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The mitogen-activated protein kinase (MAPK) signaling pathways are highly conserved in eukaryotes, regulating various cellular processes. The MAPK kinases (MKKs) are dual specificity kinases, serving as convergence and divergence points of the tripartite MAPK cascades. Here, we investigate the biochemical characteristics and three-dimensional structure of MKK5 in Arabidopsis (AtMKK5). The recombinant full-length AtMKK5 is phosphorylated and can activate its physiological substrate AtMPK6. There is a conserved kinase interacting motif (KIM) at the N-terminus of AtMKK5, indispensable for specific recognition of AtMPK6. The kinase domain of AtMKK5 adopts active conformation, of which the extended activation segment is stabilized by the phosphorylated Ser221 and Thr215 residues. In line with sequence divergence from other MKKs, the αD and αK helices are missing in AtMKK5, suggesting that the AtMKK5 may adopt distinct modes of upstream kinase/substrate binding. Our data shed lights on the molecular mechanisms of MKK activation and substrate recognition, which may help design specific inhibitors targeting human and plant MKKs.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , FosforilaçãoRESUMO
Constructing hierarchical porosity and designing rational hybrid composition are effective strategies for enhancing the electrocatalytic performance of hybrid catalysts for electrochemical energy conversion. Here, we develop a multistep "molecule/ion-exchange" strategy toward the synthesis of hierarchically macro/mesoporous Fe,Ni-doped CoSe/N-doped carbon nanoshells with tunable pore structures and compositions. Polystyrene (PS)@Co-based amorphous coordination polymer (Co-CP) core-shell particles with hierarchically macro/mesoporous nanoshells are first prepared by ligand-molecule-exchange etching of the outer layers in PS@Co-based metal-organic framework precursors. Afterward, a liquid-solid dual-ion-exchange reaction of PS@Co-CP particles with [Fe(CN)6]3- and [Ni(CN)4]2- ions leads to the formation of PS@Co-CP/Co-Fe Prussian blue analogue (PBA)/Co-Ni PBA particles, which are further transformed into hierarchically macro/mesoporous Fe,Ni-doped CoSe/N-doped carbon particles via a vapor-solid selenization reaction. Moreover, this approach could be extended to synthesize different hierarchically porous core-shell composites with various morphologies and tailored compositions. Because of their unique hierarchically porous nanoarchitecture, these Fe,Ni-doped CoSe/N-doped carbon particles with optimized composition show enhanced performance for electrocatalytic oxygen evolution.
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RNA-binding proteins (RBPs) play pivotal roles in directing RNA fate and function. Yet the current annotation of RBPs is largely limited to proteins carrying known RNA-binding domains. To systematically reveal dynamic RNA-protein interactions, we surveyed the human proteome by a protein array-based approach and identified 671 proteins with RNA-binding activity. Among these proteins, 525 lack annotated RNA-binding domains and are enriched in transcriptional and epigenetic regulators, metabolic enzymes, and small GTPases. Using an improved CLIP (crosslinking and immunoprecipitation) method, we performed genome-wide target profiling of isocitrate dehydrogenase 1 (IDH1), a novel RBP. IDH1 binds to thousands of RNA transcripts with enriched functions in transcription and chromatin regulation, cell cycle and RNA processing. Purified IDH1, but not an oncogenic mutant, binds directly to GA- or AU-rich RNA that are also enriched in IDH1 CLIP targets. Our study provides useful resources of unconventional RBPs and IDH1-bound transcriptome, and convincingly illustrates, for the first time, the in vivo and in vitro RNA targets and binding preferences of IDH1, revealing an unanticipated complexity of RNA regulation in diverse cellular processes.
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Isocitrato Desidrogenase/metabolismo , Proteoma/metabolismo , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transcriptoma , Elementos Ricos em Adenilato e Uridilato , Cromatina/genética , Cromatina/metabolismo , Reagentes de Ligações Cruzadas/química , Células-Tronco Embrionárias , GTP Fosfo-Hidrolases/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Imunoprecipitação , Isocitrato Desidrogenase/genética , Redes e Vias Metabólicas/genética , Motivos de Nucleotídeos , Análise Serial de Proteínas , Ligação Proteica , RNA Mensageiro/genética , Reprodutibilidade dos TestesRESUMO
Mixed infections and heteroresistance of Mycobacterium tuberculosis contribute to the difficulty of diagnosis, treatment, and control of tuberculosis. However, there is still no proper solution for these issues. This study aimed to investigate the potential relationship between mixed infections and heteroresistance and to determine the high-risk groups related to these factors. A total of 499 resistant and susceptible isolates were subjected to spoligotyping and 24-locus variable-number tandem repeat methods to analyze their genotypic lineages and the occurrence of mixed infections. Two hundred ninety-two randomly selected isolates were sequenced on their rpoB gene to examine mutations and heteroresistance. The results showed that 12 patients had mixed infections, and the corresponding isolates belonged to Manu2 (n = 8), Beijing (n = 2), T (n = 1), and unknown (n = 1) lineages. Manu2 was found to be significantly associated with mixed infections (odds ratio, 47.72; confidence interval, 9.68 to 235.23; P < 0.01). Four isolates (1.37%) were confirmed to be heteroresistant, which was caused by mixed infections in three (75%) isolates; these belonged to Manu2. Additionally, 3.8% of the rifampin-resistant isolates showing no mutation in the rpoB gene were significantly associated with mixed infections (χ(2), 56.78; P < 0.01). This study revealed for the first time that Manu2 was the predominant group in the cases of mixed infections, and this might be the main reason for heteroresistance and a possible mechanism for isolates without any mutation in the rpoB gene to become rifampin resistant. Further studies should focus on this lineage to clarify its relevance to mixed infections.
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Antituberculosos/farmacologia , Coinfecção/microbiologia , Farmacorresistência Bacteriana , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/farmacologia , Tuberculose/microbiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Coinfecção/epidemiologia , Estudos Transversais , RNA Polimerases Dirigidas por DNA/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Tipagem Molecular , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Estudos Retrospectivos , Análise de Sequência de DNA , Tuberculose/epidemiologia , Adulto JovemRESUMO
To address the escalating power consumption of processors in data centers and the growing emphasis on environmental sustainability, the prospective shift from traditional air-cooling to immersion liquid cooling necessitates multiple functional integrations in polymer-based thermal conductive materials. Here, drawing inspiration from mussels, we showed a copolymer, poly(dimethylsiloxane-co-dopamine methacrylate) (PDMS-DMA), with a variety of reversible molecular interactions and simply combined with liquid metal (EGaIn) can yield a flexible, waterproof, and electrically insulating thermal conductive composite. The obtained PDMS-DMA/EGaIn composites demonstrate a harmonious blend of attributes, including a low modulus (75.8 kPa), high thermal conductivity of 6.9 W m-1 K-1, and rapid room-temperature self-healing capabilities, capable of complete repair within 20 min, even under water. Based on its electrically insulating and water resistance properties, PDMS-DMA/EGaIn emerges as a promising candidate for efficient and stable heat transfer in both air and underwater thermal management. Consequently, this water-resistant polymer-based composite holds significance for application in thermal protective layers for future immersion liquid cooling systems.
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Interface thermal resistance has become a crucial barrier to effective thermal management in high-performance electronics and sensors. The growing complexity of operational conditions, such as irregular and dynamic surfaces, demands thermal interface materials (TIMs) to possess high thermal conductivity and soft elasticity. However, developing materials that simultaneously combine soft elasticity and high thermal conductivity remains a challenging task. Herein, we utilize a vertically oriented graphene aerogel (VGA) and rationally design liquid metal (LM) networks to achieve directional and adjustable pathways within the composite. Subsequently, we leverage the advantages of the low elastic modulus and high deformation capabilities of brush-shaped polydimethylsiloxane (BPDMS), together with the bicontinuous thermal conduction path constructed by VGA and LM networks. Ultimately, the designed composite of patterned liquid metal/vertically oriented graphene aerogel/brush-shaped PDMS (LM-VGA/BPDMS) shows a high thermal conductivity (7.11 W m-1 K-1), an ultra-low elastic modulus (10.13 kPa), excellent resilience, and a low interface thermal resistance (14.1 K mm2 W-1). This LM-VGA/BPDMS soft composite showcases a stable heat dissipation capability at dynamically changing interfaces, as well as excellent adaptability to different irregular surfaces. This strategy holds important application prospects in the fields of interface thermal management and thermal sensing in extremely complex environments.
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Background: The COVID-19 pandemic not only posed a serious threat to public life and health but also had a serious impact on people's mental health, especially that of medical staff. Perceived social support is an important factor in one's sense of security. Objective: Following the COVID-19 pandemic, the goal is to explore the potential mediating role of resilience in the relationship between perceived social support and the sense of security of Chinese medical personnel. Methods: The multi-stage proportionally stratified convenience sampling method was adopted to select 4,076 medical professionals from 29 hospitals in Guangdong Province between September 2020 and October 2020. The Sense of Security Scale for Medical Staff, the Chinese version of the Connor-Davidson Resilience Scale, and the Perceived Social Support Scale were employed in this study. For statistical analysis and structural equation modeling (SEM), the SPSS 23.0 and Amos 24.0 software packages were used. Regression analysis was used to select the control variables to be included in the SEM. SEM analysis was conducted to verify the mediating effect of resilience on the relationship between perceived social support and a sense of security. Results: Pearson's correlation analysis showed that perceived social support and resilience were positively associated with a sense of security (correlation coefficients range from 0.350 to 0.607, P < 0.01), and perceived social support (correlation coefficients range from 0.398 to 0.589, P < 0.01) was positively associated with resilience. Structural equation modeling revealed that resilience played a partial mediating role in the association between perceived social support and a sense of security (60.3% of the effect of perceived social support on security was direct, and 39.7% of the effect was mediated by resilience). Conclusions: Hospital managers should make efforts to develop resilience. Interventions based on resilience should be developed to enhance the perception of social support and strengthen one's sense of security.
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Objective: The objective of this study was to explore the sense of job security and its influencing factors among healthcare workers in Guangdong, China. Methods: This cross-sectional study used stratified random sampling to enroll healthcare workers employed by hospitals across Guangdong province between September 2020 and October 2020. Results: A total of 4,173 questionnaires were distributed, and 4,076 were returned for an effective recovery rate of 97.68%. The overall score for the sense of security was 64.85 ± 20.09, and the item means score was 2.95 ± 0.91. Multiple-linear regression analysis showed that work experience (years), education level, job position, specialty unit, employment type, marital status, job satisfaction, WPV frequency, daily sleep duration, weekly overtime hours, average monthly earnings (RMB), hospital level, and region were significantly associated with senses of poor security among healthcare workers (all P < 0.05). Conclusions: Hospital workers in Guangdong reported relatively low levels of job security. Levels of job security were significantly associated with multiple factors which could be addressed by hospital practices to improve the sense of job security among healthcare workers.
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Renda , Recursos Humanos em Hospital , Humanos , Estudos Transversais , China , HospitaisRESUMO
The controllability of the microstructure of a compressed hierarchical building block is essential for optimizing a variety of performance parameters, such as thermal management. However, owing to the strong orientation effect during compression molding, optimizing the alignment of materials perpendicular to the direction of pressure is challenging. Herein, to illustrate the effect of the ordered microstructure on heat dissipation, thermally conductive carbon-based materials are fabricated by tailoring dense, orientation-tunable, and interleaved structures. Vertically aligned carbon nanotube arrays (VACNTs) interconnected with graphene films (GF) are prepared as a 3D core-ordered material to fabricate compressed building blocks of O-VA-GF and S-VA-GF. Leveraging the densified interleaved structure offered by VACNTs, the hierarchical O-VA-GF achieves excellent through-plane (41.7 W m-1 K-1 ) and in-plane (397.9 W m-1 K-1 ) thermal conductivities, outperforming similar composites of S-VA-GF (through-plane: 10.3 W m-1 K-1 and in-plane: 240.9 W m-1 K-1 ) with horizontally collapsed carbon nanotubes. As heat dissipation plates, these orderly assembled composites yield a 144% and 44% enhancement in the cooling coefficient compared with conventional Si3 N4 for cooling high-power light-emitting diode chips.
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Background: COVID-19 pandemic has entered a normal stage in China. During this phase, nurses have an increased workload and mental health issues that threaten the sense of security. Poor sense of security may have a considerable impact on turnover intention through low work engagement. It was challenging to maintain the nurse workforce. Fewer studies have been conducted on the effect of nurses' sense of security on their turnover intention in that phase. This study aimed to investigate the interrelationship between nurses' sense of security, work engagement, and turnover intention during the normalization phase of the epidemic in China and to explore the impact of sense of security on turnover intention. Methods: A cross-sectional survey was conducted from September 2020 to May 2021 in Guangdong Province, China. Data were collected online using Sense of Security Scale for Medical Staff (SSS-MS), Utrecht Work Engagement Scale (UWES), and Turnover Intention Scale. Pearson's correlation analysis was used to assess the correlation between sense of security, work engagement, and turnover intention. The hypothesis model used multiple linear regression models and the bootstrapping procedure to analyze the relationship between these variables. Results: Data were collected from 2,480 nurses who met the inclusion criteria. Over half(64.5%) of nurses had a high and very high turnover intention. After controlling the demographic and working variables, sense of security (ß = 0.291, P < 0.001) had a direct positive effect on work engagement. Sense of security (ß = -0.447, P < 0.001) and work engagement (ß = -0.484, P < 0.001) had a direct negative effect on turnover intention. Sense of security and all of its components were associated with turnover intention through the partially mediating effects of work engagement. Conclusions: Nurses' turnover intention was at a high level during the normalization phase of the epidemic. Sense of security and its components act as positive resources to reduce turnover intention by improving work engagement. Policy makers and managers may pay attention to the needs of nurses' sense of security, which may be a new perspective to help managers reduce their turnover intention and stabilize the nurse team.
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COVID-19 , Enfermeiras e Enfermeiros , Recursos Humanos de Enfermagem Hospitalar , Humanos , Engajamento no Trabalho , Intenção , Estudos Transversais , Pandemias , Recursos Humanos de Enfermagem Hospitalar/psicologia , Inquéritos e Questionários , COVID-19/epidemiologiaRESUMO
AIM: To assess the impact of the obesity epidemic on type 2 diabetes (T2D), prediabetes and glycometabolic indices in children and adolescents. METHODS: We searched four electronic databases (PubMed, Embase, Cochrane and Web of Science). Cross-sectional or cohort studies that reported on obesity and the prevalence of T2D or prediabetes in children and adolescents were reviewed. The study design, sample size and clinical outcomes were extracted from each study. The prevalence of T2D and prediabetes from the studies were pooled using meta-analysis methods. RESULTS: Meta-analysis of 228184 participants showed that the prevalence of T2D was 1.3% (95% confidence interval (CI), 0.6-2.1%) in obese subjects, which was 13 times that in normal weight subjects (0.1%, 95% CI, 0.01-0.2%). The prevalence of prediabetes in obese subjects was 3 times that in normal subjects at 17.0% (13.0-22.0%) vs. 6.0% (0.01-11.0%). Moreover, BMI was positively correlated with the prevalence of T2D, prediabetes and glycometabolic indices in obese children and adolescents. CONCLUSION: The pooled results confirm that obesity in children and adolescents leads to statistically significant increases in the prevalence of T2D and prediabetes and in glycometabolic indicator levels.
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Diabetes Mellitus Tipo 2 , Obesidade Infantil , Estado Pré-Diabético , Adolescente , Criança , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Estado Pré-Diabético/diagnóstico , Estado Pré-Diabético/epidemiologia , Glicemia/análise , Obesidade Infantil/diagnóstico , Obesidade Infantil/epidemiologia , Estudos TransversaisRESUMO
The activity of 5'-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. When glucose levels are low, the glycolytic enzyme aldolase is not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals to activate lysosomal AMPK. Here, we show that blocking FBP binding to aldolase with the small molecule aldometanib selectively activates the lysosomal pool of AMPK and has beneficial metabolic effects in rodents. We identify aldometanib in a screen for aldolase inhibitors and show that it prevents FBP from binding to v-ATPase-associated aldolase and activates lysosomal AMPK, thereby mimicking a cellular state of glucose starvation. In male mice, aldometanib elicits an insulin-independent glucose-lowering effect, without causing hypoglycaemia. Aldometanib also alleviates fatty liver and nonalcoholic steatohepatitis in obese male rodents. Moreover, aldometanib extends lifespan and healthspan in both Caenorhabditis elegans and mice. Taken together, aldometanib mimics and adopts the lysosomal AMPK activation pathway associated with glucose starvation to exert physiological roles, and might have potential as a therapeutic for metabolic disorders in humans.
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Insulinas , Inanição , Humanos , Masculino , Camundongos , Animais , Proteínas Quinases Ativadas por AMP/metabolismo , Glucose/metabolismo , Frutose-Bifosfato Aldolase/metabolismo , Lisossomos/metabolismo , Inanição/metabolismo , Adenosina Trifosfatases/metabolismo , Caenorhabditis elegans , Monofosfato de Adenosina/metabolismo , Frutose/metabolismo , Insulinas/metabolismoRESUMO
BACKGROUND: Loneliness, a negative emotion that is common in college students, may cause psychological disorders and behavioral issues. Particularly vulnerable are visually impaired college students, who are at an increased risk of loneliness. OBJECTIVES: This study was aimed at explaining the current situation of loneliness among visually impaired college students as well as its influencing factors and exploring the intermediary role of self-acceptance between self-stigma and loneliness. METHOD: Seventy-eight college students with visual impairment completed a series of self-report questionnaires, including the Self-Stigma of Disabled Scale (SSDS), the Self-Acceptance Questionnaire (SAQ), and the University of California-Los Angeles (UCLA) Loneliness Scale. Mediation analyses were conducted using PROCESS in SPSS. RESULTS: Participants' mean loneliness score was 44.97 ± 9.35. Two survey factors were significantly associated with loneliness: visual impairment status and relationship with parents (p < 0.05). When controlling for extent of visual damage and relationship with parents, self-stigma showed a significant predictive effect on loneliness (B = 0.37, t = 4.1023, p < 0.01). CONCLUSIONS: In China, visually impaired students suffer from a high level of loneliness, and self-acceptance plays a central role in connecting their self-stigma and loneliness.