability compared to EBV DNA. In this study, we constructed a novel model for prognostic prediction and immunotherapeutic response prediction in NPC patients, which may provide clinical assistance in selecting those patients who are likely to gain long-lasting clinical benefits to anti-PD-1 therapy.
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Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Infecciones por Virus de Epstein-Barr/complicaciones , Carcinoma Nasofaríngeo/terapia , Herpesvirus Humano 4 , Inmunoterapia , Pronóstico , Antígenos CD19 , Neoplasias Nasofaríngeas/terapia , ADNRESUMEN
Sterols have long been associated with diverse fields, such as cancer treatment, drug development, and plant growth; however, their underlying mechanisms and functions remain enigmatic. Here, we unveil a critical role played by a GmNF-YC9-mediated CCAAT-box transcription complex in modulating the steroid metabolism pathway within soybeans. Specifically, this complex directly activates squalene monooxygenase (GmSQE1), which is a rate-limiting enzyme in steroid synthesis. Our findings demonstrate that overexpression of either GmNF-YC9 or GmSQE1 significantly enhances soybean stress tolerance, while the inhibition of SQE weakens this tolerance. Field experiments conducted over two seasons further reveal increased yields per plant in both GmNF-YC9 and GmSQE1 overexpressing plants under drought stress conditions. This enhanced stress tolerance is attributed to the reduction of abiotic stress-induced cell oxidative damage. Transcriptome and metabolome analyses shed light on the upregulation of multiple sterol compounds, including fucosterol and soyasaponin II, in GmNF-YC9 and GmSQE1 overexpressing soybean plants under stress conditions. Intriguingly, the application of soybean steroids, including fucosterol and soyasaponin II, significantly improves drought tolerance in soybean, wheat, foxtail millet, and maize. These findings underscore the pivotal role of soybean steroids in countering oxidative stress in plants and offer a new research strategy for enhancing crop stress tolerance and quality from gene regulation to chemical intervention.
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Glycine max , Estrés Fisiológico , Glycine max/genética , Glycine max/fisiología , Glycine max/metabolismo , Estrés Fisiológico/genética , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Plantas Modificadas Genéticamente , Esteroides/metabolismo , Sequías , Productos Agrícolas/genética , Productos Agrícolas/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genéticaRESUMEN
Copper (Cu) is an essential micronutrient for all living organisms but is also highly toxic in excess. Cellular homoeostasis of Cu is maintained by various transporters and metallochaperones. Here, we investigated the biological function of OsCOPT7, a member of the copper transporters (COPT) family, in Cu homoeostasis in rice. OsCOPT7 was mainly expressed in the roots and the expression was upregulated by Cu deficiency. OsCOPT7 was localized at the tonoplast and the endoplasmic reticulum. Knockout of OsCOPT7 increased Cu accumulation in the roots but decreased Cu concentrations in the shoots and grain. The knockout mutants contained higher concentrations of Cu in the roots cell sap but markedly lower concentrations of Cu in the xylem sap than wild-type plants. Seed setting and grain yield were reduced significantly in the knockout mutants grown in a low Cu soil. Knockout mutants were more tolerant to Cu toxicity. Yeast two-hybrid and bimolecular fluorescence complementation assays showed that OsCOPT7 interacts physically with the rice Cu chaperone antioxidant protein 1 (OsATX1). Taken together, our results indicate that OsCOPT7 is a specific Cu transporter functioning to export Cu from the vacuoles and the ER and plays an important role in controlling the root-to-shoot Cu translocation in rice.
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Cobre , Retículo Endoplásmico , Regulación de la Expresión Génica de las Plantas , Oryza , Proteínas de Plantas , Transporte Biológico , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/genética , Cobre/metabolismo , Grano Comestible/metabolismo , Grano Comestible/genética , Retículo Endoplásmico/metabolismo , Técnicas de Inactivación de Genes , Oryza/metabolismo , Oryza/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Raíces de Plantas/metabolismo , Brotes de la Planta/metabolismo , Semillas/metabolismo , Semillas/genética , Vacuolas/metabolismoRESUMEN
Cadmium (Cd) is a toxic metal that poses serious threats to human health. Rice is a major source of dietary Cd but how rice plants transport Cd to the grain is not fully understood. Here, we characterize the function of the ZIP (ZRT, IRT-like protein) family protein, OsZIP2, in the root-to-shoot translocation of Cd and intervascular transfer of Cd in nodes. OsZIP2 is localized at the plasma membrane and exhibited Cd2+ transport activity when heterologously expressed in yeast. OsZIP2 is strongly expressed in xylem parenchyma cells in roots and in enlarged vascular bundles in nodes. Knockout of OsZIP2 significantly enhanced root-to-shoot translocation of Cd and alleviated the inhibition of root elongation by excess Cd stress; whereas overexpression of OsZIP2 decreased Cd translocation to shoots and resulted in Cd sensitivity. Knockout of OsZIP2 increased Cd allocation to the flag leaf but decreased Cd allocation to the panicle and grain. We further reveal that the variation of OsZIP2 expression level contributes to grain Cd concentration among rice germplasms. Our results demonstrate that OsZIP2 functions in root-to-shoot translocation of Cd in roots and intervascular transfer of Cd in nodes, which can be used for breeding low Cd rice varieties.
RESUMEN
Cadmium (Cd) is highly toxic to plants, but the targets and modes of toxicity remain unclear. We isolated a Cd-hypersensitive mutant of Arabidopsis thaliana, Cd-induced short root 2 (cdsr2), in the background of the phytochelatin synthase-defective mutant cad1-3. Both cdsr2 and cdsr2 cad1-3 displayed shorter roots and were more sensitive to Cd than their respective wild type. Using genomic resequencing and complementation, IAR4 was identified as the causal gene, which encodes a putative mitochondrial pyruvate dehydrogenase E1α subunit. cdsr2 showed decreased pyruvate dehydrogenase activity and NADH content, but markedly increased concentrations of pyruvate and alanine in roots. Both Cd stress and IAR4 mutation decreased auxin level in the root tips, and the effect was additive. A higher growth temperature rescued the phenotypes in cdsr2. Exogenous alanine inhibited root growth and decreased auxin level in the wild type. Cadmium stress suppressed the expression of genes involved in auxin biosynthesis, hydrolysis of auxin-conjugates and auxin polar transport. Our results suggest that auxin homeostasis is a key target of Cd toxicity, which is aggravated by IAR4 mutation due to decreased pyruvate dehydrogenase activity. Decreased auxin level in cdsr2 is likely caused by increased auxin-alanine conjugation and decreased energy status in roots.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Cadmio/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Homeostasis , Mutación , Ácidos Indolacéticos/metabolismo , Alanina , Piruvatos/metabolismo , Piruvatos/farmacología , Oxidorreductasas/metabolismo , Raíces de Plantas/metabolismoRESUMEN
Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1's phenotype.
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Síndrome de Prader-Willi , Humanos , Ratones , Animales , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/psicología , Microglía , Proteínas Portadoras/genética , Fenotipo , Fagosomas , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
Atg2 is a key gene in autophagy formation and plays an important role in regulating aging progress. Exercise is an important tool to resist oxidative stress in cells and delay muscle aging. However, the relationship between exercise and the muscle Atg2 gene in regulating skeletal muscle aging remains unclear. Here, overexpression or knockdown of muscle Atg2 gene was achieved by constructing the AtgUAS/MhcGal4 system in Drosophila, and these flies were also subjected to an exercise intervention for 2 weeks. The results showed that both overexpression of Atg2 and exercise significantly increased the climbing speed, climbing endurance, cardiac function, and lifespan of aging flies. They also significantly up-regulated the expression of muscle Atg2, AMPK, Sirt1, and PGC-1α genes, and they significantly reduced muscle malondialdehyde and triglyceride. These positive benefits were even more pronounced when the two were combined. However, the effects of Atg2 knockdown on skeletal muscle, heart, and lifespan were reversed compared to its overexpression. Importantly, exercise ameliorated age-related changes induced by Atg2 knockdown. Therefore, current results confirmed that both overexpression of muscle Atg2 and exercise delayed age-related deteriorations of skeletal muscle, the heart function, and lifespan, and exercise could also reverse age-related changes induced by Atg2 knockdown. The molecular mechanism is related to the overexpression of the Atg2 gene and exercise, which increase the activity of the AMPK/Sirt1/PGC-1α pathway, oxidation and antioxidant balance, and lipid metabolism in aging muscle.
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Proteínas de Drosophila , Condicionamiento Físico Animal , Animales , Masculino , Humanos , Sirtuina 1/genética , Sirtuina 1/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Drosophila/metabolismo , Músculo Esquelético/metabolismo , Condicionamiento Físico Animal/fisiología , Terapia por Ejercicio , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Proteínas Relacionadas con la Autofagia/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismoRESUMEN
The phosphatase and tensin congeners (Pten) gene affects cell growth, cell proliferation, and rearrangement of connections, and it is closely related to cellular senescence, but it remains unclear the role of muscle-Pten gene in exercise against age-related deterioration in skeletal muscle and mortality induced by a high-salt diet (HSD). In here, overexpression and knockdown of muscle Pten gene were constructed by building MhcGAL4 /PtenUAS-overexpression and MhcGAL4 /PtenUAS-RNAi system in flies, and flies were given exercise training and a HSD for 2 weeks. The results showed that muscle Pten knockdown significantly reduced the climbing speed, climbing endurance, GPX activity, and the expression of Pten, Sirt1, PGC-1α genes, and it significantly increased the expression of Akt and ROS level, and impaired myofibril and mitochondria of aged skeletal muscle. Pten knockdown prevented exercise from countering the HSD-induced age-related deterioration of skeletal muscle. Pten overexpression has the opposite effect on skeletal muscle aging when compared to it knockdown, and it promoted exercise against HSD-induced age-related deterioration of skeletal muscle. Pten overexpression significantly increased lifespan, but its knockdown significantly decreased lifespan of flies. Thus, current results confirmed that differential expression of muscle Pten gene played an important role in regulating skeletal muscle aging and lifespan, and it also affected the adaptability of aging skeletal muscle to physical exercise since it determined the activity of muscle Pten/Akt pathway and Pten/Sirt1/PGC-1α pathway.
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Condicionamiento Físico Animal , Sirtuina 1 , Animales , Sirtuina 1/metabolismo , Drosophila/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Condicionamiento Físico Animal/fisiología , Músculo Esquelético/metabolismo , Dieta , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismoRESUMEN
The present case study reported a patient diagnosed with hypertrophic olivary degeneration, a rare condition characterized by a trans-neuronal degeneration and signal enhancement in T2-weighted images on magnetic resonance imaging, usually caused by cerebral hemorrhage, cerebral infarction, and trauma. Furthermore, the relevant literature review was performed. The existing pharmacological treatment has limited clinical benefits on the patient. Since spontaneous remission hardly occurs in the disease, there are no other effective treatments. In this case, the patient was a 55-year-old Chinese male who presented progressive gait difficulty for several months due to both-sided ataxia. Neurological examination revealed upper extremity and lower limb bilateral spasticity, ataxia, slurred speech, and dysmetria. Therefore, our study treated the patient through the inventive application of cerebello-spinal transcranial direct current stimulation and body weight-supported treadmill training. After a 4-week treatment, the patient could walk independently, without aid, speeding up by 7%, as well as the ataxia symptoms, and balance has improved significantly. It was demonstrated in this case report that the combination of cerebello-spinal tDCS and body weight-supported treadmill training can be an effective treatment for patients with Hypertrophic olivary degeneration.
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Hipertrofia , Núcleo Olivar , Estimulación Transcraneal de Corriente Directa , Humanos , Masculino , Persona de Mediana Edad , Núcleo Olivar/patología , Núcleo Olivar/diagnóstico por imagen , Estimulación Transcraneal de Corriente Directa/métodos , Terapia por Ejercicio/métodos , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Enfermedades Neurodegenerativas/terapia , Degeneración OlivarRESUMEN
Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuroregulatory technique used to treat neurodegenerative diseases, holds promise for spinocerebellar ataxia type 3 (SCA3) treatment, although its efficacy and mechanisms remain unclear. This study aims to observe the short-term impact of cerebellar rTMS on motor function in SCA3 patients and utilize resting-state functional magnetic resonance imaging (RS-fMRI) to assess potential therapeutic mechanisms. Twenty-two SCA3 patients were randomly assigned to receive actual rTMS (AC group, n = 11, three men and eight women; age 32-55 years) or sham rTMS (SH group, n = 11, three men and eight women; age 26-58 years). Both groups underwent cerebellar rTMS or sham rTMS daily for 15 days. The primary outcome measured was the ICARS scores and parameters for regional brain activity. Compared to baseline, ICARS scores decreased more significantly in the AC group than in the SH group after the 15-day intervention. Imaging indicators revealed increased Amplitude of Low Frequency Fluctuation (ALFF) values in the posterior cerebellar lobe and cerebellar tonsil following AC stimulation. This study suggests that rTMS enhances motor functions in SCA3 patients by modulating the excitability of specific brain regions and associated pathways, reinforcing the potential clinical utility of rTMS in SCA3 treatment. The Chinese Clinical Trial Registry identifier is ChiCTR1800020133.
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INTRODUCTION/AIMS: The current diagnosis of ulnar neuropathy at the elbow (UNE) relies mainly on the clinical presentation and nerve electrodiagnostic (EDX) testing, which can be uncomfortable and yield false negatives. The aim of this study was to investigate the diagnostic value of conventional ultrasound, shear wave elastography (SWE), and superb microvascular imaging (SMI) in diagnosing UNE. METHODS: We enrolled 40 patients (48 elbows) with UNE and 48 healthy volunteers (48 elbows). The patients were categorized as having mild, moderate or severe UNE based on the findings of EDX testing. The cross-sectional area (CSA) was measured using conventional ultrasound. Ulnar nerve (UN) shear wave velocity (SWV) and SMI were performed in a longitudinal plane. RESULTS: Based on the EDX findings, UNE severity was graded as mild in 4, moderate in 10, and severe in 34. The patient group showed increased ulnar nerve CSA and stiffness at the site of maximal enlargement (CSA mean at the site of max enlargement [CSAmax] and SWV mean at the site of max enlargement [SWVmax]), ulnar nerve CSA ratio, and stiffness ratio (elbow-to-upper arm), compared with the control group (p < .001). Furthermore, the severe UNE group showed higher ulnar nerve CSAmax and SWVmax compared with the mild and moderate UNE groups (p < .001). The cutoff values for diagnosis of UNE were 9.5 mm2 for CSAmax, 3.06 m/s for SWVmax, 2.00 for CSA ratio, 1.36 for stiffness ratio, and grade 1 for SMI. DISCUSSION: Our findings suggest that SWE and SMI are valuable diagnostic tools for the diagnosis and assessment of severity of UNE.
Asunto(s)
Diagnóstico por Imagen de Elasticidad , Codo , Nervio Cubital , Neuropatías Cubitales , Ultrasonografía , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Diagnóstico por Imagen de Elasticidad/métodos , Neuropatías Cubitales/diagnóstico por imagen , Neuropatías Cubitales/fisiopatología , Codo/diagnóstico por imagen , Ultrasonografía/métodos , Anciano , Nervio Cubital/diagnóstico por imagen , Nervio Cubital/fisiopatología , Microvasos/diagnóstico por imagen , Electrodiagnóstico/métodosRESUMEN
The nature of glassy states in realistic finite dimensions is still under fierce debate. Lattice models can offer valuable insights and facilitate deeper theoretical understanding. Recently, a disordered-interacting lattice model with distinguishable particles in two dimensions (2D) has been shown to produce a wide range of dynamical properties of structural glasses, including the slow and heterogeneous characteristics of the glassy dynamics, various fragility behaviors of glasses, and so on. These findings support the usefulness of this model for modeling structural glasses. An important question is whether such properties still hold in the more realistic three dimensions. In this study, we aim to extend the distinguishable-particle lattice model (DPLM) to three dimensions (3D) and explore the corresponding glassy dynamics. Through extensive kinetic Monte Carlo simulations, we found that the 3D DPLM exhibits many typical glassy behaviors, such as plateaus in the mean square displacement of particles and the self-intermediate scattering function, dynamic heterogeneity, variability of glass fragilities, and so on, validating the effectiveness of the DPLM in a broader realistic setting. The observed glassy behaviors of the 3D DPLM appear similar to those of its 2D counterpart, in accordance with recent findings in molecular models of glasses. We further investigate the role of void-induced motions in dynamical relaxations and discuss their relation to dynamic facilitation. As lattice models tend to keep the minimal but important modeling elements, they are typically much more amenable to analysis. Therefore, we envisage that the DPLM will benefit future theoretical developments, such as the configuration tree theory, towards a more comprehensive understanding of structural glasses.