RESUMEN
Fusarium crown and root rot (FCRR) has emerged as a highly destructive soil-borne disease, posing a significant threat to the safe cultivation of tomatoes in recent years. The pathogen of tomato FCRR is Fusarium oxysporum f. sp. radicis-lycopersici (Forl). To explore potential phytotoxins from Forl, eight undescribed diterpenoids namely fusariumic acids A-H (1-8) were isolated. Their structures were elucidated by using spectroscopic data analyses, quantum chemical calculations, and X-ray crystallography. Fusariumic acids A (1) and C-H (3-8) were typical isocassadiene-type diterpenoids, while fusariumic acid B (2) contained a cage-like structure with an unusual 7,8-seco-isocassadiene skeleton. A biosynthetic pathway of 2 was proposed. Fusariumic acids A (1) and C-H (3-8) were further assessed for their phytotoxic effects on tomato seedlings at 200 µg/mL. Among them, fusariumic acid F (6) exhibited the strongest inhibition against the hypocotyl and root elongation of tomato seedlings, with inhibitory rates of 61.3 and 45.3%, respectively.
Asunto(s)
Diterpenos , Fusarium , Enfermedades de las Plantas , Raíces de Plantas , Solanum lycopersicum , Fusarium/efectos de los fármacos , Solanum lycopersicum/microbiología , Diterpenos/química , Diterpenos/farmacología , Enfermedades de las Plantas/microbiología , Raíces de Plantas/microbiología , Raíces de Plantas/química , Estructura MolecularRESUMEN
The digestive characteristics of wheat starch are closely related to human health. However, the digestive mechanisms of distinct wheat starch granules are not well understood. To address this problem, A- and B-type wheat starch granules (AWS and BWS, respectively) were digested in vitro and the structural evolution of the digestive remnants was compared. After stomach-intestinal digestion of AWS, its crystallinity decreased from 12.75â¯% to 6.65â¯%, its fractal dimension decreased from 3.12 to 2.35, and the median particle size decreased from 20.613 to 10.135⯵m. Additionally, the number of short chains (polymerization degree<14) and thermodynamic stability decreased after digestion. For BWS, Fourier transform infrared ratio of 1047/1022â¯cm-1 and 995/1022â¯cm-1 increased from 0.665 and 0.725 to 0.990 and 0.800, respectively. The median particle size decreased from 5.480 to 4.769⯵m. An enzyme-resistant scattering peak was observed in the 1.35â¯nm-1 lamellar structure. Additionally, the number of B2 and B3 chains and the thermodynamic stability increased after digestion. Our study confirmed that BWS is more likely than AWS to form enzyme-resistant structures during digestion. These findings provide insights into the distinct digestion mechanisms of AWS and BWS, and serve as a foundation for modifying wheat starch to increase its nutritional value.
RESUMEN
Obesity is characterized by dysregulated adipogenesis that leads to increased number and/or size of adipocytes. Understanding the molecular mechanisms governing adipogenesis is therefore key to designing therapeutic interventions against obesity. In our study, we analyzed 3'-end sequencing data that we generated from human preadipocytes and adipocytes, as well as previously published RNA-seq datasets, to elucidate mechanisms of regulation via long non-coding RNA (lncRNA), alternative splicing (AS) and alternative polyadenylation (APA). We discovered lncRNAs that have not been previously characterized but may be key regulators of white adipogenesis. We also detected 100 AS events and, using motif enrichment analysis, identified RNA binding proteins (RBPs) that could mediate exon skipping-the most prevalent AS event. In addition, we show that usage of alternative poly(A) sites in introns or 3'-UTRs of key adipogenesis genes leads to isoform diversity, which can have significant biological consequences on differentiation efficiency. We also identified RBPs that may modulate APA and defined how 3'-UTR APA can regulate gene expression through gain or loss of specific microRNA binding sites. Taken together, our bioinformatics-based analysis reveals potential therapeutic avenues for obesity through manipulation of lncRNA levels and the profile of mRNA isoforms via alternative splicing and polyadenylation.
Asunto(s)
Adipogénesis , Empalme Alternativo , Perfilación de la Expresión Génica , Poliadenilación , ARN Largo no Codificante , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Adipogénesis/genética , Humanos , Adipocitos/metabolismo , Adipocitos/citología , Regiones no Traducidas 3' , MicroARNs/genética , MicroARNs/metabolismo , Transcriptoma , Regulación de la Expresión Génica , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Biología Computacional/métodosRESUMEN
The microRNAs (miRNAs) of their hosts play an important role in regulating both the innate and adaptive immune responses to Cryptosporidium parvum infection. The mechanisms of autophagy and apoptosis are important components of the defense system against C. parvum infection. In this study, we investigate the role of miRNA-199a-3p in regulating MTOR-mediated autophagy and apoptosis in HCT-8 cells induced by C. parvum. The expression of miR-199a-3p increased at 3, 6 and 12 hours postinfection (hpi) but decreased at 24 and 48 hpi. The upregulation of miR-199a-3p promoted autophagy and apoptosis and limited the parasite burden in HCT-8 cells after C. parvum infection. The downregulation of miR-199a-3p inhibited the autophagy and apoptosis induced by C. parvum and enhanced the parasite burden in HCT-8 cells. A luciferase reporter showed that MTOR was a target gene of miR-199a-3p. Suppressed expression of MTOR by small interfering RNA (siRNA) promoted autophagy and apoptosis and limited C. parvum burden in HCT-8 cells. Co-transfection with miR-199a-3p inhibitor or si-mTOR revealed that miR-199a-3p regulates autophagy and apoptosis in HCT-8 cells through MTOR, to resist C. parvum infection. In conclusion, intestinal epithelial cells defend against C. parvum infection by regulating their autophagy and apoptosis through the miR-199a-3p-MTOR axis.
Asunto(s)
Apoptosis , Autofagia , Criptosporidiosis , Cryptosporidium parvum , MicroARNs , Serina-Treonina Quinasas TOR , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Autofagia/genética , Apoptosis/genética , Cryptosporidium parvum/genética , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Criptosporidiosis/parasitología , Criptosporidiosis/genética , Línea Celular TumoralRESUMEN
Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3-7. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels4-7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.
Asunto(s)
Canales Iónicos Sensibles al Ácido , Isquemia Encefálica , Ácido Glutámico , Animales , Femenino , Humanos , Masculino , Ratones , 2-Amino-5-fosfonovalerato/efectos adversos , 2-Amino-5-fosfonovalerato/metabolismo , 2-Amino-5-fosfonovalerato/farmacología , Canales Iónicos Sensibles al Ácido/química , Canales Iónicos Sensibles al Ácido/deficiencia , Canales Iónicos Sensibles al Ácido/efectos de los fármacos , Canales Iónicos Sensibles al Ácido/genética , Canales Iónicos Sensibles al Ácido/metabolismo , Regulación Alostérica/efectos de los fármacos , Sitios de Unión/genética , Isquemia Encefálica/inducido químicamente , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ácido Glutámico/análogos & derivados , Ácido Glutámico/metabolismo , Ácido Glutámico/farmacología , Ácido Glutámico/toxicidad , Ratones Noqueados , Mutagénesis Sitio-Dirigida , Protones , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Autonomic nervous system disorders play a pivotal role in the pathophysiology of cardiovascular diseases. Regulating it is essential for preventing and treating acute ventricular arrhythmias (VAs). Photothermal neuromodulation is a nonimplanted technique, but the response temperature ranges of transient receptor potential vanilloid 1 (TRPV1) and TWIK-related K+ Channel 1 (TREK1) exhibit differences while being closely aligned, and the acute nature of VAs require that it must be rapid and precise. However, the low photothermal conversion efficiency (PCE) still poses limitations in achieving rapid and precise treatment. Here, we achieve a nearly perfect blackbody absorption and a high PCE in the second near infrared (NIR-II) window (73.7% at 1064 nm) via a Pt nanoparticle shell (PtNP-shell). By precisely manipulating the photothermal effect, we successfully achieve rapid and precise multimodal neuromodulation encompassing neural activation (41.0-42.9 °C) and inhibition (45.0-46.9 °C) in a male canine model. The NIR-II photothermal modulation additionally achieves multimodal reversible autonomic modulation and confers protection against acute VAs associated with myocardial ischemia and reperfusion injury in interventional therapy.
Asunto(s)
Arritmias Cardíacas , Rayos Infrarrojos , Animales , Arritmias Cardíacas/terapia , Perros , Masculino , Rayos Infrarrojos/uso terapéutico , Platino (Metal)/química , Nanopartículas del Metal/química , Terapia Fototérmica/métodos , Modelos Animales de EnfermedadRESUMEN
Intercellular communication in the nervous system occurs through the release of neurotransmitters into the synaptic cleft between neurons. In the presynaptic neuron, the proton pumping vesicular- or vacuolar-type ATPase (V-ATPase) powers neurotransmitter loading into synaptic vesicles (SVs), with the V1 complex dissociating from the membrane region of the enzyme before exocytosis. We isolated SVs from rat brain using SidK, a V-ATPase-binding bacterial effector protein. Single-particle electron cryomicroscopy allowed high-resolution structure determination of V-ATPase within the native SV membrane. In the structure, regularly spaced cholesterol molecules decorate the enzyme's rotor and the abundant SV protein synaptophysin binds the complex stoichiometrically. ATP hydrolysis during vesicle loading results in a loss of the V1 region of V-ATPase from the SV membrane, suggesting that loading is sufficient to induce dissociation of the enzyme.
Asunto(s)
Vesículas Sinápticas , ATPasas de Translocación de Protón Vacuolares , Animales , Ratas , Proteínas Bacterianas/química , Encéfalo/ultraestructura , Encéfalo/enzimología , Colesterol/química , Microscopía por Crioelectrón , Hidrólisis , Vesículas Sinápticas/enzimología , Vesículas Sinápticas/ultraestructura , Sinaptofisina/metabolismo , ATPasas de Translocación de Protón Vacuolares/química , ATPasas de Translocación de Protón Vacuolares/aislamiento & purificación , ATPasas de Translocación de Protón Vacuolares/ultraestructura , Conformación ProteicaRESUMEN
With the worsening indoor air quality in developing countries, more and more attention is being paid to indoor air pollution, especially formaldehyde and volatile organic compounds (VOCs) emitted from indoor building materials. A series of methods, such as the C-history method, have been proposed to determine the mechanistic parameters of formaldehyde and other VOC emissions. However, these methods require a relatively long test duration (at least 3 days) and may yield a multi-solution problem for these parameters. Therefore, we have developed a novel method, the two-parameter C-history method, to overcome these limitations by measuring the two early-stage emission characteristic parameters for formaldehyde/VOCs. The experimental results validate the accuracy of this method for different building materials and showed that the test duration can be substantially shortened to within 12 h. Based on this, we propose a new method to quickly predict the two emission characteristic parameters at different temperatures. We optimize the experimental parameters and discuss their influence to further improve accuracy. This method will be useful in engineering applications.
RESUMEN
Mutations in the phosphatase and tensin homolog (PTEN) gene are associated with severe neurodevelopmental disorders. Loss of PTEN leads to hyperactivation of the mechanistic target of rapamycin (mTOR), which functions in two distinct protein complexes, mTORC1 and mTORC2. The downstream signaling mechanisms that contribute to PTEN mutant phenotypes are not well delineated. Here, we show that pluripotent stem cell-derived PTEN mutant human neurons, neural precursors, and cortical organoids recapitulate disease-relevant phenotypes, including hypertrophy, electrical hyperactivity, enhanced proliferation, and structural overgrowth. PTEN loss leads to simultaneous hyperactivation of mTORC1 and mTORC2. We dissect the contribution of mTORC1 and mTORC2 by generating double mutants of PTEN and RPTOR or RICTOR, respectively. Our results reveal that the synergistic hyperactivation of both mTORC1 and mTORC2 is essential for the PTEN mutant human neural phenotypes. Together, our findings provide insights into the molecular mechanisms that underlie PTEN-related neural disorders and highlight novel therapeutic targets.
Asunto(s)
Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina , Neuronas , Organoides , Fosfohidrolasa PTEN , Humanos , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Organoides/metabolismo , Neuronas/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Mutación/genética , Proteína Asociada al mTOR Insensible a la Rapamicina/metabolismo , Proteína Asociada al mTOR Insensible a la Rapamicina/genética , Transducción de Señal , Proliferación Celular , Proteína Reguladora Asociada a mTOR/metabolismo , Proteína Reguladora Asociada a mTOR/genética , FenotipoRESUMEN
Opioids are the most prescribed drugs for the alleviation of pain. Both clinical and preclinical studies have reported strong evidence for sex-related divergence regarding opioid analgesia. There is an increasing amount of evidence indicating that gonadal hormones regulate the analgesic efficacy of opioids. This review presents an overview of the importance of gonadal steroids in modulating opioid analgesic responsiveness and focuses on elaborating what is currently known regarding the underlyingmechanism. We sought to identify the link between gonadal hormones and the effect of oipiod antinociception.
Gonadal hormones contribute to the sexual dimorphism of opioid antinociception.Generally, oestradiol is a negative modulator of opioid analgesia via both non-genomic and genomic effects.Testosterone facilitates opioid analgesia mainly through the transcriptional activities of androgen receptors.Under normal physiological conditions, progestin and oestrogen exist in parallel and have a combined effect. However, progestin alone could promote opioid analgesia by increasing the expression of opioid receptors.
Asunto(s)
Analgésicos Opioides , Hormonas Gonadales , Dolor , Analgésicos Opioides/farmacología , Humanos , Animales , Hormonas Gonadales/metabolismo , Masculino , Dolor/tratamiento farmacológico , Dolor/metabolismo , FemeninoRESUMEN
Mimicking the function of human skin is highly desired for electronic skins (e-skins) to perceive the tactile stimuli by both their intensity and spatial location. The common strategy using pixelated pressure sensor arrays and display panels greatly increases the device complexity and compromises the portability of e-skins. Herein, we tackled this challenge by developing a user-interactive iontronic skin that simultaneously achieves electrical pressure sensing and on-site, nonpixelated pressure mapping visualization. By merging the electrochromic and iontronic pressure sensing units into an integrated multilayer device, the interlayer charge transfer is regulated by applied pressure, which induces both color shifting and a capacitance change. The iontronic skin could visualize the trajectory of dynamic forces and reveal both the intensity and spatial information on various human activities. The integration of dual-mode pressure responsivity, together with the scalable fabrication and explicit signal output, makes the iontronic skin highly promising in biosignal monitoring and human-machine interaction.
RESUMEN
Hyaluronic acid (HA), as a multifunctional hydrophilic polysaccharide, is potentially beneficial in improving the thermal stability of fermented modified starches, but relevant insights at the molecular level are lacking. The aim of this study was to investigate the effect of different levels (0 %, 3 %, 6 %, 9 %, 12 % and 15 %) of HA on the structural, thermal and pasting properties of wheat starch co-fermented with Saccharomyces cerevisiae and Lactobacillus plantarum. We found that the addition of HA increased the median particle size of fermented starch granules from 16.387 to 17.070 µm. Meanwhile, the crystallinity of fermented starch was negatively correlated with the HA content, decreasing from 14.70 % to 12.80 % (p < 0.05). Fourier transform infrared spectroscopy results confirmed that HA interacted with starch granules and water molecules mainly through hydrogen bonding. Thermal analyses showed that the thermal peak of the composite correlated with the HA concentration, reaching a maximum of 73.17 °C at 12 % HA. In addition, HA increases the pasting temperature, reduces the peak, breakdown and setback viscosities of starch. This study demonstrates the role of HA in improving the thermal stability of fermented starch, providing new insights for traditional fermented food research and the application of HA in food processing.
Asunto(s)
Fermentación , Ácido Hialurónico , Lactobacillus plantarum , Saccharomyces cerevisiae , Almidón , Triticum , Lactobacillus plantarum/metabolismo , Saccharomyces cerevisiae/metabolismo , Almidón/química , Almidón/metabolismo , Ácido Hialurónico/química , Ácido Hialurónico/metabolismo , Triticum/química , Temperatura , Espectroscopía Infrarroja por Transformada de Fourier , ViscosidadRESUMEN
BACKGROUND: Cryptosporidium parvum is an apicomplexan zoonotic parasite causing the diarrheal illness cryptosporidiosis in humans and animals. To invade the host intestinal epithelial cells, parasitic proteins expressed on the surface of sporozoites interact with host cells to facilitate the formation of parasitophorous vacuole for the parasite to reside and develop. The gp40 of C. parvum, named Cpgp40 and located on the surface of sporozoites, was proven to participate in the process of host cell invasion. METHODS: We utilized the purified Cpgp40 as a bait to obtain host cell proteins interacting with Cpgp40 through the glutathione S-transferase (GST) pull-down method. In vitro analysis, through bimolecular fluorescence complementation assay (BiFC) and coimmunoprecipitation (Co-IP), confirmed the solid interaction between Cpgp40 and ENO1. In addition, by using protein mutation and parasite infection rate analysis, it was demonstrated that ENO1 plays an important role in the C. parvum invasion of HCT-8 cells. RESULTS: To illustrate the functional activity of Cpgp40 interacting with host cells, we identified the alpha-enolase protein (ENO1) from HCT-8 cells, which showed direct interaction with Cpgp40. The mRNA level of ENO1 gene was significantly decreased at 3 and 24 h after C. parvum infection. Antibodies and siRNA specific to ENO1 showed the ability to neutralize C. parvum infection in vitro, which indicated the participation of ENO1 during the parasite invasion of HCT-8 cells. In addition, we further demonstrated that ENO1 protein was involved in the regulation of cytoplasmic matrix of HCT-8 cells during C. parvum invasion. Functional study of the protein mutation illustrated that ENO1 was also required for the endogenous development of C. parvum. CONCLUSIONS: In this study, we utilized the purified Cpgp40 as a bait to obtain host cell proteins ENO1 interacting with Cpgp40. Functional studies illustrated that the host cell protein ENO1 was involved in the regulation of tight junction and adherent junction proteins during C. parvum invasion and was required for endogenous development of C. parvum.
Asunto(s)
Criptosporidiosis , Cryptosporidium parvum , Cryptosporidium , Humanos , Animales , Cryptosporidium parvum/genética , Criptosporidiosis/parasitología , Esporozoítos/metabolismo , Proteínas Protozoarias/metabolismo , Proteínas de la Membrana/metabolismo , Fosfopiruvato Hidratasa/genética , Fosfopiruvato Hidratasa/metabolismo , Proteínas de Unión al ADN/metabolismo , Biomarcadores de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Few studies have investigated the association between PM2.5 and hypertension among floating populations. We therefore examined the relationship using binary logistic regression. Each grade of increment in the annual average PM2.5 (grade one: ≤15 µg/m3; grade two: 15-25 µg/m3; grade three: 25-35 µg/m3 [Excluding 25]; grade four: ≥35 µg/m3) was associated with an increased risk of hypertension (odds ratio [OR] = 1.081, 95% confidence interval (CI): 1.034-1.129). Among the female floating population (OR = 1.114, 95% CI: 1.030-1.204), those with education level of primary school and below (OR = 1.140, 95% CI: 1.058-1.229), construction workers (OR = 1.228, 95% CI: 1.058-1.426), and those living in the eastern region of China (OR = 1.241, 95% CI: 1.145-1.346) were more vulnerable to PM2.5. These results indicate that PM2.5 is positively associated with hypertension in floating populations. Floating populations who are female, less educated, construction workers, and living in the eastern region of China are more vulnerable to the adverse impacts of PM2.5.
Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Hipertensión , Humanos , Femenino , Masculino , Material Particulado/toxicidad , Material Particulado/análisis , Contaminantes Atmosféricos/toxicidad , Contaminantes Atmosféricos/análisis , Estudios Transversales , Hipertensión/epidemiología , Hipertensión/etiología , China/epidemiología , Exposición a Riesgos AmbientalesRESUMEN
There are limited studies investigating the association between short-term exposure to PM2.5 and incident cardiovascular disease (CVD) cases in China. This study aims to examine the short-term effects of PM2.5 on the incidence of cardiovascular diseases. A combination of Poisson-distribution generalized linear model and distributed lag non-linear model was used to examine the association between short-term exposure to PM2.5 and incident cases of CVD. The results revealed that per 10 µg/m3 increment of PM2.5 would increase the incident CVD cases by 0.147% (Relative Risk: 1.00147, 95% Confidence Interval: 1.00008-1.00286) at a lag of 2 days. The stratified analyses showed higher effects risk in females, older residents (aged 60-75 years), and acute myocardial infarction group (p-value for difference <0.05). This study indicates that short-term exposure to PM2.5 may increase the risk of CVD and highlights the necessity for a higher air quality standard in Yantai, China.
Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Enfermedades Cardiovasculares , Femenino , Humanos , Contaminantes Atmosféricos/toxicidad , Contaminantes Atmosféricos/análisis , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/epidemiología , Material Particulado/toxicidad , Material Particulado/análisis , Exposición a Riesgos Ambientales/análisis , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , China/epidemiologíaRESUMEN
We investigated the association between flavonoid intake and coronary artery disease (CAD) risk in older adults. Data were extracted from the National Health and Nutrition Examination Survey (age ≥ 70 years; 2007-2010 and 2017-2018; n = 2 417). The total flavonoid and flavonoid subclass intake was calculated using validated food frequency questionnaires. The association between flavonoid intake and CAD risk was examined using generalized linear models with restricted cubic spline models. After multivariate adjustment, anthocyanin intake was positively associated with CAD risk; no significant associations were observed between other flavonoid subcategories and endpoint outcomes. Anthocyanins exhibited a non-linear association with CAD risk, and threshold effect analysis showed an inflection point of 15.8 mg/day for anthocyanins. Per unit increase in anthocyanins, the odds of CAD on the left of the inflection point decreased by 2%, while the odds on the right increased by 35.8%. Excessive flavonoid intake may increase CAD risk in the older population.
Asunto(s)
Enfermedad de la Arteria Coronaria , Flavonoides , Humanos , Anciano , Flavonoides/análisis , Antocianinas , Encuestas Nutricionales , Enfermedad de la Arteria Coronaria/epidemiología , Factores de Riesgo , DietaRESUMEN
BACKGROUND: Analgesic tolerance due to long-term use of morphine remains a challenge for pain management. Morphine acts on µ-opioid receptors and downstream of the phosphatidylinositol 3-kinase signaling pathway to activate the mammalian target of rapamycin (mTOR) pathway. Rheb is an important regulator of growth and cell-cycle progression in the central nervous system owing to its critical role in the activation of mTOR. The hypothesis was that signaling via the GTP-binding protein Rheb in the dorsal horn of the spinal cord is involved in morphine-induced tolerance. METHODS: Male and female wild-type C57BL/6J mice or transgenic mice (6 to 8 weeks old) were injected intrathecally with saline or morphine twice daily at 12-h intervals for 5 consecutive days to establish a tolerance model. Analgesia was assessed 60 min later using the tail-flick assay. After 5 days, the spine was harvested for Western blot or immunofluorescence analysis. RESULTS: Chronic morphine administration resulted in the upregulation of spinal Rheb by 4.27 ± 0.195-fold (P = 0.0036, n = 6), in turn activating mTOR by targeting rapamycin complex 1 (mTORC1). Genetic overexpression of Rheb impaired morphine analgesia, resulting in a tail-flick latency of 4.65 ± 1.10 s (P < 0.0001, n = 7) in Rheb knock-in mice compared to 10 s in control mice (10 ± 0 s). Additionally, Rheb overexpression in spinal excitatory neurons led to mTORC1 signaling overactivation. Genetic knockout of Rheb or inhibition of mTORC1 signaling by rapamycin potentiated morphine-induced tolerance (maximum possible effect, 52.60 ± 9.56% in the morphine + rapamycin group vs. 16.60 ± 8.54% in the morphine group; P < 0.0001). Moreover, activation of endogenous adenosine 5'-monophosphate-activated protein kinase inhibited Rheb upregulation and retarded the development of morphine-dependent tolerance (maximum possible effect, 39.51 ± 7.40% in morphine + metformin group vs. 15.58 ± 5.79% in morphine group; P < 0.0001). CONCLUSIONS: This study suggests spinal Rheb as a key molecular factor for regulating mammalian target of rapamycin signaling.
Asunto(s)
Proteínas de Unión al GTP Monoméricas , Femenino , Masculino , Ratones , Animales , Proteínas de Unión al GTP Monoméricas/genética , Proteínas de Unión al GTP Monoméricas/metabolismo , Morfina/farmacología , Sirolimus/farmacología , Ratones Endogámicos C57BL , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Dolor , Mamíferos/metabolismoRESUMEN
Downsizing silicon-based transistors can result in lower power consumption, faster speeds, and greater computational capacity, although it is accompanied by the appearance of short-channel effects. The integration of high-mobility 2D semiconductor channels with ultrathin high dielectric constant (high-κ) dielectric in transistors is expected to suppress the effect. Nevertheless, the absence of a high-κ dielectric layer featuring an atomically smooth surface devoid of dangling bonds poses a significant obstacle in the advancement of 2D electronics. Here, ultrathin van der Waals (vdW) lanthanum oxychloride (LaOCl) dielectrics are successfully synthesized by precisely controlling the growth kinetics. These dielectrics demonstrate an impressive high-κ value of 10.8 and exhibit a remarkable breakdown field strength (Ebd ) exceeding 10 MV cm-1 . Remarkably, the conventional molybdenum disulfide (MoS2 ) field-effect transistor (FET) featuring a dielectric made of LaOCl showcases an almost negligible hysteresis when compared to FETs employing alternative gate dielectrics. This can be attributed to the flawlessly formed vdW interface and excellent compatibility established between LaOCl and MoS2 . These findings will motivate the further exploration of rare-earth oxychlorides and the development of more-than-Moore nanoelectronic devices.
RESUMEN
BACKGROUND: Hepatitis C threatens human health and brings a heavy economic burden. Shandong Province is the second most populous province in China and has uneven regional economic development. Therefore, we analyzed the incidence rate trend and regional differences of hepatitis C in Shandong Province from 2004 to 2021. METHODS: The monthly and annual incidence rates of hepatitis C in Shandong Province from 2022 to 2030 were predicted by fitting Autoregressive Integrated Moving Average model (ARIMA), Long Short-Term Memory (LSTM) and ARIMA-LSTM combined model. RESULTS: From 2004 to 2021, annual new cases of hepatitis C in Shandong Province increased from 635 to 5834, with a total of 61,707 cases. The incidence rate increased from 0.69/100 thousand in 2004 to 6.40/100 thousand in 2019, with a slight decrease in 2020 and 2021. The average annual incidence rate was 3.47/100 thousand. In terms of regional distribution, the hepatitis C incidence rate in Shandong Province was generally high in the west and low in the east. It is estimated that the hepatitis C incidence rate in Shandong Province will be 9.21 per 100 thousand in 2030. CONCLUSION: The hepatitis C incidence rate in Shandong Province showed an increasing trend from 2004 to 2019 and a decreasing trend in 2020 and 2021. Significant regional variations in incidence rate existed. An upward trend in incidence rate is predicted from 2022 to 2030. It is necessary to strengthen the prevention and control of hepatitis C to achieve the goal of eliminating viral hepatitis by 2030.