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Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.
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Apoptose , Senescência Celular , Citosol , DNA Mitocondrial , Mitocôndrias , Animais , Camundongos , Citosol/metabolismo , DNA Mitocondrial/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Necrose Dirigida por Permeabilidade Transmembrânica da Mitocôndria , Estudo de Prova de Conceito , Inflamação/metabolismo , Fenótipo , Longevidade , Envelhecimento SaudávelRESUMO
Cellular senescence is a potent tumor suppressor mechanism but also contributes to aging and aging-related diseases. Senescence is characterized by a stable cell cycle arrest and a complex proinflammatory secretome, termed the senescence-associated secretory phenotype (SASP). We recently discovered that cytoplasmic chromatin fragments (CCFs), extruded from the nucleus of senescent cells, trigger the SASP through activation of the innate immunity cytosolic DNA sensing cGAS-STING pathway. However, the upstream signaling events that instigate CCF formation remain unknown. Here, we show that dysfunctional mitochondria, linked to down-regulation of nuclear-encoded mitochondrial oxidative phosphorylation genes, trigger a ROS-JNK retrograde signaling pathway that drives CCF formation and hence the SASP. JNK links to 53BP1, a nuclear protein that negatively regulates DNA double-strand break (DSB) end resection and CCF formation. Importantly, we show that low-dose HDAC inhibitors restore expression of most nuclear-encoded mitochondrial oxidative phosphorylation genes, improve mitochondrial function, and suppress CCFs and the SASP in senescent cells. In mouse models, HDAC inhibitors also suppress oxidative stress, CCF, inflammation, and tissue damage caused by senescence-inducing irradiation and/or acetaminophen-induced mitochondria dysfunction. Overall, our findings outline an extended mitochondria-to-nucleus retrograde signaling pathway that initiates formation of CCF during senescence and is a potential target for drug-based interventions to inhibit the proaging SASP.
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Núcleo Celular/patologia , Senescência Celular/fisiologia , Cromatina/patologia , Citoplasma/patologia , Mitocôndrias/patologia , Transdução de Sinais , Animais , Núcleo Celular/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Inflamação/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismoRESUMO
ABSTRACT: Aberrant expression of stem cell-associated genes is a common feature in acute myeloid leukemia (AML) and is linked to leukemic self-renewal and therapy resistance. Using AF10-rearranged leukemia as a prototypical example of the recurrently activated "stemness" network in AML, we screened for chromatin regulators that sustain its expression. We deployed a CRISPR-Cas9 screen with a bespoke domain-focused library and identified several novel chromatin-modifying complexes as regulators of the TALE domain transcription factor MEIS1, a key leukemia stem cell (LSC)-associated gene. CRISPR droplet sequencing revealed that many of these MEIS1 regulators coordinately controlled the transcription of several AML oncogenes. In particular, we identified a novel role for the Tudor-domain-containing chromatin reader protein SGF29 in the transcription of AML oncogenes. Furthermore, SGF29 deletion impaired leukemogenesis in models representative of multiple AML subtypes in multiple AML subtype models. Our studies reveal a novel role for SGF29 as a nononcogenic dependency in AML and identify the SGF29 Tudor domain as an attractive target for drug discovery.
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Proteínas de Homeodomínio , Leucemia Mieloide Aguda , Humanos , Proteínas de Homeodomínio/genética , Cromatina/genética , Fatores de Transcrição/genética , Proteína Meis1/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , CarcinogêneseRESUMO
We report the structure-based pathogenicity relationship identifier (SPRI), a novel computational tool for accurate evaluation of pathological effects of missense single mutations and prediction of higher-order spatially organized units of mutational clusters. SPRI can effectively extract properties determining pathogenicity encoded in protein structures, and can identify deleterious missense mutations of germ line origin associated with Mendelian diseases, as well as mutations of somatic origin associated with cancer drivers. It compares favorably to other methods in predicting deleterious mutations. Furthermore, SPRI can discover spatially organized pathogenic higher-order spatial clusters (patHOS) of deleterious mutations, including those of low recurrence, and can be used for discovery of candidate cancer driver genes and driver mutations. We further demonstrate that SPRI can take advantage of AlphaFold2 predicted structures and can be deployed for saturation mutation analysis of the whole human proteome.
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Mutação de Sentido Incorreto , Neoplasias , Humanos , Virulência , Mutação , Neoplasias/genética , Biologia Computacional/métodosRESUMO
In multicellular eukaryotes, autophagy is a conserved process that delivers cellular components to the vacuole or lysosome for recycling during development and stress responses. Induction of autophagy activates AUTOPHAGY-RELATED PROTEIN 1 (ATG1) and ATG13 to form a protein kinase complex that initiates autophagosome formation. However, the detailed molecular mechanism underlying the regulation of this protein complex in plants remains unclear. Here, we determined that in Arabidopsis thaliana, the regulatory proteins 14-3-3λ and 14-3-3κ redundantly modulate autophagy dynamics by facilitating SEVEN IN ABSENTIA OF ARABIDOPSIS THALIANA (SINAT)-mediated proteolysis of ATG13a and ATG13b. 14-3-3λ and 14-3-3κ directly interacted with SINATs and ATG13a/b in vitro and in vivo. Compared to wild-type (WT), the 14-3-3λ 14-3-3κ double mutant showed increased tolerance to nutrient starvation, delayed leaf senescence, and enhanced starvation-induced autophagic vesicles. Moreover, 14-3-3s were required for SINAT1-mediated ubiquitination and degradation of ATG13a. Consistent with their roles in ATG degradation, the 14-3-3λ 14-3-3κ double mutant accumulated higher levels of ATG1a/b/c and ATG13a/b than the WT upon nutrient deprivation. Furthermore, the specific association of 14-3-3s with phosphorylated ATG13a was crucial for ATG13a stability and formation of the ATG1-ATG13 complex. Thus, our findings demonstrate that 14-3-3λ and 14-3-3κ function as molecular adaptors to regulate autophagy by modulating the homeostasis of phosphorylated ATG13.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Autofagia/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Induction of autophagic death in cancer cells is one of the promising strategies for the development of anti-cancer therapeutics. In the present study, we designed and synthesized a series of isatin Schiff base derivatives containing thioether structures. After discovering the highly active target compound H13 (IC50 = 4.83 µM) based on in vitro antiproliferation, we also found it had a high safety against normal cells HEK293 with CC50 of 69.01 µM, indicating a sufficient therapeutic window. In addition, to provide reference for subsequent studies, a model was successfully constructed by Sybyl software. Preliminary mechanistic studies suggested that H13-induced apoptosis may be closely related to ROS accumulation and mitochondrial dysfunction. Subsequent studies revealed that H13 inhibited cell proliferation by inducing cellular autophagy mainly through blocking signal of the PI3K/AKT/mTOR pathway. Altogether, these results suggested that H13 was potentially valuable as a lead compound.
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OBJECTIVE: As women approach perimenopause, the incidence of Subjective Cognitive Decline (SCD) rises. This study aims to investigate the association between SCD and the severity of perimenopausal symptoms. SETTING: Conducted at The Affiliated Hospital of Guizhou Medical University Menopause Clinic from November 2022 to June 2023. Participants, aged 40-55 years, were classified as perimenopausal using the STRAW + 10 criteria. METHODS: SCD was assessed separately using the Chinese version of the SCD-Q9 scale and the SCD International Working Group (SCD-I) conceptual framework, while perimenopausal symptoms were evaluated with the Modified Kupperman Index (MKI). Linear relationships between MKI scores and SCD-Q9 scores were clarified using both univariate and multivariate linear regression analyses. Additionally, a multivariate Logistic regression analysis was conducted to examine the association between MKI scores and SCD classification based on SCD-I criteria. MAIN OUTCOME MEASURES: The primary outcomes were the Modified Kupperman Index scores, SCD-Q9 questionnaire scores, and the diagnosis of SCD based on SCD-I criteria. RESULTS: Among 101 participants, the average MKI score was 18.90 ± 9.74, and the average SCD-Q9 score was 4.57 ± 2.29. Both univariate and multivariate linear regressions demonstrated a positive correlation between these scores. A multivariate Logistic regression analysis, using MKI as the independent variable and SCD-I criteria classification as the dependent variable, revealed a significant positive association. CONCLUSIONS: A notable association exists between SCD and perimenopausal symptoms severity. This underscores the potential clinical importance of addressing perimenopausal symptoms to mitigate SCD risks in women. Further studies should focus on clarifying the causality between these factors.
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Disfunção Cognitiva , Perimenopausa , Humanos , Feminino , Perimenopausa/psicologia , Pessoa de Meia-Idade , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Adulto , Índice de Gravidade de Doença , Inquéritos e Questionários , China/epidemiologiaRESUMO
Mass shootings are horrific events that annually take scores of innocent lives in the United States. Federal, state, and local governments as well as educational, religious, and private-sector organizations propose and enact polices and strategies to protect people from and during active shooter situations. A probabilistic risk assessment of a mass shooting for a specific organization, jurisdiction, or location can be the first step toward evaluating the effectiveness of risk mitigation strategies and determining which strategies might be most appropriate for a location. This article proposes a novel hierarchical method to assess the probability of a mass shooting at specific locations based on available historical data. First, the method generates a probability distribution over the annual number of mass shootings in the United States. Second, the article uses this national number of mass shootings to determine the risk for each state. Third, the state risk assessment is decomposed to calculate the probability of a mass shooting in a specific location such as a school. Multiple ways to assess the risk are presented, leading to slightly different probability assessments for a location. Results indicate that annual probability of a mass shooting in the largest high school in California is on the order of 10 - 6 - 10 - 5 $10^{-6}-10^{-5}$ , and the annual probability of a mass shooting in the largest high school in Iowa is about half as likely as in the California school.
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Proton exchange membrane water electrolysis is a highly promising hydrogen production technique for sustainable energy supply, however, achieving a highly active and durable catalyst for acidic water oxidation still remains a formidable challenge. Herein, we propose a local microenvironment regulation strategy for precisely tuning In-RuO2 /graphene (In-RuO2 /G) catalyst with intrinsic electrochemical activity and stability to boost acidic water oxidation. The In-RuO2 /G displays robust acid oxygen evolution reaction performance with a mass activity of 671â A gcat -1 at 1.5â V, an overpotential of 187â mV at 10â mA cm-2 , and long-lasting stability of 350â h at 100â mA cm-2 , which arises from the asymmetric Ru-O-In local structure interactions. Further, it is unraveled theoretically that the asymmetric Ru-O-In structure breaks the thermodynamic activity limit of the traditional adsorption evolution mechanism which significantly weakens the formation energy barrier of OOH*, thus inducing a new rate-determining step of OH* absorption. Therefore, this strategy showcases the immense potential for constructing high-performance acidic catalysts for water electrolyzers.
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Tuning the coordination environment of the metal center in metal-nitrogen-carbon (M-N-C) single-atom catalysts via heteroatom-doping (oxygen, phosphorus, sulfur, etc.) is effective for promoting electrocatalytic CO2 reduction reaction (CO2 RR). However, few studies are investigated establishing efficient CO2 reduction by introducing boron (B) atoms to regulate the M-N-C structure. Herein, a B-C3 N4 self-sacrifice strategy is developed to synthesize B, N co-coordinated Ni single atom catalyst (Ni-BNC). X-ray absorption spectroscopy and high-angle annular dark field scanning transmission electron microscopy confirm the structure (Ni-N3 B/C). The Ni-BNC catalyst presents a maximum CO Faradaic efficiency (FECO ) of 98.8% and a large CO current density (jCO ) of -62.9 mA cm-2 at -0.75 and -1.05 V versus reversible hydrogen electrode, respectively. Furthermore, FECO could be maintained above 95% in a wide range of potential windows from -0.65 to -1.05 V. In situ experiments and density functional theory calculations demonstrate the Ni-BNC catalyst with B atoms coordinated to the central Ni atoms could significantly reduce the energy barrier for the conversion of *CO2 to *COOH, leading to excellent CO2 RR performance.
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Heteroatom-doping is an effective method for modifying the geometric symmetry of metal-nitrogen-carbon (M-N-C) single-atom catalysts and thereby tuning the electronic structure. Up to now, most of the current reports have concentrated on introducing heteroatoms into the highly symmetrical M-N4 structure. The coordination-unsaturated M-N2 structure is more sterically favorable for the insertion of alien atoms to optimize the electronic structure. Herein, a Ni-N2 catalyst with out-of-plane coordinated chlorine (Cl) atoms (Ni-N2 Cl/C) is successfully constructed on chlorine-functionalized carbon supports (C-Cl) for an efficient carbon dioxide reduction reaction (CO2 RR). Density functional theory calculations demonstrate that the prepared Ni-N2 Cl/C catalyst exhibits a higher capability in balancing COOH* formation and CO* desorption. In addition, in situ Raman spectra confirm that the lower CO binding energy on the Ni-N2 Cl/C facilitates CO escape, leading to excellent CO2 RR performance. A high CO Faradaic efficiency (FECO ) of more than 80% is achieved from -0.6 to -1.2 V versus reversible hydrogen electrode on the Ni-N2 Cl/C and it exhibits negligible FECO and current declination over a 40-h stability test. Furthermore, a high turnover frequency (TOF) value of 15 808 h-1 is obtained, which is more than ten times that of Ni-N2 /C (1476 h-1 ) without coordinated Cl atoms.
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Leukemias bearing fusions of the AF10/MLLT10 gene are associated with poor prognosis, and therapies targeting these fusion proteins (FPs) are lacking. To understand mechanisms underlying AF10 fusion-mediated leukemogenesis, we generated inducible mouse models of acute myeloid leukemia (AML) driven by the most common AF10 FPs, PICALM/CALM-AF10 and KMT2A/MLL-AF10, and performed comprehensive characterization of the disease using transcriptomic, epigenomic, proteomic, and functional genomic approaches. Our studies provide a detailed map of gene networks and protein interactors associated with key AF10 fusions involved in leukemia. Specifically, we report that AF10 fusions activate a cascade of JAK/STAT-mediated inflammatory signaling through direct recruitment of JAK1 kinase. Inhibition of the JAK/STAT signaling by genetic Jak1 deletion or through pharmacological JAK/STAT inhibition elicited potent antioncogenic effects in mouse and human models of AF10 fusion AML. Collectively, our study identifies JAK1 as a tractable therapeutic target in AF10-rearranged leukemias.
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Carcinogênese , Rearranjo Gênico , Janus Quinases , Sistema de Sinalização das MAP Quinases/genética , Proteínas de Neoplasias , Fatores de Transcrição STAT , Fatores de Transcrição , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Feminino , Humanos , Janus Quinases/genética , Janus Quinases/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Células U937RESUMO
In eukaryotes, autophagy maintains cellular homeostasis by recycling cytoplasmic components. The autophagy-related proteins (ATGs) ATG1 and ATG13 form a protein kinase complex that regulates autophagosome formation; however, mechanisms regulating ATG1 and ATG13 remain poorly understood. Here, we show that, under different nutrient conditions, the RING-type E3 ligases SEVEN IN ABSENTIA OF ARABIDOPSIS THALIANA1 (SINAT1), SINAT2, and SINAT6 control ATG1 and ATG13 stability and autophagy dynamics by modulating ATG13 ubiquitylation in Arabidopsis (Arabidopsis thaliana). During prolonged starvation and recovery, ATG1 and ATG13 were degraded through the 26S proteasome pathway. TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR1a (TRAF1a) and TRAF1b interacted in planta with ATG13a and ATG13b and required SINAT1 and SINAT2 to ubiquitylate and degrade ATG13s in vivo. Moreover, lysines K607 and K609 of ATG13a protein contributed to K48-linked ubiquitylation and destabilization, and suppression of autophagy. Under starvation conditions, SINAT6 competitively interacted with ATG13 and induced autophagosome biogenesis. Furthermore, under starvation conditions, ATG1 promoted TRAF1a protein stability in vivo, suggesting feedback regulation of autophagy. Consistent with ATGs functioning in autophagy, the atg1a atg1b atg1c triple knockout mutants exhibited premature leaf senescence, hypersensitivity to nutrient starvation, and reduction in TRAF1a stability. Therefore, these findings demonstrate that SINAT family proteins facilitate ATG13 ubiquitylation and stability and thus regulate autophagy.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Autofagia/fisiologia , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Transporte/metabolismo , Proteínas de Membrana , Proteínas Mitocondriais , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral , Ubiquitina-Proteína Ligases/genética , UbiquitinaçãoRESUMO
BACKGROUND: Early exposure to sevoflurane may cause brain tissue degeneration; however, the mechanism involved in this process has not been explored. In this study, we investigated the role of long non-coding RNA small nucleolar RNA host gene 3 (lncRNA SNHG3) in sevoflurane-induced neuronal injury. METHODS: The injury models of HT22 and primary cultures of neurons were constructed using sevoflurane treatment. The WST-8 reduction was detected by CCK-8 assay, the level of inflammatory factors was detected by enzyme-linked immunosorbent assay (ELISA), and cell pyroptosis was detected by flow cytometry. The expression of genes and proteins was detected by qRT-PCR and Western blot, respectively. The level of ß-tubulin III in primary cultures of hippocampal neurons was analyzed by immunofluorescence. The relationship among SNHG3, PTBP1 and NEK7 was confirmed by RIP assay. RESULTS: The expression of SNHG3 and NEK7 were enhanced in sevoflurane-treated HT22 cells. Sevoflurane inhibited the WST-8 reduction in a concentration-dependent manner, promoted the pyroptosis, and increased pyroptosis-related protein expression. SNHG3 knockdown significantly inhibited sevoflurane-induced pyroptosis and inflammatory injury in HT22 cells and primary cultures of neurons. Furthermore, SNHG3 regulated NEK7 expression by binding to PTBP1. NEK7 knockdown reversed the decrease in WST-8 reduction, inhibited pyroptosis, and decreased the release of inflammatory factors and pyroptosis-related protein expression by inactivation of NLRP3 signaling in sevoflurane-induced HT22 cells. Moreover, NEK7 overexpression attenuated the effect of SNHG3 knockdown on neuronal pyroptosis and inflammation injury. CONCLUSION: Downregulation of SNHG3 attenuates sevoflurane-induced neuronal inflammation and pyroptosis by mediating the NEK7/NLRP3 axis, suggesting that SNHG3 could be a potential target gene for neuronal injury.
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MicroRNAs , RNA Longo não Codificante , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Sevoflurano/toxicidade , Inflamação/induzido quimicamente , Inflamação/metabolismo , Neurônios/metabolismo , MicroRNAs/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Quinases Relacionadas a NIMA/metabolismoRESUMO
Cisplatin (DDP) based chemotherapy occurs a reduced therapeutic effect on the later treatment of ovarian cancer (OC) due to DDP resistance. Astragaloside II (ASII), a natural product extracted from Radix Astragali, has shown promising anticancer effects. However, the effects of ASII on OC have not been clarified. In this study, we found that ASII inhibited cell growth and promoted cell apoptosis of DDP-resistant OC cells in vitro and in vivo. Further study showed that ASII downregulated multidrug resistance-related protein MDR1 and cell cycle-related protein Cyclin D1 and PCNA, and also upregulated apoptosis-related protein leaved PRAP and cleaved caspase-3. In addition, ASII induced autophagy, characterized by upregulation of LC3II expression, downregulation of p62 expression, and elevation of LC3 punctuation, may be associated with inhibition of the AKT/mTOR signaling pathway. Moreover, the messenger RNA-sequencing was used to identify potential molecules regulated by ASII. In conclusion, these findings indicated that ASII increased sensitivity of DDP in the treatment of OC.
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Antineoplásicos , Neoplasias Ovarianas , Humanos , Feminino , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Apoptose , AutofagiaRESUMO
BACKGROUND: Laparoscopic cholecystectomy is the gold standard surgical procedure for treating gallstone disease. Despite it being minimally invasive, various medications and methods are used to alleviate postoperative pain, and some patients still experience moderate-to-severe pain. This is a crucial problem that must be solved to avoid chronic pain. As part of postoperative multimodal analgesia, regional block is being increasingly applied in surgery under ultrasound guidance. We aimed to evaluate the analgesic effect of erector spinae plane block in adult patients undergoing laparoscopic cholecystectomy. METHODS: PubMed, Cochrane Library, EMBASE, and Web of Science were searched for randomized controlled trials investigating the efficacy of erector spinae plane block on postoperative pain after laparoscopic cholecystectomy. The primary outcome was the postoperative pain score. The secondary outcomes were the cumulative intraoperative and postoperative opioid consumption at 24 h, incidence of postoperative nausea and vomiting, and shoulder pain after surgery. The results were pooled using the fixed- or random-effects model with Review Manager 5.3. RESULTS: Fifteen randomized controlled trials involving 947 patients were included in the analysis. Postoperative pain score in the erector spinae plane block group was lower than that in the control group at postoperative 12 h (MD - 0.81, 95% CI - 1.1 to - 0.51, p < 0.00001) and 24 h (MD - 0.41, 95% CI - 0.62 to - 0.19, p = 0.0002). Cumulative opioid consumption was lower in the erector spinae plane block group than in the control group at postoperative 24 h (MD - 7.88, 95% CI - 10.17 to - 5.58, p < 0.00001). The erector spinae plane block group also experienced a lower incidence of postoperative nausea and vomiting than the control group. Opioid consumption and the incidence of postoperative nausea and vomiting were similar between the erector spinae plane block group and other block groups, including the oblique subcostal transversus abdominis plane block and quadratus lumborum block groups. CONCLUSIONS: Ultrasound-guided erector spinae plane block provides effective postoperative analgesia in adults undergoing laparoscopic cholecystectomy.
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Colecistectomia Laparoscópica , Bloqueio Nervoso , Humanos , Adulto , Analgésicos Opioides , Náusea e Vômito Pós-Operatórios/epidemiologia , Náusea e Vômito Pós-Operatórios/prevenção & controle , Colecistectomia Laparoscópica/métodos , Ultrassonografia de Intervenção/métodos , Medição da Dor/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Bloqueio Nervoso/métodos , Dor Pós-Operatória/tratamento farmacológicoRESUMO
Objective: Autophagy is the catabolic process where the components of eukaryotes experience damage, and the affected or superfluous components undergo self-degradation. However autophagy can promote cancer cell apoptosis or facilitate cell growth. This work aimed to investigat the significance of autophagy-related genes (ARGs) in predicting the prognosis of breast cancer (BC) intervened with Cremastra. Methods: Active ingredients and action targets were obtained using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and SwissTargetPrediction. Then, the BC transcriptome and clinical data were downloaded in The Cancer Genome Atlas (TCGA), whereas ARGs were collected in the Human Autophagy Database (HADb). Meanwhile, Perl and R software were used for data processing and analysis. Firstly, the transcriptome data of BC were mapped to ARGs to screen the BC-ARGs. Secondly, the above genes were mapped to the action targets of Cremastra, ARGs of Cremastra-intervened BC were then screened out. Moreover, an enrichment analysis of biological function was carried out. Univariate Cox regression was carried out on ARGs of BC for preliminarily selecting the independent prognostic genes and constructing the autophagy prognosis model. These genes were mapped to ARGs involved in Cremastra-intervened BC. Finally, those mapped genes were optimized by multi-factor Cox regression, and the key ARGs and potential compounds were obtained. Finally, all cases were classified as low- or high-risk group based on the median risk score. Receiver operating characteristic (ROC) curve, Kaplan-Meier (K-M) survival, independent prognosis and clinical correlation analyses were conducted for model evaluation and identification of factors to independently predict prognosis. Results: Altogether, 66 active components and 38 targets of the Cremastra-intervened autophagy of BC were screened and the autophagy prognosis model demonstrate good predictive performance. As suggested by the survival curve, low-risk patients had a markedly increased survival rate compared with high-risk patients (P < .01). Besides, the gene expression levels of the high-risk group increased with the increases in patients' risk scores. Upon univariate regression, 34 differentially expressed ARGs related to BC treatment were screened. Multivariate regression identified 4 key ARGs, which were mainly derived from glycosides, lignans, flavonoids, and dibenzyl compounds. Thereafter, key genes were subjected to correlation analysis between clinicopathological features and prognosis, among which BCL2 and TP63, showed independent prognostic value. Conclusions: In this study, an autophagy prognosis model was established, and BCL2 and TP63 were predicted for the Cremastra intervention of BC by Bioinformatics, which will be applied to further work.
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Eutrophic lakes are a major source of the atmospheric greenhouse gas methane (CH4), and CH4 ebullition emissions from inland lakes have important implications for the carbon cycle. However, the spatio-temporal heterogeneity of CH4 ebullition emission and its influencing factors in shallow eutrophic lakes of arid and semi-arid regions remain unclear. This study aimed to determine the mechanism of CH4 emission via eutrophication in Lake Ulansuhai, a large shallow eutrophic lake in a semi-arid region of China.To this end, monthly field surveys were conducted from May to October 2021, and gas chromatography was applied using the headspace equilibrium technique with an inverted funnel arrangement. The total CH4 fluxes ranged from 0.102 mmol m-2 d-1 to 59.296 mmol m-2 d-1 with an average value of 4.984 ± 1.82 mmol m-2 d-1. CH4 ebullition emissions showed significant temporal and spatial variations. The highest CH4 ebullition emission was observed in July with a grand mean of 9.299 mmol m-2 d-1, and the lowest CH4 ebullition emissions occurred in October with an average of 0.235 mmol m-2 d-1. Among seven sites (S1-S7), the maximum (3.657 mmol m-2 d-1) and minimum (1.297 mmol m-2 d-1). CH4 ebullition emissions were observed at S2 and S7, respectively. As the main route of CH4 emission to the atmosphere in Lake Ulansuhai, the CH4 ebullition flux during May to October accounted for 69% of the total CH4 flux. Statistical analysis showed that CH4 ebullition was positively correlated with temperature (R = 0.391, P < 0.01) and negatively correlated with air pressure (R = 0.286, P < 0.00). Temperature and air pressure were found to strongly regulate the production and oxidation of CH4. Moreover, nutritional status indicators such as TP and NH4+-N significantly affect CH4 ebullition emissions (R = 0.232, P < 0.01; R = -0.241, P < 0.01). This study reveals the influencing factors of CH4 ebullition emission in Lake Ulansuhai, and provides theoretical reference and data support for carbon emission from eutrophic lakes. Nevertheless, research on eutrophic shallow lakes needs to be further strengthened. Future research should incorporate improved flux measurement techniques with process-based models to improve the accuracy from regional to large-scale estimation of CH4 emissions and clarify the carbon budget of aquatic ecosystems. In this manner, the understanding and predictability of CH4 ebullition emission from shallow lakes can be improved.
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Lagos , Metano , Metano/análise , Ecossistema , China , Carbono/análiseRESUMO
The nature of gig work and its growth have important implications for organizational justice theory. Aspects of gig work, including the transactional compensation arrangement, strict algorithmic rating system, and power asymmetry between drivers and customers, have implications for understanding how dimensions of distributive, informational, and interpersonal injustice manifest and impact job performance in the gig context. An understanding of this topic can inform justice theory more broadly and help explain inconsistent findings in the literature. Here, we report the results of two studies examining the unique effects of these respective dimensions of injustice on emotions and, ultimately, the driving performance and service quality in a ridesharing service context. In Study 1, we modeled the passenger-driver interaction of the ridesharing context using a driving simulator in a laboratory setting to differentiate the real-time and carry-over effects of specific dimensions of injustice. The results from 99 participants showed that perceptions of interpersonal injustice increased anger and unhappiness during the ride, in turn impairing driving and service performance. Antecedent-focused emotion regulation strategies (ERS) reduced felt unhappiness. Moreover, unexpectedly, perceived distributive injustice as caused by the customer rating had opposite (direct versus indirect) effects on service performance in the subsequent ride. Study 2 was an online simulation vignette scenario with 294 participants. The results replicated the findings of Study 1 and revealed two moderators of the unexpected distributive justice-performance relationship. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-022-04215-3.