RESUMO
In the present research, the impacts of Ce additions at various concentrations (0, 1.0, 3.4, and 4.0 wt.%) on the evolution of the microstructure, mechanical properties, and thermal conductivity of as-cast and as-extruded Mg-3Sn alloys were investigated. The findings demonstrate that adding Ce caused the creation of a new ternary MgSnCe phase in the magnesium matrix. Some new Mg17Ce2 phases are generated in the microstructure when Ce levels reach 4%. The thermal conductivity of the Mg-3Sn alloy is significantly improved due to Ce addition, and the Mg-3Sn-3.4Ce alloy exhibits the highest thermal conductivity, up to 133.8 W/(m·K) at 298 K. After extrusion, both the thermal conductivity and mechanical properties are further improved. The thermal conductivity perpendicular to the extrusion direction of Mg-3Sn-3.4Ce alloy could achieve 136.28 W/(m·K), and the tensile and yield strengths reach 264.3 MPa and 227.2 MPa, with an elongation of 7.9%. Adding Ce decreases the dissolved Sn atoms and breaks the eutectic α-Mg and Mg2Sn network organization, leading to a considerable increase in the thermal conductivity of as-cast Mg-3Sn alloys. Weakening the deformed grain texture contributed to the further enhancement of the thermal conductivity after extrusion.
RESUMO
The effect of the extrusion process on the microstructure, corrosion, and mechanical properties of Mg-Zn-Ca-Zr alloy has been investigated. Zn and Ca were both in a solid solution and only the Zr-rich phase was observed in the homogenized and extruded alloys. The Zr-rich phase was obviously refined after extrusion. The corrosion rate of the homogenized alloy decreased by about 25% after extrusion. This is because the refined Zr-rich phase was easier to cover with the deposited corrosion products, which reduced the cathodic reaction activity of the Zr-rich phase. The corrosion rate is similar for the alloys extruded at 320 °C and 350 °C since the size and distribution of the Zr-rich phase were not different in the two conditions. The alloy extruded at 320 °C has a smaller grain size and better comprehensive mechanical properties.
RESUMO
A series of novel piperidamide-3-carboxamide derivatives were synthesized and evaluated for their inhibitory activities against cathepsin K. Among these derivatives, compound H-9 exhibited the most potent inhibition, with an IC50 value of 0.08 µM. Molecular docking studies revealed that H-9 formed several hydrogen bonds and hydrophobic interactions with key active-site residues of cathepsin K. In vitro, H-9 demonstrated anti-bone resorption effects that were comparable to those of MIV-711, a cathepsin K inhibitor currently in phase 2a clinical trials for the treatment of bone metabolic disease. Western blot analysis confirmed that H-9 effectively downregulated cathepsin K expression in RANKL-reduced RAW264.7 cells. Moreover, in vivo experiments showed that H-9 increased the bone mineral density of OVX-induced osteoporosis mice. These results suggest that H-9 is a potent anti-bone resorption agent targeting cathepsin K and warrants further investigation for its potential anti-osteoporosis values.
Assuntos
Catepsina K , Simulação de Acoplamento Molecular , Osteoporose , Piperidinas , Catepsina K/antagonistas & inibidores , Catepsina K/metabolismo , Animais , Camundongos , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Piperidinas/farmacologia , Piperidinas/química , Piperidinas/síntese química , Células RAW 264.7 , Reabsorção Óssea/tratamento farmacológico , Feminino , Densidade Óssea/efeitos dos fármacos , Ligante RANK/metabolismo , Relação Estrutura-Atividade , Humanos , Estrutura MolecularRESUMO
This study aimed to explore the response of archaeal communities and antibiotic-resistance genes (ARGs) to ciprofloxacin (CIP, 0.05-40 mg/L) and copper (Cu, 3 mg/L) combined pollution during stress- and post-effect periods in an activated sludge system. With the increase in the CIP concentration, the diversity of archaea decreased, but the richness increased under the stress of 10 mg/L CIP. Under stress and post effects, the change in unknown archaeal community structure was more significant than that of the known archaea. The relative abundance of unknown archaea was significantly reduced with the increase in CIP concentration. Meanwhile, there were certain archaea that belonged to abundant and rare taxa with different resistance and recovery characteristics. Among them, Methanosaeta (49.15-83.66%), Methanoculleus (0.11-0.45%), and Nitrososphaera (0.03-0.36%) were the typical resistant archaea to combined pollution. And the resistance of the abundant taxa to combined pollution was significantly higher than that of the rare taxa. Symbiotic and competitive relationships were observed between the known and the unknown archaea. The interactions of abundant known taxa were mainly symbiotic relationships. While the rare unknown taxa were mainly competitive relationships in the post-effect period. Rare archaea showed an important ecological niche under the stress-effect. Some archaea displayed positive correlation with ARGs and played important roles as potential hosts of ARGs during stress- and post-periods. Methanospirillum, Methanosphaerula, Nitrososphaera and some rare unknown archaea also significantly co-occurred with a large number of ARGs. Overall, this study points out the importance of interactions among known and unknown archaeal communities and ARGs in a wastewater treatment system under the stress of antibiotics and heavy metal combined pollution.
RESUMO
AIMS: Papillary thyroid cancer (PTC) is a serious threat to human health worldwide, while metastasis in the early phase limits therapeutic success and leads to poor survival outcomes. The CXC chemokine receptor type 4 (CXCR4) plays an important role in many cellular movements such as transcriptional modulation, cell skeleton rearrangement, and cell migration, and the change in CXCR4 levels are crucial in various diseases including cancer. In this study, we explored the role of CXCR4 in the migration and invasion of PTC and investigated the potential mechanisms underlying its effects. SUBJECTS AND METHODS: We analyzed the expression levels of CXCR4 in PTC tissues and cell lines. Would healing migration, Transwell invasion assay in vitro, and tail-vein lung metastasis assay In vivo were performed to evaluated the migration and invasion abilities of PTC cells with stable CXCR4 knockdown or overexpression. Signal transducers and activators of transcription (STAT3) signaling pathway-related protein expressions were examined by Western blotting assays. RESULTS: The results showed that CXCR4 was highly expressed in PTC cell lines and PTC tissues. CXCR4 knockdown in PTC cells dampened the migration, invasion, and epithelial-mesenchymal transition (EMT), whereas CXCR4 overexpression enhanced these properties. In vivo, we also found that CXCR4 promoted the metastasis of PTC. Mechanistic studies showed that CXCR4 played these vital roles through the STAT3 signaling pathway. Furthermore, PTC patients with high CXCR4 or p-STAT3 expression correlated with aggressive clinical characteristics such as extrathyroidal extension (ETE), and lymph node metastasis (LNM). CONCLUSIONS: We provided evidence that CXCR4 might activate the STAT3 signaling pathway and further promote PTC development. Thus, CXCR4 might be a novel therapeutic target for PTC.
Assuntos
Movimento Celular , Transição Epitelial-Mesenquimal , Invasividade Neoplásica , Receptores CXCR4 , Transdução de Sinais , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
ABSTRACT: Facial grimacing is used to quantify spontaneous pain in mice and other mammals, but scoring relies on humans with different levels of proficiency. Here, we developed a cloud-based software platform called PainFace ( http://painface.net ) that uses machine learning to detect 4 facial action units of the mouse grimace scale (orbitals, nose, ears, whiskers) and score facial grimaces of black-coated C57BL/6 male and female mice on a 0 to 8 scale. Platform accuracy was validated in 2 different laboratories, with 3 conditions that evoke grimacing-laparotomy surgery, bilateral hindpaw injection of carrageenan, and intraplantar injection of formalin. PainFace can generate up to 1 grimace score per second from a standard 30 frames/s video, making it possible to quantify facial grimacing over time, and operates at a speed that scales with computing power. By analyzing the frequency distribution of grimace scores, we found that mice spent 7x more time in a "high grimace" state following laparotomy surgery relative to sham surgery controls. Our study shows that PainFace reproducibly quantifies facial grimaces indicative of nonevoked spontaneous pain and enables laboratories to standardize and scale-up facial grimace analyses.
Assuntos
Expressão Facial , Camundongos Endogâmicos C57BL , Medição da Dor , Software , Animais , Camundongos , Feminino , Software/normas , Medição da Dor/métodos , Medição da Dor/normas , Masculino , Dor/diagnósticoRESUMO
Conventional near-field acoustic holography based on compressive sensing either does not fully exploit the underlying block-sparse structures of the signal or suffers from a mismatch between the actual and predefined block structure due to the lack of prior information about block partitions, resulting in poor accuracy in sound field reconstruction. In this paper, a pattern-coupled Bayesian compressive sensing method is proposed for sparse reconstruction of sound fields. The proposed method establishes a hierarchical Gaussian-Gamma probability model with a pattern-coupled prior based on the equivalent source method, transforming the sound field reconstruction problem into recovering the sparse coefficient vector of the equivalent source strengths within the compressive sensing framework. A set of hyperparameters is introduced to control the sparsity of each element in the sparse coefficient vector of the equivalent source strengths, where the sparsity of each element is determined by both its own hyperparameters and those of its immediate neighbors. This approach enables the promotion of block sparse solutions and achieves better performance in solving for the sparse coefficient vector of the equivalent source strengths without prior information of block partitions. The effectiveness and superiority of the proposed method in reconstructing sound fields are verified by simulations and experiments.
RESUMO
The development of precise RNA-editing tools is essential for the advancement of RNA therapeutics. CRISPR (clustered regularly interspaced short palindromic repeats) PspCas13b is a programmable RNA nuclease predicted to offer superior specificity because of its 30-nucleotide spacer sequence. However, its design principles and its on-target, off-target and collateral activities remain poorly characterized. Here, we present single-base tiled screening and computational analyses that identify key design principles for potent and highly selective RNA recognition and cleavage in human cells. We show that the de novo design of spacers containing guanosine bases at precise positions can greatly enhance the catalytic activity of inefficient CRISPR RNAs (crRNAs). These validated design principles (integrated into an online tool, https://cas13target.azurewebsites.net/ ) can predict highly effective crRNAs with ~90% accuracy. Furthermore, the comprehensive spacer-target mutagenesis revealed that PspCas13b can tolerate only up to four mismatches and requires ~26-nucleotide base pairing with the target to activate its nuclease domains, highlighting its superior specificity compared to other RNA or DNA interference tools. On the basis of this targeting resolution, we predict an extremely low probability of PspCas13b having off-target effects on other cellular transcripts. Proteomic analysis validated this prediction and showed that, unlike other Cas13 orthologs, PspCas13b exhibits potent on-target activity and lacks collateral effects.
RESUMO
Delayed neuropsychiatric sequelae (DNS) significantly impact the quality of life in patients following acute carbon monoxide poisoning (COP). This systematic review and meta-analysis aimed to assess the relationship between serum neuron-specific enolase (NSE) levels at admission and the risk of DNS in adults after acute COP. Relevant observational studies with longitudinal follow-up were identified through searches in PubMed, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure databases. The random-effects model was used to aggregate results, accounting for potential heterogeneity. Nine cohort studies, including 1501 patients, were analyzed, with 254 (16.9%) developing DNS during follow-up. The pooled data indicated that elevated serum NSE in the early phase was linked to a higher risk of subsequent DNS (odds ratio per 1 ng/mL increase in NSE: 1.10, 95% confidence interval: 1.06 to 1.15, P < 0.001). Moderate heterogeneity (I2 = 46%) among the studies was entirely attributed to one study with the longest follow-up duration (22.3 months; I2 = 0% after excluding this study). Subgroup analyses based on country, study design, sample size, age, sex, admission carboxyhemoglobin levels, DNS incidence, follow-up duration, and quality score yielded consistent results (P for subgroup differences all > 0.05). In summary, high serum NSE levels in the early phase of acute COP are associated with an increased risk of developing DNS during follow-up.
RESUMO
BACKGROUND & AIMS: New antiviral approaches that target multiple aspects of the HBV replication cycle to improve rates of functional cure are urgently required. HBV RNA represents a novel therapeutic target. Here, we programmed CRISPR-Cas13b endonuclease to specifically target the HBV pregenomic RNA and viral mRNAs in a novel approach to reduce HBV replication and protein expression. METHODS: Cas13b CRISPR RNAs (crRNAs) were designed to target multiple regions of HBV pregenomic RNA. Mammalian cells transfected with replication competent wild-type HBV DNA of different genotypes, a HBV-expressing stable cell line, a HBV infection model and a hepatitis B surface antigen (HBsAg)-expressing stable cell line were transfected with PspCas13b-BFP (blue fluorescent protein) and crRNA plasmids, and the impact on HBV replication and protein expression was measured. Wild-type HBV DNA, PspCas13b-BFP and crRNA plasmids were simultaneously hydrodynamically injected into mice, and serum HBsAg was measured. PspCas13b mRNA and crRNA were also delivered to a HBsAg-expressing stable cell line via lipid nanoparticles and the impact on secreted HBsAg determined. RESULTS: Our HBV-targeting crRNAs strongly suppressed HBV replication and protein expression in mammalian cells by up to 96% (p <0.0001). HBV protein expression was also reduced in a HBV-expressing stable cell line and in the HBV infection model. CRISPR-Cas13b crRNAs reduced HBsAg expression by 50% (p <0.0001) in vivo. Lipid nanoparticle-encapsulated PspCas13b mRNA reduced secreted HBsAg by 87% (p = 0.0168) in a HBsAg-expressing stable cell line. CONCLUSIONS: Together, these results show that CRISPR-Cas13b can be programmed to specifically target and degrade HBV RNAs to reduce HBV replication and protein expression, demonstrating its potential as a novel therapeutic option for chronic HBV infection. IMPACT AND IMPLICATIONS: Owing to the limitations of current antiviral therapies for hepatitis B, there is an urgent need for new treatments that target multiple aspects of the HBV replication cycle to improve rates of functional cure. Here, we present CRISPR-Cas13b as a novel strategy to target HBV replication and protein expression, paving the way for its development as a potential new treatment option for patients living with chronic hepatitis B.
RESUMO
SLC26A2 is a vital solute carrier responsible for transporting essential nutritional ions, including sulfate, within the human body. Pathogenic mutations within SLC26A2 give rise to a spectrum of human diseases, ranging from lethal to mild symptoms. The molecular details regarding the versatile substrate-transporter interactions and the impact of pathogenic mutations on SLC26A2 transporter function remain unclear. Here, using cryo-electron microscopy, we determine three high-resolution structures of SLC26A2 in complexes with different substrates. These structures unveil valuable insights, including the distinct features of the homodimer assembly, the dynamic nature of substrate binding, and the potential ramifications of pathogenic mutations. This structural-functional information regarding SLC26A2 will advance our understanding of cellular sulfate transport mechanisms and provide foundations for future therapeutic development against various human diseases.
Assuntos
Microscopia Crioeletrônica , Transportadores de Sulfato , Humanos , Transportadores de Sulfato/metabolismo , Transportadores de Sulfato/genética , Transportadores de Sulfato/química , Mutação , Ligação Proteica , Modelos Moleculares , Sulfatos/metabolismo , Multimerização Proteica , Células HEK293 , Sítios de LigaçãoRESUMO
Recently, several ATP-binding cassette (ABC) importers have been found to adopt the typical fold of type IV ABC exporters. Presumably, these importers would function under the transport scheme of "alternating access" like those exporters, cycling through inward-open, occluded, and outward-open conformations. Understanding how the exporter-like importers move substrates in the opposite direction requires structural studies on all the major conformations. To shed light on this, here we report the structure of yersiniabactin importer YbtPQ from uropathogenic Escherichia coli in the occluded conformation trapped by ADP-vanadate (ADP-Vi) at a 3.1 Å resolution determined by cryo-electron microscopy. The structure shows unusual local rearrangements in multiple helices and loops in its transmembrane domains (TMDs). In addition, the dimerization of the nucleotide-binding domains (NBDs) promoted by the vanadate trapping is highlighted by the "screwdriver" action at one of the two hinge points. These structural observations are rare and thus provide valuable information to understand the structural plasticity of the exporter-like ABC importers.
Assuntos
Transportadores de Cassetes de Ligação de ATP , Vanadatos , Conformação Proteica , Transportadores de Cassetes de Ligação de ATP/metabolismo , Microscopia Crioeletrônica , Modelos Moleculares , Trifosfato de AdenosinaRESUMO
The study measured the levels of azoxystrobin (AZ) and thiabendazole (TBZ) in wallboards and metabolite levels of these fungicides in children. The paper covering of wallboard samples contained a higher concentration of AZ and TBZ than the gypsum core, and similar amounts (w/w) of these two fungicides were present in the samples. These data suggest that commercial products containing a 1:1 (w/w) amount of AZ and TBZ, such as Sporgard® WB or Azo Tech™, were applied to the wallboard paper. This is the first detection of TBZ in mold-and-mildew resistant wallboards. The TBZ metabolite, 5OH-TBZ, was detected in 48% of urine samples collected from children aged 40-84 months, and was co-detected with AZ-acid, a common AZ metabolite, in 37.5% of the urine samples. The detection frequency of 5OH-TBZ was positively associated with the detection frequency of AZ-acid. These findings suggest that certain types of wallboards used in homes and commercial buildings may be a potential source of co-exposure to AZ and TBZ in humans.
RESUMO
BACKGROUND: In contemporary society, with the accelerated pace of work and life, more and more people feel different degrees of stress. Long-term stress may not only lead to insomnia, but also to mental health problems (e.g., anxiety and depression), which has a significant impact on people's quality of life and mental health. OBJECTIVE: This study primarily investigates the mechanism through which stress affects sleep quality among college students. METHODS: We conducted research on 1653 Chinese college students using four scales with high reliability and validity: stress, the Pittsburgh Sleep Quality Index, social anxiety, and rumination. RESULTS: The study found: (1) Stress can significantly and positively predict sleep quality and rumination; (2) Rumination can positively predict social anxiety; (3) Social anxiety can positively predict sleep quality; (4) Stress can affect sleep quality through social anxiety and rumination separately, and stress can also affect sleep quality through the chained mediation of rumination and social anxiety. CONCLUSION: This study reveals the relationship and mechanisms between stress and sleep quality. It not only deepens the research on the impact of stress on sleep quality but also provides theoretical support and new methods for mental health professionals to help clients improve their sleep quality. In practice, in addition to using some common psychological intervention methods to help individuals reduce stress, we should pay more attention to how to help clients reduce rumination and social anxiety, This is significant in improving the quality of an individual's sleep.
RESUMO
Background In contemporary society, with the accelerated pace of work and life, more and more people feel different degrees of stress. Long-term stress may not only lead to insomnia, but also to mental health problems (e.g., anxiety and depression), which has a significant impact on people's quality of life and mental health. Objective This study primarily investigates the mechanism through which stress affects sleep quality among college students. Methods We conducted research on 1653 Chinese college students using four scales with high reliability and validity: stress, the Pittsburgh Sleep Quality Index, social anxiety, and rumination. Results The study found: (1) Stress can significantly and positively predict sleep quality and rumination; (2) Rumination can positively predict social anxiety; (3) Social anxiety can positively predict sleep quality; (4) Stress can affect sleep quality through social anxiety and rumination separately, and stress can also affect sleep quality through the chained mediation of rumination and social anxiety. Conclusion This study reveals the relationship and mechanisms between stress and sleep quality. It not only deepens the research on the impact of stress on sleep quality but also provides theoretical support and new methods for mental health professionals to help clients improve their sleep quality. In practice, in addition to using some common psychological intervention methods to help individuals reduce stress, we should pay more attention to how to help clients reduce rumination and social anxiety, This is significant in improving the quality of an individual's sleep. (AU)
Assuntos
Humanos , Masculino , Feminino , Adulto , Ansiedade , Estresse Psicológico/epidemiologia , Estudantes/psicologia , Ruminação Cognitiva , Qualidade do Sono , Universidades , ChinaRESUMO
While environmental factors have been considered contributors to atherosclerosis, it remains unclear whether drinking water promotes foam cell formation, the initial event of atherosclerosis. This study revealed that drinking water from six major cities in China, namely, Harbin, Jinan, Shanghai, Wuhan, Chongqing, and Zhuhai, significantly promoted foam cell formation in an in vitro macrophage model at a minimum concentration fold of 2. Moreover, cholesterol efflux was significantly impeded by all samples at 2-16-fold, while cholesterol influx was induced only by samples from Jinan and Chongqing at 16-fold, suggesting the dominant role of efflux in foam cell formation. Interestingly, except for the sample from Jinan, the samples exhibited complete inhibition of liver X receptor α (LXRα) activities at 160-fold, indicating the potential role of chemicals in drinking water in promoting foam cell formation by antagonizing LXRα. Through LXRα protein affinity selection-mass spectrometry, we identified ten LXRα-binding compounds, with efavirenz being revealed for the first time as a significant inducer of foam cell formation through LXRα antagonism. Overall, this study clarifies the atherosclerotic risks posed by drinking water and demonstrates the efavirenz-related atherosclerotic effects.
Assuntos
Aterosclerose , Água Potável , Receptores X do Fígado , Humanos , Aterosclerose/induzido quimicamente , Aterosclerose/metabolismo , China , Colesterol/metabolismo , Cidades , Receptores X do Fígado/antagonistas & inibidoresRESUMO
The rubber antioxidant 6PPD has gained significant attention due to its highly toxic transformation product, 6PPD-quinone (6PPDQ). Despite their detection in urines of pregnant women, the placental transfer and developmental toxicity of 6PPD and 6PPDQ are unknown. Here, we treated C57Bl/6 mice with 4 mg/kg 6PPD or 6PPDQ to investigate their urine excretion and placental transfer. Female and male mice exhibited sex difference in excretion profiles of 6PPD and 6PPDQ. Urine concentrations of 6PPDQ were one order of magnitude lower than those of 6PPD, suggesting lower excretion and higher bioaccumulation of 6PPDQ. In pregnant mice treated with 6PPD or 6PPDQ from embryonic day 11.5 to 15.5, 6PPDQ showed â¼1.5-8 times higher concentrations than 6PPD in placenta, embryo body, and embryo brain, suggesting higher placental transfer of 6PPDQ. Using in vitro dual-luciferase reporter assays, we revealed that 6PPDQ activated the human retinoic acid receptor α (RARα) and retinoid X receptor α (RXRα) at concentrations as low as 0.3 µM, which was â¼10-fold higher than the concentrations detected in human urines. 6PPD activated the RXRα at concentrations as low as 1.2 µM. These results demonstrate the exposure risks of 6PPD and 6PPDQ during pregnancy and emphasize the need for further toxicological and epidemiological investigations.
Assuntos
Benzoquinonas , Desenvolvimento Embrionário , Fenilenodiaminas , Animais , Feminino , Humanos , Masculino , Camundongos , Gravidez , Benzoquinonas/metabolismo , Benzoquinonas/toxicidade , Benzoquinonas/urina , Placenta/metabolismo , Fenilenodiaminas/metabolismo , Fenilenodiaminas/toxicidade , Fenilenodiaminas/urina , Camundongos Endogâmicos C57BL , Distribuição Tecidual , Fatores Sexuais , Desenvolvimento Embrionário/efeitos dos fármacos , Células HEK293 , Receptor alfa de Ácido Retinoico/metabolismo , Receptor X Retinoide alfa/metabolismoRESUMO
The expression of defensive responses to alerting sensory cues requires both general arousal and a specific arousal state associated with defensive emotions. However, it remains unclear whether these two forms of arousal can be regulated by common brain regions. We discovered that the medial sector of the auditory thalamus (ATm) in mice is a thalamic hub controlling both general and defensive arousal. The spontaneous activity of VGluT2-expressing ATm (ATmVGluT2+) neurons was correlated with and causally contributed to wakefulness. In sleeping mice, sustained ATmVGluT2+ population responses were predictive of sensory-induced arousal, the likelihood of which was markedly decreased by inhibiting ATmVGluT2+ neurons or multiple downstream pathways. In awake mice, ATmVGluT2+ activation led to heightened arousal accompanied by excessive anxiety and avoidance behavior. Notably, blocking their neurotransmission abolished alerting stimuli-induced defensive behaviors. These findings may shed light on the comorbidity of sleep disturbances and abnormal sensory sensitivity in specific brain disorders.
Assuntos
Nível de Alerta , Tálamo , Camundongos , Animais , Nível de Alerta/fisiologia , Tálamo/fisiologia , Vigília/fisiologia , Neurônios/fisiologia , Transmissão SinápticaRESUMO
To solve the problem of sound field reconstruction with fewer measurement points, a sound field reconstruction method based on Bayesian compressive sensing is proposed. In this method, a sound field reconstruction model based on a combination of the equivalent source method and sparse Bayesian compressive sensing is established. The MacKay iteration of the relevant vector machine is used to infer the hyperparameters and estimate the maximum a posteriori probability of both the sound source strength and noise variance. The optimal solution for sparse coefficients with an equivalent sound source is determined to achieve the sparse reconstruction of the sound field. The numerical simulation results demonstrate that the proposed method has higher accuracy over the entire frequency range compared to the equivalent source method, indicating a better reconstruction performance and wider frequency applicability with undersampling. Moreover, in environments with low signal-to-noise ratios, the proposed method exhibits significantly lower reconstruction errors than the equivalent source method, indicating a superior anti-noise performance and greater robustness in sound field reconstruction. The experimental results further verify the superiority and reliability of the proposed method for sound field reconstruction with limited measurement points.
Assuntos
Acústica , Modelos Teóricos , Teorema de Bayes , Reprodutibilidade dos Testes , SomRESUMO
BACKGROUND AND AIMS: Steatosis is the early pathological change in alcohol-associated liver disease. However, its precise mechanism is still unclear. The present study is aimed to explore the role and mechanism of acetyl-CoA synthetase 2 (ACSS2) in acute alcohol-induced lipogenesis. METHODS: The increase in ACSS2 nuclear import and histone H3 acetylation were observed in mice after intraperitoneally injected with 2 g/kg ethanol or oral administration of 5 g/kg ethanol and also validated in hepatocytes stimulated with ethanol or acetate. The role of ACSS2 was further explored in liver-specific ACSS2 knockdown mice fed with ethanol-containing diet. RESULTS: Alcohol challenge induced hepatic lipid deposition and upregulated lipogenic genes in mice. It also promoted ACSS2 nuclear import and increased histone H3 acetylation. In hepatocytes, ethanol induced similar phenomena whereas ACSS2 knockdown blocked histone acetylation and lipogenic gene induction. P300/CBP associated factor (PCAF), but not general control nonderepressible 5, CREB-binding protein (CBP) and p300, facilitated H3K9 acetylation responding to ethanol challenge. CUT&RUN assay showed the enrichment of acetylated histone H3K9 surrounding Fasn and Acaca promoters. These results indicated that ethanol metabolism promoted ACSS2 nuclear import to support lipogenesis via H3K9 acetylation. In alcohol-feeding mice, liver-specific ACSS2 knockdown blocked the interaction between PCAF and H3K9 and suppressed lipogenic gene induction in the liver, demonstrating the critical role of ACSS2 in lipogenesis. CONCLUSIONS: Our study demonstrated that alcohol metabolism generated acetyl-CoA in the nucleus dependently on nuclear ACSS2, contributing to epigenetic regulation of lipogenesis in hepatic steatosis. Targeting ACSS2 may be a potential therapeutical strategy for acute alcoholic liver steatosis.