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Recent evidence has demonstrated that the transsynaptic nanoscale organization of synaptic proteins plays a crucial role in regulating synaptic strength in excitatory synapses. However, the molecular mechanism underlying this transsynaptic nanostructure in inhibitory synapses still remains unclear and its impact on synapse function in physiological or pathological contexts has not been demonstrated. In this study, we utilized an engineered proteolysis technique to investigate the effects of acute cleavage of neuroligin-2 (NL2) on synaptic transmission. Our results show that the rapid cleavage of NL2 led to impaired synaptic transmission by reducing both neurotransmitter release probability and quantum size. These changes were attributed to the dispersion of RIM1/2 and GABAA receptors and a weakened spatial alignment between them at the subsynaptic scale, as observed through superresolution imaging and model simulations. Importantly, we found that endogenous NL2 undergoes rapid MMP9-dependent cleavage during epileptic activities, which further exacerbates the decrease in inhibitory transmission. Overall, our study demonstrates the significant impact of nanoscale structural reorganization on inhibitory transmission and unveils ongoing modulation of mature GABAergic synapses through active cleavage of NL2 in response to hyperactivity.
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Moléculas de Adesão Celular Neuronais , Proteínas do Tecido Nervoso , Sinapses , Transmissão Sináptica , Animais , Camundongos , Moléculas de Adesão Celular Neuronais/metabolismo , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Epilepsia/patologia , Hipocampo/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Proteólise , Receptores de GABA-A/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/fisiologiaRESUMO
Lowe syndrome, a rare X-linked multisystem disorder presenting with major abnormalities in the eyes, kidneys, and central nervous system, is caused by mutations in OCRL gene (NG_008638.1). Encoding an inositol polyphosphate 5-phosphatase, OCRL catalyzes the hydrolysis of PI(4,5)P2 into PI4P. There are no effective targeted treatments for Lowe syndrome. Here, we demonstrate a novel gene therapy for Lowe syndrome in patient fibroblasts using an adenine base editor (ABE) that can efficiently correct pathogenic point mutations. We show that ABE8e-NG-based correction of a disease-causing mutation in a Lowe patient-derived fibroblast line containing R844X mutation in OCRL gene, restores OCRL expression at mRNA and protein levels. It also restores cellular abnormalities that are hallmarks of OCRL dysfunction, including defects in ciliogenesis, microtubule anchoring, α-actinin distribution, and F-actin network. The study indicates that ABE-mediated gene therapy is a feasible treatment for Lowe syndrome, laying the foundation for therapeutic application of ABE in the currently incurable disease.
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Fibroblastos , Edição de Genes , Terapia Genética , Síndrome Oculocerebrorrenal , Monoéster Fosfórico Hidrolases , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/metabolismo , Humanos , Fibroblastos/metabolismo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Terapia Genética/métodos , Edição de Genes/métodos , Mutação , Adenina/metabolismoRESUMO
A classic example of experience-dependent plasticity is ocular dominance (OD) shift, in which the responsiveness of neurons in the visual cortex is profoundly altered following monocular deprivation (MD). It has been postulated that OD shifts also modify global neural networks, but such effects have never been demonstrated. Here, we use wide-field fluorescence optical imaging (WFOI) to characterize calcium-based resting-state functional connectivity during acute (3â d) MD in female and male mice with genetically encoded calcium indicators (Thy1-GCaMP6f). We first establish the fundamental performance of WFOI by computing signal to noise properties throughout our data processing pipeline. Following MD, we found that Δ band (0.4-4â Hz) GCaMP6 activity in the deprived visual cortex decreased, suggesting that excitatory activity in this region was reduced by MD. In addition, interhemispheric visual homotopic functional connectivity decreased following MD, which was accompanied by a reduction in parietal and motor homotopic connectivity. Finally, we observed enhanced internetwork connectivity between the visual and parietal cortex that peaked 2â d after MD. Together, these findings support the hypothesis that early MD induces dynamic reorganization of disparate functional networks including the association cortices.
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Camundongos Endogâmicos C57BL , Rede Nervosa , Privação Sensorial , Córtex Visual , Animais , Camundongos , Masculino , Feminino , Privação Sensorial/fisiologia , Córtex Visual/fisiologia , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Dominância Ocular/fisiologia , Período Crítico Psicológico , Vias Visuais/fisiologiaRESUMO
Thiamine functions as a crucial activator modulating plant health and broad-spectrum stress tolerances. However, the role of thiamine in regulating plant virus infection is largely unknown. Here, we report that the multifunctional 17K protein encoded by barley yellow dwarf virus-GAV (BYDV-GAV) interacted with barley pyrimidine synthase (HvTHIC), a key enzyme in thiamine biosynthesis. HvTHIC was found to be localized in chloroplast via an N-terminal 74-amino acid domain. However, the 17K-HvTHIC interaction restricted HvTHIC targeting to chloroplasts and triggered autophagy-mediated HvTHIC degradation. Upon BYDV-GAV infection, the expression of the HvTHIC gene was significantly induced, and this was accompanied by accumulation of thiamine and salicylic acid. Silencing of HvTHIC expression promoted BYDV-GAV accumulation. Transcriptomic analysis of HvTHIC silenced and non-silenced barley plants showed that the differentially expressed genes were mainly involved in plant-pathogen interaction, plant hormone signal induction, phenylpropanoid biosynthesis, starch and sucrose metabolism, photosynthesis-antenna protein, and MAPK signaling pathway. Thiamine treatment enhanced barley resistance to BYDV-GAV. Taken together, our findings reveal a molecular mechanism underlying how BYDV impedes thiamine biosynthesis to uphold viral infection in plants.
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Hordeum , Doenças das Plantas , Proteínas de Plantas , Tiamina , Hordeum/virologia , Hordeum/genética , Hordeum/metabolismo , Tiamina/metabolismo , Tiamina/biossíntese , Doenças das Plantas/virologia , Doenças das Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Luteovirus/fisiologia , Regulação da Expressão Gênica de Plantas , Proteínas Virais/metabolismo , Proteínas Virais/genética , Cloroplastos/metabolismo , Ácido Salicílico/metabolismo , Interações Hospedeiro-Patógeno , Resistência à Doença/genéticaRESUMO
BACKGROUND: Mothers play a crucial role in influencing their daughters' HPV vaccination decisions. Addressing barriers to receiving HPV vaccination among mothers of girls may achieve two goals in one strike: increasing vaccination coverage among both mothers and their daughters. This study aims to examine the HPV vaccination uptake and its determinants among mothers of girls in China at both the individual and interpersonal levels. METHODS: From July to October 2023, a cross-sectional online study was conducted to investigate HPV vaccine refusal for daughters aged 9-17 years among 11,678 mothers in Shenzhen, China. A randomized selection method was employed, targeting 11 primary schools and 13 secondary schools in Shenzhen. The research team invited mothers of girls to participate in an anonymous online survey. Multilevel logistic regression models (level 1: schools; level 2: individual participants) were employed to analyze the data. RESULTS: Among 11,678 mothers, 41.1% self-reported receiving at least one dose of HPV vaccination. Through multilevel logistic regression analysis, eight items measuring illness representations of HPV, which refers to how people think about HPV, were associated with higher HPV vaccination uptake (AOR: 1.02-1.14). These items included identity (identifying symptoms of HPV), timeline (whether HPV is acute/chronic), negative consequences, personal and treatment control (whether HPV is under volitional control), concern, negative emotions, and coherence (overall understanding of HPV). In addition, participants refusing HPV vaccines for the index daughters (AOR: 0.82, 95%CI: 0.76, 0.89) had lower vaccine uptake. Perceived more difficulties in accessing the 9-valent vaccines (AOR: 1.06, 95%CI: 1.04, 1.08) and more satisfaction with vaccine-related promotional materials (AOR: 1.50, 95%CI: 1.46, 1.54) at the individual level were associated with higher vaccine uptake. At the interpersonal factors, higher frequency of exposure to testimonials given by others about HPV vaccination on social media (AOR: 1.19, 95%CI: 1.14, 1.25) and thoughtful consideration of the veracity of the information (AOR: 1.11, 95%CI: 1.07, 1.16) were correlated with higher HPV vaccination uptake. CONCLUSIONS: These findings offer essential implications for modifying HPV disease perceptions, addressing difficulties in accessing the 9-valent HPV vaccines, and enhancing health communication needs to improve HPV vaccine uptake among mothers of girls.
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Mães , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Mídias Sociais , Humanos , Estudos Transversais , Feminino , Adolescente , China , Vacinas contra Papillomavirus/administração & dosagem , Infecções por Papillomavirus/prevenção & controle , Criança , Mães/psicologia , Adulto , Vacinação/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Núcleo Familiar , Aceitação pelo Paciente de Cuidados de Saúde , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
Driven by the pressing demand for stable energy systems, zinc-air batteries (ZABs) have emerged as crucial energy storage solutions. However, the quest for cost-effective catalysts to enhance vital oxygen evolution and reduction reactions remains challenging. FeNiCo|MnGaOx heterostructure nanoparticles on carbon nanotubes (CNTs) are synthesized using liquid-phase reduction and H2 calcination approach. Compared to its component, such FeNiCo|MnGaOx/CNT shows a high synergistic effect, low impedance, and modulated electronic structure, leading to a superior bifunctional catalytic performance with an overpotential of 255 mV at 10 mA cm-2 and half-wave potential of 0.824 V (ω = 1600 rpm and 0.1 m KOH electrolyte). Moreover, ZABs based on FeNiCo|MnGaOx/CNT demonstrate notable features, including a peak power density of 136.1 mW cm-2, a high specific capacity of 808.3 mAh gZn -1, and outstanding stability throughout >158 h of uninterrupted charge-discharge cycling. Theoretical calculations reveal that the non-homogeneous interface can introduce more carriers and altered electronic structures to refine intermediate adsorption reactions, especially promoting O* formation, thereby enhancing electrocatalytic performance. This work demonstrates the importance of heterostructure interfacial modulation of electronic structure and enhancement of adsorption capacity in promoting the implementation of OER/ORR, ZABs, and related applications.
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Metal-organic frameworks (MOFs) are normally moisture-sensitive and unstable in aqueous environments, which has considerably limited their practical applications because water/moisture is ubiquitous in many industrial processes. New materials with superior water stability are, therefore, in great demand and vital to their practical applications. Here, a novel oil/water interfacial assembly strategy is demonstrated for the synthesis of a new class of metal-organic monoacid framework (MOmAF) with exceptional water stability and chemical stability. Superhydrophobic 2D sheets are synthesized at room temperature, while 1D nanotubes are obtained via the self-scrolling of their 2D sheets for the first time. In addition, a simple sequential drop-casting method is developed to coat as-synthesized MOmAF structures onto porous membranes. This can potentially open up new avenues in the design of superhydrophobic self-cleaning MOmAF materials without tedious post-synthetic modifications and usher in a new class of materials meeting industrial needs.
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MAIN CONCLUSION: OsNAC103 negatively regulates rice plant height by influencing the cell cycle and crosstalk of phytohormones. Plant height is an important characteristic of rice farming and is directly related to agricultural yield. Although there has been great progress in research on plant growth regulation, numerous genes remain to be elucidated. NAC transcription factors are widespread in plants and have a vital function in plant growth. Here, we observed that the overexpression of OsNAC103 resulted in a dwarf phenotype, whereas RNA interference (RNAi) plants and osnac103 mutants showed no significant difference. Further investigation revealed that the cell length did not change, indicating that the dwarfing of plants was caused by a decrease in cell number due to cell cycle arrest. The content of the bioactive cytokinin N6-Δ2-isopentenyladenine (iP) decreased as a result of the cytokinin synthesis gene being downregulated and the enhanced degradation of cytokinin oxidase. OsNAC103 overexpression also inhibited cell cycle progression and regulated the activity of the cell cyclin OsCYCP2;1 to arrest the cell cycle. We propose that OsNAC103 may further influence rice development and gibberellin-cytokinin crosstalk by regulating the Oryza sativa homeobox 71 (OSH71). Collectively, these results offer novel perspectives on the role of OsNAC103 in controlling plant architecture.
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Oryza , Fatores de Transcrição , Fatores de Transcrição/genética , Oryza/genética , Ciclo Celular/genética , Divisão Celular , CitocininasRESUMO
Cardiac sympathetic overactivation is a critical driver in the progression of acute myocardial infarction (AMI). The left middle cervical ganglion (LMCG) is an important extracardiac sympathetic ganglion. However, the regulatory effects of LMCG on AMI have not yet been fully documented. In the present study, we detected that the LMCG was innervated by abundant sympathetic components and exerted an excitatory effect on the cardiac sympathetic nervous system in response to stimulation. In canine models of AMI, targeted ablation of LMCG reduced the sympathetic indexes of heart rate variability and serum norepinephrine, resulting in suppressed cardiac sympathetic activity. Moreover, LMCG ablation could improve ventricular electrophysiological stability, evidenced by the prolonged ventricular effective refractory period, elevated action potential duration, increased ventricular fibrillation threshold, and enhanced connexin43 expression, consequently showing antiarrhythmic effects. Additionally, compared with the control group, myocardial infarction size, circulating cardiac troponin I, and myocardial apoptosis were significantly reduced, accompanied by preserved cardiac function in canines subjected to LMCG ablation. Finally, we performed the left stellate ganglion (LSG) ablation and compared its effects with LMCG destruction. The results indicated that LMCG ablation prevented ventricular electrophysiological instability, cardiac sympathetic activation, and AMI-induced ventricular arrhythmias with similar efficiency as LSG denervation. In conclusion, this study demonstrated that LMCG ablation suppressed cardiac sympathetic activity, stabilized ventricular electrophysiological properties and mitigated cardiomyocyte death, resultantly preventing ischemia-induced ventricular arrhythmias, myocardial injury, and cardiac dysfunction. Neuromodulation therapy targeting LMCG represented a promising strategy for the treatment of AMI.
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Infarto do Miocárdio , Animais , Cães , Arritmias Cardíacas , Coração/inervação , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/prevenção & controle , Gânglios Simpáticos/metabolismoRESUMO
BACKGROUND: Although immune checkpoint inhibitors (ICIs) have revolutionized the landscape of cancer treatment, only a minority of colorectal cancer (CRC) patients respond to them. Enhancing tumor immunogenicity by increasing major histocompatibility complex I (MHC-I) surface expression is a promising strategy to boost the antitumor efficacy of ICIs. METHODS: Dual luciferase reporter assays were performed to find drug candidates that can increase MHC-I expression. The effect of nilotinib on MHC-I expression was verified by dual luciferase reporter assays, qRT-PCR, flow cytometry and western blotting. The biological functions of nilotinib were evaluated through a series of in vitro and in vivo experiments. Using RNA-seq analysis, immunofluorescence assays, western blotting, flow cytometry, rescue experiments and microarray chip assays, the underlying molecular mechanisms were investigated. RESULTS: Nilotinib induces MHC-I expression in CRC cells, enhances CD8+ T-cell cytotoxicity and subsequently enhances the antitumor effects of anti-PDL1 in both microsatellite instability and microsatellite stable models. Mechanistically, nilotinib promotes MHC-I mRNA expression via the cGAS-STING-NF-κB pathway and reduces MHC-I degradation by suppressing PCSK9 expression in CRC cells. PCSK9 may serve as a potential therapeutic target for CRC, with nilotinib potentially targeting PCSK9 to exert anti-CRC effects. CONCLUSION: This study reveals a previously unknown role of nilotinib in antitumor immunity by inducing MHC-I expression in CRC cells. Our findings suggest that combining nilotinib with anti-PDL1 therapy may be an effective strategy for the treatment of CRC.
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Neoplasias Colorretais , Pirimidinas , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Humanos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Camundongos , Instabilidade de Microssatélites/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Transdução de Sinais/efeitos dos fármacosRESUMO
Catalase (CAT) is the main reactive oxygen species (ROS)-scavenging enzyme in plants and insects. However, it remains elusive whether and how insect saliva CAT suppresses ROS-mediated plant defense, thereby promoting initial virus transmission by insect vectors. Here, we investigated how leafhopper Recilia dorsalis catalase (RdCAT) was secreted from insect salivary glands into rice phloem, and how it was perceived by rice chaperone NO CATALASE ACTIVITY1 (OsNCA1) to scavenge excessive H2O2 during insect-to-plant virus transmission. We found that the interaction of OsNCA1 with RdCAT activated its enzymatic activity to decompose H2O2 in rice plants during leafhopper feeding. However, initial insect feeding did not significantly change rice CATs transcripts. Knockout of OsNCA1 in transgenic lines decreased leafhopper feeding-activated CAT activity and caused higher H2O2 accumulation. A devastating rice reovirus activated RdCAT expression and promoted the cosecretion of virions and RdCAT into leafhopper salivary cavities and ultimately into the phloem. Virus-mediated increase of RdCAT secretion suppressed excessive H2O2, thereby promoting host attractiveness to insect vectors and initial virus transmission. Our findings provide insights into how insect saliva CAT is secreted and perceived by plant chaperones to suppress the early H2O2 burst during insect feeding, thereby facilitating viral transmission.
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Chalcogenide glass has achieved great success in manufacturing axial-type infrared gradient refractive index (IR-GRIN) lenses. However, studies on radial-type IR-GRIN lenses, which are more ideal for optical design, remain rare. The present study introduces what we believe to be a new method for preparing radial IR-GRIN lens by creating high refractive index (n) In2S3 nanocrystals within a 65GeS2-25In2S3-10CsCl (GIC, in molar percentage) glass matrix. Upon introduction of multi-temperature field manipulation, we have successfully achieved central crystallization and simultaneous gradient attenuation spreading toward the edge within GIC glass, providing a radial GRIN profile with Δn over 0.1 while maintaining excellent IR transparency. In addition, the optical and structural properties of the GIC GRIN samples were characterized. The relationship between Raman intensity and the n of glass ceramics at different heat treatment temperatures was investigated, thereby enabling the indirect confirmation of the presence of radial gradient crystallization within the prepared GIC GRIN samples through Raman intensity. Multiple experimental results have shown that this approach has excellent reproducibility and potential for large-scale productions.
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In order to reduce the power consumption of digital signal processing (DSP) in a coherent optical communication system, a low complexity equalization scheme in DSP flow of a 400â Gb/s DP-16QAM system has been proposed. This scheme is based on Fermat number transform (FNT), which sequentially performs static equalization (SE) and dynamic equalization (DE) in the transform domain. For different distances, the proposed scheme finds the optimal solution under the condition that transform length and data bit width are mutually restricted under different transmission distances while achieving low complexity and optimal performance. The experimental results show that the adopted transform-domain equalization (TrDE) scheme has much lower computational complexity than the traditional frequency-domain equalization (FDE) and time-domain equalization (TDE) nearly without any performance loss. In the 80, 160, and 240â km scenarios, the number of multiplier is reduced by more than 72%, and the advantage becomes more obvious as the transmission capacity increases.
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We propose integrated long-period fiber gratings (LPFGs) fabricated by a CO2 laser to realize a multi-channel and multi-order orbital angular momentum (OAM) mode generator. The integrated LPFG is inscribed on multiple surfaces of the few-mode fiber (FMF) by rotating the fiber in the opposite direction at an angle θ. By controlling the rotation angle, the number of integrated LPFGs can be set. The selected rotation angle is 43 ∘, which can integrate up to nine LPFGs, i.e., realizing that the number of channels for first-order orbital angular momentum (OAM) mode conversion is nine. The integrated LPFGs fabricated in this method allow a flexible design of channel spacing. In addition, the flexible selection of the integrated grating period achieves the simultaneous generation of multi-channel second-order and third-order OAM mode conversion. The multi-channel and multi-order OAM mode generators have important application in optical communication multiplexing systems and OAM sensing.
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High-quality swept-source optical coherence tomography (SS-OCT) requires accurate k-sampling, which is equally vital for optical coherence tomography angiography (OCTA). Most SS-OCT systems are equipped with hardware-driven k-sampling. However, this conventional approach raises concerns over system cost, optical alignment, imaging depth, and stability in the clocking circuit. This work introduces an optimized numerical k-sampling method to replace the additional k-clock hardware. Using this method, we can realize high axial resolution (4.9-µm full-width-half-maximum, in air) and low roll-off (2.3â dB loss) over a 4-mm imaging depth. The high axial resolution and sensitivity achieved by this simple numerical method can reveal anatomic and microvascular structures with structural OCT and OCTA in both macular and deeper tissues, including the lamina cribrosa, suggesting its usefulness in imaging retinopathy and optic neuropathy.
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Angiografia , Tomografia de Coerência Óptica , Tomografia de Coerência Óptica/métodos , Angiofluoresceinografia/métodosRESUMO
We demonstrate a new non-mydriatic ultra-widefield optical coherence tomography retinal imaging system, designed with custom optics to improve the imaging field of view, lateral resolution, and patient comfort. The key motivation is to address the challenge with conventional systems that require pupillary dilation, adding time, expense, discomfort, and medical risk to the examination of the retina. Our system provides an ultrawide 100° field of view (beam scanning angle at the scanning pivot point) and maintains a lateral resolution of 20â µm on the center. It also allows a generous working distance of 16â mm, 2-3 times longer than existing ultra-widefield OCT imaging systems. This advanced system was able to avoid iris vignetting artifacts without pharmacological dilation and ensure diffraction-limited ultra-widefield imaging under a generalized eye model. This enables a comprehensive evaluation of retina diseases, especially those affecting the peripheral regions.
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Retina , Tomografia de Coerência Óptica , Tomografia de Coerência Óptica/métodos , Retina/diagnóstico por imagem , HumanosRESUMO
We report the experimental measurement of millijoule terahertz (THz) radiation emitted in the backward direction from laser wakefields driven by a femtosecond laser pulse of few joules interacting with a gas target. By utilizing frequency-resolved energy measurement, it is found that the THz spectrum exhibits two peaks located at about 4.5 and 9.0 THz, respectively. In particular, the high frequency component emerges when the drive laser energy exceeds 1.26 J, at which electron acceleration in the forward direction is detected simultaneously. Theoretical analysis and particle-in-cell simulations indicate that the THz radiation is generated via mode conversion from the laser wakefields excited in plasma with an up-ramp profile, where radiations both at the local electron plasma frequency and its harmonics are produced. Such intense THz sources may find many applications in ultrafast science, e.g., manipulating the transient states of matter.
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AIMS: Diabetic Kidney Disease (DKD), one of the major complications of diabetes, is also a major cause of end-stage renal disease. Metabolomics can provide a unique metabolic profile of the disease and thus predict or diagnose the development of the disease. Therefore, this study summarises a more comprehensive set of clinical biomarkers related to DKD to identify functional metabolites significantly associated with the development of DKD and reveal their driving mechanisms for DKD. MATERIALS AND METHODS: We searched PubMed, Embase, the Cochrane Library and Web of Science databases through October 2022. A meta-analysis was conducted on untargeted or targeted metabolomics research data based on the strategy of standardized mean differences and the process of ratio of means as the effect size, respectively. We compared the changes in metabolite levels between the DKD patients and the controls and explored the source of heterogeneity through subgroup analyses, sensitivity analysis and meta-regression analysis. RESULTS: The 34 clinical-based metabolomics studies clarified the differential metabolites between DKD and controls, containing 4503 control subjects and 1875 patients with DKD. The results showed that a total of 60 common differential metabolites were found in both meta-analyses, of which 5 metabolites (p < 0.05) were identified as essential metabolites. Compared with the control group, metabolites glycine, aconitic acid, glycolic acid and uracil decreased significantly in DKD patients; cysteine was significantly higher. This indicates that amino acid metabolism, lipid metabolism and pyrimidine metabolism in DKD patients are disordered. CONCLUSIONS: We have identified 5 metabolites and metabolic pathways related to DKD which can serve as biomarkers or targets for disease prevention and drug therapy.
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Diabetes Mellitus , Nefropatias Diabéticas , Falência Renal Crônica , Humanos , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Metabolômica/métodos , Metaboloma , Biomarcadores/metabolismoRESUMO
BACKGROUND: Interleukin 24 (IL-24) has been implicated in the nociceptive signaling. However, direct evidence and the precise molecular mechanism underlying IL-24's role in peripheral nociception remain unclear. METHODS: Using patch clamp recording, molecular biological analysis, immunofluorescence labeling, siRNA-mediated knockdown approach and behavior tests, we elucidated the effects of IL-24 on sensory neuronal excitability and peripheral pain sensitivity mediated by T-type Ca2+ channels (T-type channels). RESULTS: IL-24 enhances T-type channel currents (T-currents) in trigeminal ganglion (TG) neurons in a reversible and dose-dependent manner, primarily by activating the interleukin-22 receptor 1 (IL-22R1). Furthermore, we found that the IL-24-induced T-type channel response is mediated through tyrosine-protein kinase Lyn, but not its common downstream target JAK1. IL-24 application significantly activated protein kinase A; this effect was independent of cAMP and prevented by Lyn antagonism. Inhibition of PKA prevented the IL-24-induced T-current response, whereas inhibition of protein kinase C or MAPK kinases had no effect. Functionally, IL-24 increased TG neuronal excitability and enhanced pain sensitivity to mechanical stimuli in mice, both of which were suppressed by blocking T-type channels. In a trigeminal neuropathic pain model induced by chronic constriction injury of the infraorbital nerve, inhibiting IL-22R1 signaling alleviated mechanical allodynia, which was reversed by blocking T-type channels or knocking down Cav3.2. CONCLUSION: Our findings reveal that IL-24 enhances T-currents by stimulating IL-22R1 coupled to Lyn-dependent PKA signaling, leading to TG neuronal hyperexcitability and pain hypersensitivity. Understanding the mechanism of IL-24/IL-22R1 signaling in sensory neurons may pave the way for innovative therapeutic strategies in pain management.
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Canais de Cálcio Tipo T , Proteínas Quinases Dependentes de AMP Cíclico , Receptores de Interleucina , Células Receptoras Sensoriais , Transdução de Sinais , Gânglio Trigeminal , Quinases da Família src , Animais , Canais de Cálcio Tipo T/metabolismo , Canais de Cálcio Tipo T/genética , Quinases da Família src/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Gânglio Trigeminal/metabolismo , Masculino , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/fisiologia , Receptores de Interleucina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Interleucinas/metabolismoRESUMO
As device feature sizes continue to decrease and fin field effect transistors reach their physical limits, gate all around field effect transistors (GAAFETs) have emerged with larger gate control areas and stackable characteristics for better suppression of second-order effects such as short-channel effects due to their gate encircling characteristics. Traditional methods for studying the electrical characteristics of devices are mostly based on the technology computer-aided design. Still, it is not conducive to developing new devices due to its time-consuming and inefficient drawbacks. Deep learning (DL) and machine learning (ML) have been well-used in recent years in many fields. In this paper, we propose an integrated learning model that integrates the advantages of DL and ML to solve many problems in traditional methods. This integrated learning model predicts the direct current characteristics, capacitance characteristics, and electrical parameters of GAAFET better than those predicted by DL or ML methods alone, with a linear regression factor (R2) greater than 0.99 and very small root mean square error. The proposed integrated learning model achieves fast and accurate prediction of GAAFET electrical characteristics, which provides a new idea for device and circuit simulation and characteristics prediction in microelectronics.