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The obligate endosymbiont Wolbachia induces pathogen interference in the primary disease vector Aedes aegypti, facilitating the utilization of Wolbachia-based mosquito control for arbovirus prevention, particularly against dengue virus (DENV). However, the mechanisms underlying Wolbachia-mediated virus blockade have not been fully elucidated. Here, we report that Wolbachia activates the host cytoplasmic miRNA biogenesis pathway to suppress DENV infection. Through the suppression of the long noncoding RNA aae-lnc-2268 by Wolbachia wAlbB, aae-miR-34-3p, a miRNA upregulated by the Wolbachia strains wAlbB and wMelPop, promoted the expression of the antiviral effector defensin and cecropin genes through the Toll pathway regulator MyD88. Notably, anti-DENV resistance induced by Wolbachia can be further enhanced, with the potential to achieve complete virus blockade by increasing the expression of aae-miR-34-3p in Ae. aegypti. Furthermore, the downregulation of aae-miR-34-3p compromised Wolbachia-mediated virus blockade. These findings reveal a novel mechanism by which Wolbachia establishes crosstalk between the cytoplasmic miRNA pathway and the Toll pathway via aae-miR-34-3p to strengthen antiviral immune responses against DENV. Our results will aid in the advancement of Wolbachia for arbovirus control by enhancing its virus-blocking efficiency.
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Aedes , Virus del Dengue , Dengue , MicroARNs , Wolbachia , Wolbachia/fisiología , Aedes/microbiología , Aedes/virología , Aedes/inmunología , Animales , MicroARNs/genética , MicroARNs/metabolismo , Virus del Dengue/inmunología , Dengue/inmunología , Dengue/virología , Receptores Toll-Like/metabolismo , Receptores Toll-Like/inmunología , Mosquitos Vectores/virología , Mosquitos Vectores/microbiología , Mosquitos Vectores/inmunología , Transducción de Señal , ARN Largo no Codificante/genética , ARN Largo no Codificante/inmunología , Inmunidad Innata , SimbiosisRESUMEN
Enhancers are crucial cis-regulatory elements that control gene expression in a cell-type-specific manner. Despite extensive genetic and computational studies, accurately predicting enhancer activity in different cell types remains a challenge, and the grammar of enhancers is still poorly understood. Here, we present HEAP (high-resolution enhancer activity prediction), an explainable deep learning framework for predicting enhancers and exploring enhancer grammar. The framework includes three modules that use grammar-based reasoning for enhancer prediction. The algorithm can incorporate DNA sequences and epigenetic modifications to obtain better accuracy. We use a novel two-step multi-task learning method, task adaptive parameter sharing (TAPS), to efficiently predict enhancers in different cell types. We first train a shared model with all cell-type datasets. Then we adapt to specific tasks by adding several task-specific subset layers. Experiments demonstrate that HEAP outperforms published methods and showcases the effectiveness of the TAPS, especially for those with limited training samples. Notably, the explainable framework HEAP utilizes post-hoc interpretation to provide insights into the prediction mechanisms from three perspectives: data, model architecture and algorithm, leading to a better understanding of model decisions and enhancer grammar. To the best of our knowledge, HEAP will be a valuable tool for insight into the complex mechanisms of enhancer activity.
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Aprendizaje Profundo , Elementos de Facilitación Genéticos , Algoritmos , Secuencia de Bases , Epigénesis GenéticaRESUMEN
Pneumonia is a common infection in elderly patients. We explored the correlations of serum interleukin-6 (IL-6) and serum ferritin (SF) levels with immune function/disease severity in elderly pneumonia patients. Subjects were allocated into the mild pneumonia (MP), severe pneumonia (SP), and normal groups, with their age/sex/body mass index/ disease course and severity/blood pressure/comorbidities/medications/prealbumin (PA)/albumin (ALB)/C-reactive protein (CRP)/procalcitonin (PCT)/smoking status documented. The disease severity was evaluated by pneumonia severity index (PSI). T helper 17 (Th17)/regulatory T (Treg) cell ratios and IL-6/SF/immunoglobulin G (IgG)/Th17 cytokine (IL-21)/Treg cytokine (IL-10)/PA/ALB levels were assessed. The correlations between these indexes/independent risk factors in elderly patients with severe pneumonia were evaluated. There were differences in smoking and CRP/PCT/ALB/PA levels among the three groups, but only CRP/ALB were different between the MP/SP groups. Pneumonia patients exhibited up-regulated Th17 cell ratio and serum IL-6/SF/IL-21/IL-10/IgG levels, down-regulated Treg cell ratio, and greater differences were noted in severe cases. Serum IL-6/SF levels were positively correlated with disease severity, immune function, and IL-21/IL-10/IgG levels. Collectively, serum IL-6 and SF levels in elderly pneumonia patients were conspicuously positively correlated with disease severity and IL-21/IL-10/IgG levels. CRP, ALB, IL-6 and SF levels were independent risk factors for severe pneumonia in elderly patients.
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Interleucina-10 , Interleucina-6 , Anciano , Humanos , Citocinas , Ferritinas , Inmunoglobulina G , Factores de RiesgoRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolves rapidly under the pressure of host immunity, as evidenced by waves of emerging variants despite effective vaccinations, highlighting the need for complementing antivirals. We report that targeting a pyrimidine synthesis enzyme restores inflammatory response and depletes the nucleotide pool to impede SARS-CoV-2 infection. SARS-CoV-2 deploys Nsp9 to activate carbamoyl-phosphate synthetase, aspartate transcarbamoylase, and dihydroorotase (CAD) that catalyzes the rate-limiting steps of the de novo pyrimidine synthesis. Activated CAD not only fuels de novo nucleotide synthesis but also deamidates RelA. While RelA deamidation shuts down NF-κB activation and subsequent inflammatory response, it up-regulates key glycolytic enzymes to promote aerobic glycolysis that provides metabolites for de novo nucleotide synthesis. A newly synthesized small-molecule inhibitor of CAD restores antiviral inflammatory response and depletes the pyrimidine pool, thus effectively impeding SARS-CoV-2 replication. Targeting an essential cellular metabolic enzyme thus offers an antiviral strategy that would be more refractory to SARS-CoV-2 genetic changes.
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Antivirales , Aspartato Carbamoiltransferasa , Tratamiento Farmacológico de COVID-19 , Carbamoil-Fosfato Sintasa (Glutamina-Hidrolizante) , Dihidroorotasa , Inhibidores Enzimáticos , Pirimidinas , SARS-CoV-2 , Replicación Viral , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , Aspartato Carbamoiltransferasa/antagonistas & inhibidores , Carbamoil-Fosfato Sintasa (Glutamina-Hidrolizante)/antagonistas & inhibidores , Dihidroorotasa/antagonistas & inhibidores , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Inflamación/tratamiento farmacológico , Ratones , Pirimidinas/antagonistas & inhibidores , Pirimidinas/biosíntesis , Proteínas de Unión al ARN/metabolismo , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/fisiología , Factor de Transcripción ReIA/metabolismo , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
Single Atoms Catalysts (SACs) have emerged as a class of highly promising heterogeneous catalysts, where the traditional bottom-up synthesis approaches often encounter considerable challenges in relation to aggregation issues and poor stability. Consequently, achieving densely dispersed atomic species in a reliable and efficient manner remains a key focus in the field. Herein, we report a new facile electrochemical knock-down strategy for the formation of SACs, whereby the metal Zn clusters are transformed into single atoms. While a defect-rich substrate plays a pivotal role in capturing and stabilizing isolated Zn atoms, the feasibility of this novel strategy is demonstrated through a comprehensive investigation, combining experimental and theoretical studies. Furthermore, when studied in exploring for potential applications, the material prepared shows a remarkable improvement of 58.21% for the Li+ storage and delivers a capacity over 300 Wh kg-1 after 500 cycles upon the transformation of Zn clusters into single atoms.
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Acute lung injury (ALI) including acute respiratory distress syndrome (ARDS) is a major complication and increase the mortality of patients with cardiac surgery. We previously found that the protein cargoes enriched in circulating extracellular vesicles (EVs) are closely associated with cardiopulmonary disease. We aimed to evaluate the implication of EVs on cardiac surgery-associated ALI/ARDS. The correlations between "oncoprotein-induced transcript 3 protein (OIT3) positive" circulating EVs and postoperative ARDS were assessed. The effects of OIT3-overexpressed EVs on the cardiopulmonary bypass (CPB) -induced ALI in vivo and inflammation of human bronchial epithelial cells (BEAS-2B) were detected. OIT3 enriched in circulating EVs is reduced after cardiac surgery with CPB, especially with postoperative ARDS. The "OIT3 positive" EVs negatively correlate with lung edema, hypoxemia and CPB time. The OIT3-overexpressed EVs can be absorbed by pulmonary epithelial cells and OIT3 transferred by EVs triggered K48- and K63-linked polyubiquitination to inactivate NOD-like receptor protein 3 (NLRP3) inflammasome, and restrains pro-inflammatory cytokines releasing and immune cells infiltration in lung tissues, contributing to the alleviation of CPB-induced ALI. Overexpression of OIT3 in human bronchial epithelial cells have similar results. OIT3 promotes the E3 ligase Cbl proto-oncogene B associated with NLRP3 to induce the ubiquitination of NLRP3. Immunofluorescence tests reveal that OIT3 is reduced in the generation from the liver sinusoids endothelial cells (LSECs) and secretion in liver-derived EVs after CPB. In conclusion, OIT3 enriched in EVs is a promising biomarker of postoperative ARDS and a therapeutic target for ALI after cardiac surgery.
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BACKGROUND: Pancreatic cancer (PC) is an extremely malignant tumor with low survival rate. Effective biomarkers and therapeutic targets for PC are lacking. The roles of circular RNAs (circRNAs) in cancers have been explored in various studies, however more work is needed to understand the functional roles of specific circRNAs. In this study, we explore the specific role and mechanism of circ_0035435 (termed circCGNL1) in PC. METHODS: qRT-PCR analysis was performed to detect circCGNL1 expression, indicating circCGNL1 had low expression in PC cells and tissues. The function of circCGNL1 in PC progression was examined both in vitro and in vivo. circCGNL1-interacting proteins were identified by performing RNA pulldown, co-immunoprecipitation, GST-pulldown, and dual-luciferase reporter assays. RESULTS: Overexpressing circCGNL1 inhibited PC proliferation via promoting apoptosis. CircCGNL1 interacted with phosphatase nudix hydrolase 4 (NUDT4) to promote histone deacetylase 4 (HDAC4) dephosphorylation and subsequent HDAC4 nuclear translocation. Intranuclear HDAC4 mediated RUNX Family Transcription Factor 2 (RUNX2) deacetylation and thereby accelerating RUNX2 degradation. The transcription factor, RUNX2, inhibited guanidinoacetate N-methyltransferase (GAMT) expression. GAMT was further verified to induce PC cell apoptosis via AMPK-AKT-Bad signaling pathway. CONCLUSIONS: We discovered that circCGNL1 can interact with NUDT4 to enhance NUDT4-dependent HDAC4 dephosphorylation, subsequently activating HDAC4-RUNX2-GAMT-mediated apoptosis to suppress PC cell growth. These findings suggest new therapeutic targets for PC.
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MicroARNs , Neoplasias Pancreáticas , Humanos , ARN Circular/genética , Guanidinoacetato N-Metiltransferasa , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Factores de Transcripción/genética , Neoplasias Pancreáticas/genética , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Apoptosis , MicroARNs/genética , Proliferación Celular , Línea Celular Tumoral , Proteínas RepresorasRESUMEN
Complexation between oppositely charged polyelectrolytes offers a facile single-step strategy for assembling functional micro-nano carriers for efficient drug and vaccine delivery. However, the stability of the delivery system within the physiological environment is compromised due to the swelling of the polyelectrolyte complex, driven by the charge shielding effect, and consequently leads to uncontrollable burst release, thereby limiting its potential applications. In a pioneering approach, cellular pathway-inspired calcium carbonate precipitation pathways are developed that are integrated into polyelectrolyte capsules (MICPC). These innovative capsules are fabricated at the interface of all-aqueous microfluidic droplets, resulting in a precisely controllable and sustained release profile in physiological conditions. Unlike single-step polyelectrolyte assembly capsules which always perform rapid burst release, the MICPC exhibits a sustainable and tunable release pattern, releasing biomolecules at an average rate of 3-10% per day. Remarkably, the degree of control over MICPC's release kinetics can be finely tuned by adjusting the quantity of synthesized calcium carbonate particles within the polyelectrolyte complex. This groundbreaking work not only deepens the insights into polyelectrolyte complexation but also significantly enhances the overall stability of these complexes, opening up new avenues for expanding the range of applications involving polyelectrolyte complex-related materials.
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Carbonato de Calcio , Cápsulas , Polielectrolitos , Carbonato de Calcio/química , Cápsulas/química , Polielectrolitos/química , Precipitación Química , Electrólitos/químicaRESUMEN
All-solid-state batteries (ASSBs) represent a highly promising next-generation energy storage technology owing to their inherently high safety, device reliability, and potential for achieving high energy density in the post-ara of lithium-ion batteries, and therefore extensive searches are ongoing for ideal solid-state electrolytes (SSEs). Though promising, there is still a huge barrier that limits the large-scale applications of ASSBs, where there are a couple of bottleneck technical issues. In this perspective, a novel category of electrolytes known as frameworked electrolytes (FEs) are examined, where the solid frameworks are intentionally designed to contain 3D ionic channels at sub-nano scales, rendering them macroscopically solid. The distinctive structural design of FEs gives rise to not only high ionic conductivity but also desirable interfaces with electrode solids. This is achieved through the presence of sub-nano channels within the framework, which exhibit significantly different ion diffusion behavior due to the confinement effect. This perspective offers a compelling insight into the potential of FEs in the pursuit of ASSBs, where FEs offer an exciting opportunity to overcome the limitations of traditional solid-state electrolytes and propel the development of ASSBs as the holy grail of energy storage technology.
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MOTIVATION: Multiple sequence alignment (MSA) is one of the hotspots of current research and is commonly used in sequence analysis scenarios. However, there is no lasting solution for MSA because it is a Nondeterministic Polynomially complete problem, and the existing methods still have room to improve the accuracy. RESULTS: We propose Deep reinforcement learning with Positional encoding and self-Attention for MSA, based on deep reinforcement learning, to enhance the accuracy of the alignment Specifically, inspired by the translation technique in natural language processing, we introduce self-attention and positional encoding to improve accuracy and reliability. Firstly, positional encoding encodes the position of the sequence to prevent the loss of nucleotide position information. Secondly, the self-attention model is used to extract the key features of the sequence. Then input the features into a multi-layer perceptron, which can calculate the insertion position of the gap according to the features. In addition, a novel reinforcement learning environment is designed to convert the classic progressive alignment into progressive column alignment, gradually generating each column's sub-alignment. Finally, merge the sub-alignment into the complete alignment. Extensive experiments based on several datasets validate our method's effectiveness for MSA, outperforming some state-of-the-art methods in terms of the Sum-of-pairs and Column scores. AVAILABILITY AND IMPLEMENTATION: The process is implemented in Python and available as open-source software from https://github.com/ZhangLab312/DPAMSA.
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Algoritmos , Programas Informáticos , Alineación de Secuencia , Reproducibilidad de los Resultados , Redes Neurales de la ComputaciónRESUMEN
BACKGROUND: Muscle-invasive bladder cancer (MIBC) is a highly aggressive disease with a poor prognosis. B cells are crucial factors in tumor suppression, and tertiary lymphoid structures (TLSs) facilitate immune cell recruitment to the tumor microenvironment (TME). However, the function and mechanisms of tumor-infiltrating B cells and TLSs in MIBC need to be explored further. METHODS: We performed single-cell RNA sequencing analysis of 11,612 B cells and 55,392 T cells from 12 bladder cancer patients and found naïve B cells, proliferating B cells, plasma cells, interferon-stimulated B cells and germinal center-associated B cells, and described the phenotype, gene enrichment, cell-cell communication, biological processes. We utilized immunohistochemistry (IHC) and immunofluorescence (IF) to describe TLSs morphology in MIBC. RESULTS: The interferon-stimulated B-cell subtype (B-ISG15) and germinal center-associated B-cell subtypes (B-LMO2, B-STMN1) were significantly enriched in MIBC. TLSs in MIBC exhibited a distinct follicular structure characterized by a central region of B cells resembling a germinal center surrounded by T cells. CellChat analysis showed that CXCL13 + T cells play a pivotal role in recruiting CXCR5 + B cells. Cell migration experiments demonstrated the chemoattraction of CXCL13 toward CXCR5 + B cells. Importantly, the infiltration of the interferon-stimulated B-cell subtype and the presence of TLSs correlated with a more favorable prognosis in MIBC. CONCLUSIONS: The study revealed the heterogeneity of B-cell subtypes in MIBC and suggests a pivotal role of TLSs in MIBC outcomes. Our study provides novel insights that contribute to the precision treatment of MIBC.
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Estructuras Linfoides Terciarias , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Linfocitos B , Pronóstico , Músculos/patología , Interferones , Microambiente TumoralRESUMEN
The computation of electromagnetic wave scatterings of a layered sphere is a canonical problem. Lorentz-Mie theory is suitable for plane wave incidence whereas spherically layered media theory can deal with arbitrary incident waves. Both theories suffer from the notorious numerical instabilities due to the involved Bessel functions with large order, small argument or high loss. Logarithmic derivative method has been proposed to solve the numerical issues with these theories. In this paper, by employing the equivalence between the asymptotic formulas of Bessel functions for small argument and for large order, the numerical issues with the spherically layered theory under both large order case and small argument case can be solved in a unified manner by canceling out the diverging terms in the asymptotic formulas. The derived stable formulas are simpler and faster than those based on logarithmic derivative method. It is shown that the derived formulas are good approximations to the canonical ones but are more numerically stable. The large lossy issue can be solved similarly.
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We proposed spectrally temporally cascaded optical parametric amplification (STOPA) using pump energy recycling to simultaneously increase spectral bandwidth and conversion efficiency in optical parametric amplification (OPA). Using BiB3O6 and KTiOAsO4 nonlinear crystals, near-single-cycle mid-infrared (MIR) pulses with maximum energy conversion efficiencies exceeding 25% were obtained in simulations. We successfully demonstrated sub-two-cycle, CEP-stable pulse generation at 1.8â µm using a four-step STOPA system in the experiment. This method provides a solution to solve the limitations of the gain bandwidth of nonlinear crystals and the low conversion efficiency in broadband OPA systems, which is helpful for intense attosecond pulse generation and strong laser field physics studies.
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An approach for continuous tuning of on-chip optical delay with a microring resonator is proposed and demonstrated. By introducing an electro-optically tunable waveguide coupler, the bus waveguide to the resonance coupling can be effectively tuned from the under-coupling regime to the over-coupling regime. The optical delay is experimentally characterized by measuring the relative phase shift between lasers and shows a large dynamic range of delay from -600 to 600 ps and an efficient tuning of delay from -430 to -180 ps and from 40 to 240 ps by only a 5 V voltage.
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The Ni-catalyzed enantioselective addition reaction of aryl halides to aldehydes was studied with cyanobis(oxazoline) as chiral ligands and Mn as reductant. Aryl and heteroaryl bromides reacted with phenyl aldehyde at room temperature to produce dibenzyl alcohols in 16-99 % yields with 53-92 % ees. Moreover, the coupling of phenyl chloride with a variety of aryl, heteroaryl and alkyl aldehydes was demonstrated in the presence of cyanobis(oxazoline)/Ni(II) at 60 °C in generally high yields with moderate enantioselectivities.
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BACKGROUND: Tumor morphology, immune function, inflammatory levels, and nutritional status play critical roles in the progression of intrahepatic cholangiocarcinoma (ICC). This multicenter study aimed to investigate the association between markers related to tumor morphology, immune function, inflammatory levels, and nutritional status with the prognosis of ICC patients. Additionally, a novel tumor morphology immune inflammatory nutritional score (TIIN score), integrating these factors was constructed. METHODS: A retrospective analysis was performed on 418 patients who underwent radical surgical resection and had postoperative pathological confirmation of ICC between January 2016 and January 2020 at three medical centers. The cohort was divided into a training set (n = 272) and a validation set (n = 146). The prognostic significance of 16 relevant markers was assessed, and the TIIN score was derived using LASSO regression. Subsequently, the TIIN-nomogram models for OS and RFS were developed based on the TIIN score and the results of multivariate analysis. The predictive performance of the TIIN-nomogram models was evaluated using ROC survival curves, calibration curves, and clinical decision curve analysis (DCA). RESULTS: The TIIN score, derived from albumin-to-alkaline phosphatase ratio (AAPR), albumin-globulin ratio (AGR), monocyte-to-lymphocyte ratio (MLR), and tumor burden score (TBS), effectively categorized patients into high-risk and low-risk groups using the optimal cutoff value. Compared to individual metrics, the TIIN score demonstrated superior predictive value for both OS and RFS. Furthermore, the TIIN score exhibited strong associations with clinical indicators including obstructive jaundice, CEA, CA19-9, Child-pugh grade, perineural invasion, and 8th edition AJCC N stage. Univariate and multivariate analysis confirmed the TIIN score as an independent risk factor for postoperative OS and RFS in ICC patients (p < 0.05). Notably, the TIIN-nomogram models for OS and RFS, constructed based on the multivariate analysis and incorporating the TIIN score, demonstrated excellent predictive ability for postoperative survival in ICC patients. CONCLUSION: The development and validation of the TIIN score, a comprehensive composite index incorporating tumor morphology, immune function, inflammatory level, and nutritional status, significantly contribute to the prognostic assessment of ICC patients. Furthermore, the successful application of the TIIN-nomogram prediction model underscores its potential as a valuable tool in guiding individualized treatment strategies for ICC patients. These findings emphasize the importance of personalized approaches in improving the clinical management and outcomes of ICC.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Estado Nutricional , Humanos , Colangiocarcinoma/cirugía , Colangiocarcinoma/patología , Masculino , Femenino , Estudios Retrospectivos , Neoplasias de los Conductos Biliares/cirugía , Neoplasias de los Conductos Biliares/patología , Persona de Mediana Edad , Pronóstico , Anciano , Nomogramas , Inflamación , Biomarcadores de Tumor , Fosfatasa Alcalina/sangre , Carga Tumoral , Evaluación Nutricional , Albúmina Sérica/análisis , Albúmina Sérica/metabolismo , Curva ROC , Monocitos/patologíaRESUMEN
BACKGROUND: Mitochondria are essential organelles involved in cellular energy production. Changes in mitochondrial function can lead to dysfunction and cell death in aging and age-related disorders. Recent research suggests that mitochondrial dysfunction is closely linked to neurodegenerative diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonist has gained interest as a potential treatment for Parkinson's disease (PD). However, the exact mechanisms responsible for the therapeutic effects of GLP-1R-related agonists are not yet fully understood. METHODS: In this study, we explores the effects of early treatment with PT320, a sustained release formulation of the GLP-1R agonist Exenatide, on mitochondrial functions and morphology in a progressive PD mouse model, the MitoPark (MP) mouse. RESULTS: Our findings demonstrate that administration of a clinically translatable dose of PT320 ameliorates the reduction in tyrosine hydroxylase expression, lowers reactive oxygen species (ROS) levels, and inhibits mitochondrial cytochrome c release during nigrostriatal dopaminergic denervation in MP mice. PT320 treatment significantly preserved mitochondrial function and morphology but did not influence the reduction in mitochondria numbers during PD progression in MP mice. Genetic analysis indicated that the cytoprotective effect of PT320 is attributed to a reduction in the expression of mitochondrial fission protein 1 (Fis1) and an increase in the expression of optic atrophy type 1 (Opa1), which is known to play a role in maintaining mitochondrial homeostasis and decreasing cytochrome c release through remodeling of the cristae. CONCLUSION: Our findings suggest that the early administration of PT320 shows potential as a neuroprotective treatment for PD, as it can preserve mitochondrial function. Through enhancing mitochondrial health by regulating Opa1 and Fis1, PT320 presents a new neuroprotective therapy in PD.
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Citocromos c , Exenatida , Agonistas Receptor de Péptidos Similares al Glucagón , Enfermedades Mitocondriales , Citocromos c/uso terapéutico , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Mitocondriales/metabolismo , Exenatida/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Modelos Animales de EnfermedadRESUMEN
The comorbidity of autism spectrum disorder and anxiety is common, but the underlying circuitry is poorly understood. Here, Tmem74-/- mice showed autism- and anxiety-like behaviors along with increased excitability of pyramidal neurons (PNs) in the prelimbic cortex (PL), which were reversed by Tmem74 re-expression and chemogenetic inhibition in PNs of the PL. To determine the underlying circuitry, we performed conditional deletion of Tmem74 in the PNs of PL of mice, and we found that alterations in the PL projections to fast-spiking interneurons (FSIs) in the dorsal striatum (dSTR) (PLPNs-dSTRFSIs) mediated the hyperexcitability of FSIs and autism-like behaviors and that alterations in the PL projections to the PNs of the basolateral amygdaloid nucleus (BLA) (PLPNs-BLAPNs) mediated the hyperexcitability of PNs and anxiety-like behaviors. However, the two populations of PNs in the PL had different spatial locations, optogenetic manipulations revealed that alterations in the activity in the PL-dSTR or PL-BLA circuits led to autism- or anxiety-like behaviors, respectively. Collectively, these findings highlight that the hyperactivity of the two populations of PNs in the PL mediates autism and anxiety comorbidity through the PL-dSTR and PL-BLA circuits, which may lead to the development of new therapeutics for the autism and anxiety comorbidity.
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Trastorno del Espectro Autista , Trastorno Autístico , Complejo Nuclear Basolateral , Ratones , Animales , Trastorno Autístico/genética , Trastorno del Espectro Autista/genética , Corteza Cerebral , Ansiedad , Corteza PrefrontalRESUMEN
A new group of BF3 complexing phosphate/phosphonate ionic liquids (ILs) [Emim][X(BF3)2] (X=dimethyl phosphate, diethyl phosphate, methyl phosphonate, and ethyl phosphonate) were synthesized and characterized. Key thermophysical properties of the new complex ionic liquids, including density, viscosity, conductivity, surface tension, solid-liquid phase transition, and thermal stability were determined and compared with those of [Emim][X]. Some other important thermophysical properties such as isobaric thermal expansion coefficient, molecular volume, standard molar entropy, and lattice potential energy were obtained from measured density data, and the free volume was estimated by a linear equation presented in this article, while critical temperature, normal boiling temperature, and enthalpy of vaporization were estimated from measured surface tension and density data. Furthermore, Fragility study shows that [Emim][X(BF3)2] should be considered as fragile liquids, while [Emim][X] could be considered as extremely fragile liquids. The ionicity of [Emim][X(BF3)2] was predicted by Walden rule, and the result shows that these ILs fit well with Walden law. The key features of these complex ILs are their extremely low glass transition (-95.33~-98.46 °C) without melting, considerably low viscosities (33.876~58.117â mPa â s), and high values of free volume fraction (comparable to [Omim][BF4], [Emim][NTf2], and [Emim][TCB]).
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Aberrant energy metabolism in the brain is a common pathological feature in the preclinical Alzheimer's Disease (AD). Recent studies have reported the early elevations of glycolysis-involved enzymes in AD brain and cerebrospinal fluid according to a large-scale proteomic analysis. It's well-known that astrocytes exhibit strong glycolytic metabolic ability and play a key role in the regulation of brain homeostasis. However, its relationship with glycolytic changes and cognitive deficits in early AD patients is unclear. Here, we investigated the mechanisms by which astrocyte glycolysis is involved in early AD and its potential as a therapeutic target. Our results suggest that Aß-activated microglia can induce glycolytic-enhanced astrocytes in vitro, and that these processes are dependent on the activation of the AKT-mTOR-HIF-1α pathway. In early AD models, the increase in L-lactate produced by enhanced glycolysis of astrocytes leads to spatial cognitive impairment by disrupting synaptic plasticity and accelerating Aß aggregation. Furthermore, we find rapamycin, the mTOR inhibitor, can rescue the impaired spatial memory and Aß burden by inhibiting the glycolysis-derived L-lactate in the early AD models. In conclusion, we highlight that astrocytic glycolysis plays a critical role in the early onset of AD and that the modulation of glycolysis-derived L-lactate by rapamycin provides a new strategy for the treatment of AD.