RESUMO
The implementation of clinical-decision support algorithms for medical imaging faces challenges with reliability and interpretability. Here, we establish a diagnostic tool based on a deep-learning framework for the screening of patients with common treatable blinding retinal diseases. Our framework utilizes transfer learning, which trains a neural network with a fraction of the data of conventional approaches. Applying this approach to a dataset of optical coherence tomography images, we demonstrate performance comparable to that of human experts in classifying age-related macular degeneration and diabetic macular edema. We also provide a more transparent and interpretable diagnosis by highlighting the regions recognized by the neural network. We further demonstrate the general applicability of our AI system for diagnosis of pediatric pneumonia using chest X-ray images. This tool may ultimately aid in expediting the diagnosis and referral of these treatable conditions, thereby facilitating earlier treatment, resulting in improved clinical outcomes. VIDEO ABSTRACT.
Assuntos
Aprendizado Profundo , Diagnóstico por Imagem , Pneumonia/diagnóstico , Criança , Humanos , Redes Neurais de Computação , Pneumonia/diagnóstico por imagem , Curva ROC , Reprodutibilidade dos Testes , Tomografia de Coerência ÓpticaRESUMO
Survival requires the selection of appropriate behaviour in response to threats, and dysregulated defensive reactions are associated with psychiatric illnesses such as post-traumatic stress and panic disorder1. Threat-induced behaviours, including freezing and flight, are controlled by neuronal circuits in the central amygdala (CeA)2; however, the source of neuronal excitation of the CeA that contributes to high-intensity defensive responses is unknown. Here we used a combination of neuroanatomical mapping, in vivo calcium imaging, functional manipulations and electrophysiology to characterize a previously unknown projection from the dorsal peduncular (DP) prefrontal cortex to the CeA. DP-to-CeA neurons are glutamatergic and specifically target the medial CeA, the main amygdalar output nucleus mediating conditioned responses to threat. Using a behavioural paradigm that elicits both conditioned freezing and flight, we found that CeA-projecting DP neurons are activated by high-intensity threats in a context-dependent manner. Functional manipulations revealed that the DP-to-CeA pathway is necessary and sufficient for both avoidance behaviour and flight. Furthermore, we found that DP neurons synapse onto neurons within the medial CeA that project to midbrain flight centres. These results elucidate a non-canonical top-down pathway regulating defensive responses.
Assuntos
Aprendizagem da Esquiva , Núcleo Central da Amígdala , Vias Neurais , Neurônios , Aprendizagem da Esquiva/fisiologia , Núcleo Central da Amígdala/citologia , Núcleo Central da Amígdala/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Vias Neurais/fisiologia , Cálcio/análise , Eletrofisiologia , Ponte/citologia , Ponte/fisiologiaRESUMO
The development of advanced neural modulation techniques is crucial to neuroscience research and neuroengineering applications. Recently, optical-based, nongenetic modulation approaches have been actively investigated to remotely interrogate the nervous system with high precision. Here, we show that a thin-film, silicon (Si)-based diode device is capable to bidirectionally regulate in vitro and in vivo neural activities upon adjusted illumination. When exposed to high-power and short-pulsed light, the Si diode generates photothermal effects, evoking neuron depolarization and enhancing intracellular calcium dynamics. Conversely, low-power and long-pulsed light on the Si diode hyperpolarizes neurons and reduces calcium activities. Furthermore, the Si diode film mounted on the brain of living mice can activate or suppress cortical activities under varied irradiation conditions. The presented material and device strategies reveal an innovated optoelectronic interface for precise neural modulations.
Assuntos
Neurônios , Optogenética , Silício , Animais , Silício/química , Neurônios/fisiologia , Camundongos , Optogenética/métodos , Cálcio/metabolismo , Luz , Encéfalo/fisiologiaRESUMO
How left-right (LR) asymmetry emerges in a patterning field along the anterior-posterior axis remains an unresolved problem in developmental biology. Left-biased Nodal emanating from the LR organizer propagates from posterior to anterior (PA) and establishes the LR pattern of the whole embryo. However, little is known about the regulatory mechanism of the PA spread of Nodal and its asymmetric activation in the forebrain. Here, we identify bilaterally expressed Follistatin (Fst) as a regulator blocking the propagation of the zebrafish Nodal ortholog Southpaw (Spaw) in the right lateral plate mesoderm (LPM), and restricting Spaw transmission in the left LPM to facilitate the establishment of a robust LR asymmetric Nodal patterning. In addition, Fst inhibits the Activin-Nodal signaling pathway in the forebrain thus preventing Nodal activation prior to the arrival, at a later time, of Spaw emanating from the left LPM. This contributes to the orderly propagation of asymmetric Nodal activation along the PA axis. The LR regulation function of Fst is further confirmed in chick and frog embryos. Overall, our results suggest that a robust LR patterning emerges by counteracting a Fst barrier formed along the PA axis.
Assuntos
Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Folistatina/genética , Folistatina/metabolismo , Padronização Corporal/genética , Fator de Crescimento Transformador beta/metabolismo , Regulação da Expressão Gênica no DesenvolvimentoRESUMO
Microtia is a congenital auricle dysplasia with a high incidence and tissue engineering technology provides a promising strategy to reconstruct auricles. We previously described that the engineered cartilage constructed from microtia chondrocytes exhibited inferior levels of biochemical and biomechanical properties, which was proposed to be resulted of the decreased migration ability of microtia chondrocytes. In the current study, we found that Rho GTPase members were deficient in microtia chondrocytes. By overexpressing RhoA, Rac1, and CDC42, respectively, we further demonstrated that RhoA took great responsibility for the decreased migration ability of microtia chondrocytes. Moreover, we constructed PGA/PLA scaffold-based cartilages to verify the chondrogenic ability of RhoA overexpressed microtia chondrocytes, and the results showed that overexpressing RhoA was of limited help in improving the quality of microtia chondrocyte engineered cartilage. However, coculture of adipose-derived stem cells (ADSCs) significantly improved the biochemical and biomechanical properties of engineered cartilage. Especially, coculture of RhoA overexpressed microtia chondrocytes and ADSCs produced an excellent effect on the wet weight, cartilage-specific extracellular matrix, and biomechanical property of engineered cartilage. Furthermore, we presented that coculture of RhoA overexpressed microtia chondrocytes and ADSCs combined with human ear-shaped PGA/PLA scaffold and titanium alloy stent fabricated by CAD/CAM and 3D printing technology effectively constructed and maintained auricle structure in vivo. Collectively, our results provide evidence for the essential role of RhoA in microtia chondrocytes and a developed strategy for the construction of patient-specific tissue-engineered auricular cartilage.
Assuntos
Condrócitos , Técnicas de Cocultura , Microtia Congênita , Engenharia Tecidual , Proteína rhoA de Ligação ao GTP , Condrócitos/metabolismo , Condrócitos/citologia , Humanos , Engenharia Tecidual/métodos , Proteína rhoA de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Microtia Congênita/metabolismo , Microtia Congênita/genética , Cartilagem da Orelha/citologia , Cartilagem da Orelha/metabolismo , Células-Tronco/metabolismo , Células-Tronco/citologia , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Condrogênese/genética , Masculino , Alicerces Teciduais/química , FemininoRESUMO
Feingold syndrome type 1, caused by loss-of-function of MYCN, is characterized by varied phenotypes including esophageal and duodenal atresia. However, no adequate model exists for studying the syndrome's pathological or molecular mechanisms, nor is there a treatment strategy. Here, we developed a zebrafish Feingold syndrome type 1 model with nonfunctional mycn, which had severe intestinal atresia. Single-cell RNA-seq identified a subcluster of intestinal cells that were highly sensitive to Mycn, and impaired cell proliferation decreased the overall number of intestinal cells in the mycn mutant fish. Bulk RNA-seq and metabolomic analysis showed that expression of ribosomal genes was down-regulated and that amino acid metabolism was abnormal. Northern blot and ribosomal profiling analysis showed abnormal rRNA processing and decreases in free 40S, 60S, and 80S ribosome particles, which led to impaired translation in the mutant. Besides, both Ribo-seq and western blot analysis showed that mTOR pathway was impaired in mycn mutant, and blocking mTOR pathway by rapamycin treatment can mimic the intestinal defect, and both L-leucine and Rheb, which can elevate translation via activating TOR pathway, could rescue the intestinal phenotype of mycn mutant. In summary, by this zebrafish Feingold syndrome type 1 model, we found that disturbance of ribosomal biogenesis and blockage of protein synthesis during development are primary causes of the intestinal defect in Feingold syndrome type 1. Importantly, our work suggests that leucine supplementation may be a feasible and easy treatment option for this disease.
Assuntos
Microcefalia , Peixe-Zebra , Animais , Proteína Proto-Oncogênica N-Myc , Peixe-Zebra/metabolismo , Microcefalia/genética , Serina-Treonina Quinases TOR/metabolismo , LeucinaRESUMO
The molecular mechanism underlying white adipogenesis in humans has not been fully elucidated beyond the transcriptional level. Here, we found that the RNA-binding protein NOVA1 is required for the adipogenic differentiation of human mesenchymal stem cells. By thoroughly exploring the interactions between NOVA1 and its binding RNA, we proved that NOVA1 deficiency resulted in the aberrant splicing of DNAJC10 with an in-frame premature stop codon, reduced DNAJC10 expression at the protein level and hyperactivation of the unfolded protein response (UPR). Moreover, NOVA1 knockdown abrogated the down-regulation of NCOR2 during adipogenesis and up-regulated the 47b+ splicing isoform, which led to decreased chromatin accessibility at the loci of lipid metabolism genes. Interestingly, these effects on human adipogenesis could not be recapitulated in mice. Further analysis of multispecies genomes and transcriptomes indicated that NOVA1-targeted RNA splicing is evolutionarily regulated. Our findings provide evidence for human-specific roles of NOVA1 in coordinating splicing and cell organelle functions during white adipogenesis.
Assuntos
Cromatina , Proteínas de Ligação a RNA , Resposta a Proteínas não Dobradas , Animais , Humanos , Camundongos , Adipogenia/genética , Cromatina/genética , Antígeno Neuro-Oncológico Ventral , Splicing de RNA , Proteínas de Ligação a RNA/metabolismoRESUMO
O6-methylguanine DNA methyltransferase (MGMT) is a crucial determinant of temozolomide (TMZ) sensitivity in patients with glioblastoma (GBM). The therapeutic potential of small interfering RNA (siRNA) targeting MGMT to enhance TMZ sensitivity has been hampered by serum nuclease degradation, off-target effects, poor accumulation at tumor sites, and low circulation in blood stream. In this study, we developed a framework nucleic acid-based nanoparticles (FNN), which is constructed from a six-helix DNA bundle, to encapsulate and protect siMGMT for improving TMZ sensitivity in GBM treatment. For better blood-brain barrier (BBB) penetration and GBM targeting, we conjugated Angiopep-2 (ANG) targeting modules to each end of the FNN. Nucleolin (NCL)-responsive locks were engineered along the sides of the six-helix DNA bundle, which safeguard siMGMT before tumor entry. Upon interaction with tumor-overexpressed NCL, these locks unlock, exposing siMGMT, this allows for effective suppression of MGMT, resulting in a significant improvement of TMZ therapeutic efficacy in GBM. This innovative strategy has the potential to transform the current treatment landscape for GBM.
RESUMO
Malignant tumors have increasing morbidity and high mortality, and their occurrence and development is a complicate process. The development of sequencing technologies enabled us to gain a better understanding of the underlying genetic and molecular mechanisms in tumors. In recent years, the spatial transcriptomics sequencing technologies have been developed rapidly and allow the quantification and illustration of gene expression in the spatial context of tissues. Compared with the traditional transcriptomics technologies, spatial transcriptomics technologies not only detect gene expression levels in cells, but also inform the spatial location of genes within tissues, cell composition of biological tissues, and interaction between cells. Here we summarize the development of spatial transcriptomics technologies, spatial transcriptomics tools and its application in cancer research. We also discuss the limitations and challenges of current spatial transcriptomics approaches, as well as future development and prospects.
Assuntos
Perfilação da Expressão Gênica , Neoplasias , Transcriptoma , Humanos , Neoplasias/genética , Neoplasias/patologia , Animais , Regulação Neoplásica da Expressão Gênica , Biologia Computacional/métodos , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND AND AIM: Long-term maintenance of viral control, even HBsAg loss, remains a challenge for chronic hepatitis B (CHB) patients undergoing nucleos(t)ide analogue (NA) discontinuation. This study aimed to investigate the relationship between HBV-specific T-cell responses targeting peptides spanning the whole proteome and clinical outcomes in CHB patients after NA discontinuation. APPROACH AND RESULTS: Eighty-eight CHB patients undergoing NA discontinuation were classified as responders (remained relapse-free up to 96 weeks) or relapsers (relapsed patients who underwent NA retreatment for up to 48 weeks and reachieved stable viral control). HBV-specific T-cell responses were detected at baseline and longitudinally throughout the follow-up. We found responders had a greater magnitude of HBV polymerase (Pol)-specific T-cell responses than relapsers at baseline. After long-term NA discontinuation, simultaneously enhanced HBV Core-induced and Pol-induced responses were observed in responders. Particularly, responders with HBsAg loss possessed enhanced HBV Envelope (Env)-induced responses after short-term and long-term follow-up. Notably, CD4 + T cells accounted for the predominance of HBV-specific T-cell responses. Correspondingly, CD4-deficient mice showed attenuated HBV-specific CD8 + T-cell responses, reduced HBsAb-producing B cells, and delayed HBsAg loss; in contrast, in vitro addition of CD4 + T cells promoted HBsAb production by B cells. Besides, IL-9, rather than PD-1 blockade, enhanced HBV Pol-specific CD4 + T-cell responses. CONCLUSION: HBV-specific CD4 + T-cell responses induced by the targeted peptide possess specificities for long-term viral control and HBsAg loss in CHB patients undergoing NA discontinuation, indicating that CD4 + T cells specific to distinct HBV antigens may endow with divergent antiviral potential.
Assuntos
Linfócitos T CD4-Positivos , Antígenos de Superfície da Hepatite B , Hepatite B Crônica , Animais , Camundongos , Antivirais/uso terapêutico , DNA Viral , Antígenos E da Hepatite B , Vírus da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Resultado do Tratamento , Nucleosídeos/análogos & derivadosRESUMO
Compact routing of multimode bus waveguides is of great significance for on-chip mode-division multiplexing (MDM) systems to realize high integration density and flexible layout. In this Letter, we propose and experimentally demonstrate a novel, to the best of our knowledge, multimode photonic jumper (MPJ) on a standard silicon-on-insulator (SOI) platform. It enables an ultra-compact connection between two parallel multimode waveguides (MWGs) with an arbitrary displacement. As a proof of concept, we describe two MPJs with displacements of 5.9 µm and 0.6 µm, each supporting three modes and featuring a longitudinal distance of around 14 µm. For both MPJs, the experimental results show insertion losses (ILs) below 0.086 dB and inter-modal cross talk (CT) below -17.6 dB over the wide wavelength range of 1525-1600 nm for all three modes.
RESUMO
BACKGROUND: Chronic kidney disease (CKD) is a significant risk factor for pulmonary hypertension (PH), a complication that adversely affects patient prognosis. However, the mechanisms underlying this association remain poorly understood. A major obstacle to progress in this field is the lack of a reliable animal model replicating CKD-PH. METHODS: This study aimed to establish a stable rat model of CKD-PH. We employed a combined approach, inducing CKD through a 5/6 nephrectomy and concurrently exposing the rats to a high-salt diet. The model's hemodynamics were evaluated dynamically, alongside a comprehensive assessment of pathological changes in multiple organs. Lung tissues and serum samples were collected from the CKD-PH rats to analyze the expression of angiotensin-converting enzyme 2 (ACE2), evaluate the activity of key vascular components within the renin-angiotensin-aldosterone system (RAAS), and characterize alterations in the serum metabolic profile. RESULTS: At 14 weeks post-surgery, the CKD-PH rats displayed significant changes in hemodynamic parameters indicative of pulmonary arterial hypertension. Additionally, right ventricular hypertrophy was observed. Notably, no evidence of pulmonary vascular remodeling was found. Further analysis revealed RAAS dysregulation and downregulated ACE2 expression within the pulmonary vascular endothelium of CKD-PH rats. Moreover, the serum metabolic profile of these animals differed markedly from the sham surgery group. CONCLUSIONS: Our findings suggest that the development of pulmonary arterial hypertension in CKD-PH rats is likely a consequence of a combined effect: RAAS dysregulation, decreased ACE2 expression in pulmonary vascular endothelial cells, and metabolic disturbances.
Assuntos
Angiotensina II , Hipertensão Pulmonar , Nefrectomia , Cloreto de Sódio na Dieta , Animais , Masculino , Ratos , Angiotensina II/sangue , Enzima de Conversão de Angiotensina 2/metabolismo , Modelos Animais de Doenças , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/induzido quimicamente , Rim/metabolismo , Rim/patologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Sistema Renina-Angiotensina/fisiologia , Cloreto de Sódio na Dieta/efeitos adversosRESUMO
Circulating tumor DNA (ctDNA) is a crucial cancer biomarker for early or noninvasive monitoring, which is essential for developing ultrasensitive and selective assays in cancer diagnosis and treatment. Herein, a cascade signal amplification of duplex-functional split-DNAzyme and dendritic probes was proposed for ultrasensitive and specific detection of nasopharyngeal carcinoma-associated Epstein-Barr virus (EBV) DNA on microfluidic microbead array chips. With the assistance of Pb2+, the duplex-functional split-DNAzyme recognizes EBV DNA and then rapidly cleaves the substrate strand. Subsequently, the released target could be recycled, and its exposed capture probe, triggered the dendritic enzyme-free signal amplification. As the enhanced mass transfer capability, target recycling, and dendritic DNA structure signal amplification inherent to microfluidic bead arrays were integrated, it achieved an excellent detection limit of 0.36 fM and a wide linear range of 1 fMâ¼103 fM. Further, it was applied to content detect simulated samples of EBV DNA, recovery ranged from 97.2 % to 108.1 %, and relative standard deviation (RSD) from 3.3 % to 5.9 %, exhibiting satisfactory recovery results. The developed microfluidic biosensor was a high-sensitivity and anti-interference system for ctDNA analysis, with minimal reagent volumes (microlitres) required. Thus, it is a promising platform for ctDNA at the lowest level at their earliest incidence.
Assuntos
Técnicas Biossensoriais , DNA Catalítico , Infecções por Vírus Epstein-Barr , Humanos , DNA Catalítico/química , Microfluídica , Herpesvirus Humano 4/genética , DNA/química , Técnicas Biossensoriais/métodos , Limite de DetecçãoRESUMO
Adipose-derived stem cells (ASCs) from distinct age groups possess different characteristics; however, the age-associated changes in ASCs heterogenicity remain largely unknown. In this study, several publicly available single-cell RNA sequencing (RNA-seq) data cohorts of inguinal adipose tissues, including young (2 weeks), adult (8 weeks), and old (18 months) C57BL/6 mice, were analyzed. Transcriptomic clustering of integrated single-cell RNA-seq data from different age groups revealed the existence of five ASCs subtypes. Interestingly, ASCs showed a loss of heterogeneity with aging, and ASCs subtype 4 (ASC-4) was the dominant subpopulation accounting for more than 98% of aged ASCs converging to the terminal differentiation state. The multidirectional differentiation potentials of different ASCs subtypes were largely distinct while the adipogenic ability of ASC-4 increased with age persistently. Regulon analysis of ASC subtypes further identified Cebpb as the ASC-4-specific transcription factor, which was known as one of the major adipogenic regulators. Analysis of ligand-receptor pairs between ASCs and other cell types in adipose tissue identified age-associated upregulation of inflammatory responses-associated factors including CCL2 and CCL7. Treatment with 100 ng/mL CCL2 in vitro could significantly promote the adipogenesis of ASCs through enhanced phosphorylation of AKT and decreased expression of ß-catenin. In addition, supplementation of 100 ng/mL CCL7 could significantly increase the expression of inflammatory genes and ASC-4-specific transcriptional factors in 2-week-old ASCs, potentially acting as a driver of ASCs convergence. Our findings help to delineate the complex biological processes of ASCs aging and shed light on better regenerative and therapeutic applications of ASCs.
Assuntos
Tecido Adiposo , Células-Tronco Mesenquimais , Camundongos , Animais , Camundongos Endogâmicos C57BL , Tecido Adiposo/metabolismo , Células-Tronco Mesenquimais/metabolismo , Adipócitos/metabolismo , Diferenciação Celular , Adipogenia , EnvelhecimentoRESUMO
BACKGROUND: Hypertrophic scar is a disease of abnormal skin fibrosis caused by excessive fibroblast proliferation, and existing drugs cannot achieve satisfactory therapeutic effects. OBJECTIVES: This study aimed to explore the molecular pathogenesis of hypertrophic scars and screen effective drugs for hypertrophic scars. METHODS: Existing human hypertrophic scar RNA sequencing data were utilized to search for hypertrophic scar-related gene modules and key genes through weighted gene co-expression network analysis (WGCNA). Candidate compounds were screened in a compound library. Potential drugs were screened by molecular docking and verified in human hypertrophic scar fibroblasts and a mouse mechanical force hypertrophic scar model. RESULTS: WGCNA showed that hypertrophic scar-associated gene modules influence focal adhesion, transforming growth factor ß (TGF-ß) signaling pathway, and other biological pathways. Integrin ß1 (ITGB1) is the hub protein. Among the candidate compounds obtained by computer virtual screening and molecular docking, crizotinib, sorafenib, and SU11274 can inhibit the proliferation and migration of human hypertrophic scar fibroblasts and pro-fibrotic gene expression. Crizotinib had the best effect on hypertrophic scar attenuation in mouse models. At the same time, mouse ITGB1 small interfering RNA (siRNA) can also inhibit mouse scar hyperplasia. CONCLUSIONS: ITGB1 and TGF-ß signaling pathways are important for hypertrophic scar formation. Crizotinib could serve as a potential drug for hypertrophic scars.
RESUMO
The extensive use of opioids for chronic pain management has contributed significantly to the current opioid epidemic. While many alternative nonopioid analgesics are available, opioids remain the most potent analgesics for moderate to severe pain management. In addition to the implementation of multimodal analgesia, there is a pressing need for the development of more effective and safer opioids. In this study, we developed a thermoresponsive N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based hydromorphone (HMP) prodrug (ProGel-HMP, HMP content = 16.2 wt %, in base form). The aqueous solution of ProGel-HMP was free-flowing at 4 °C but became a hydrogel when the temperature was raised to ≥37 °C, allowing sustained local retention when administered in vivo. When tested in the destabilization of the medial meniscus (DMM) mouse model of osteoarthritis (OA), ProGel-HMP was retained after intra-articular injection in the OA knee joint for at least 2 weeks postinjection, with low extra-articular distribution. ProGel-HMP was not detected in the central nervous system (CNS). A single dose of ProGel-HMP produced rapid and sustained joint pain resolution for greater than 14 days when compared to saline and dose-equivalent HMP controls, likely mediated through peripheral µ-opioid receptors in the knee joint. Systemic analgesia effect was absent in the DMM mice treated with ProGel-HMP, as evident in the lack of difference in tail flick response between the ProGel-HMP-treated mice and the controls (i.e., Healthy, Saline, and Sham). Repeated dosing of ProGel-HMP did not induce tolerance. Collectively, these data support the further development of ProGel-HMP as a potent, safe, long-acting and nonaddictive analgesic for better clinical pain management.
Assuntos
Analgesia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Osteoartrite , Pró-Fármacos , Camundongos , Animais , Hidromorfona , Manejo da Dor , Pró-Fármacos/uso terapêutico , Dor/tratamento farmacológico , Analgésicos Opioides/efeitos adversos , Analgésicos/uso terapêuticoRESUMO
The extensive application of Tetrabromobisphenol A (TBBPA) leads to the pollution of part of the water environment and brings great safety risks to aquatic animals. As a natural extract, tea polyphenols (TPs) have antioxidant and anti-inflammatory effects. Gills are one of the immune organs of fish and constitute the first line of defense of the immune system. However, it was unclear whether TPs could mitigate TBBPA-induced gills injury. Therefore, an animal model was established to investigate the effect of TPs on TBBPA-induced gills. The results indicated that TBBPA changed the coefficient and tissue morphology of carp gills. In addition, TBBPA induced oxidative stress and inflammation, leading to ferroptosis and apoptosis in carp gills. Dietary addition of TPs significantly improved the antioxidant capacity of carp, effectively inhibited the overexpression of TLR4/NF-κB and its mediated inflammatory response. Moreover, TPs restored iron metabolism, reduced the expression of pro-apoptotic factors thereby alleviating ferroptosis and apoptosis in carp gills. This study enriched the protective effect of TPs and provided a new way to improve the innate immunity of carp.
Assuntos
Carpas , Ferroptose , Bifenil Polibromatos , Animais , NF-kappa B/genética , NF-kappa B/metabolismo , Antioxidantes/metabolismo , Receptor 4 Toll-Like/genética , Carpas/metabolismo , Brânquias , Polifenóis/farmacologia , Polifenóis/metabolismo , Transdução de Sinais , Proteínas de Peixes , Inflamação/induzido quimicamente , Inflamação/veterinária , Inflamação/metabolismo , Apoptose , Chá/metabolismoRESUMO
An unusual spiroannulation/cycloisomerization cascade of 3-(2-ethynylaryl)-N-tosylaziridines with indoles enabled by cooperative gold/scandium catalysis is presented, which facilitates the synthesis of 5H-benzo[b]carbazoles in moderate to excellent yields. This protocol features a broad substrate scope and good functional-group compatibility. Additionally, the resulting 5H-benzo[b]carbazoles exhibit good fluorescence properties, demonstrating the synthetic practicality of this method. Moreover, control experiments were performed to illustrate the reaction mechanism.
RESUMO
Altruistic punishment is a primary response to social norms violations; its neural mechanism has also attracted extensive research attention. In the present studies, we applied a low-frequency repetitive transcranial magnetic stimulation (rTMS) to the bilateral dorsolateral prefrontal cortex (DLPFC) while participants engaged in a modified Ultimatum Game (Study 1) and third-party punishment game (Study 2) to explore how the bilateral DLPFC disruption affects people's perception of violation of fairness norms and altruistic punishment decision in the gain and loss contexts. Typically, punishers intervene more often against and show more social outrage towards Dictators/Proposers who unfairly distribute losses than those who unfairly share gains. We found that disrupting the function of the left DLPFC in the second-party punishment and the bilateral DLPFC in the third-party punishment with rTMS effectively obliterated this difference, making participants punish unfairly shared gains as often as they usually would punish unfairly shared losses. In the altruistic punishment of maintaining the social fairness norms, the inhibition of the right DLPFC function will affect the deviation of individual information integration ability; the inhibition of the left DLPFC function will affect the assessment of the degree of violation of fairness norms and weaken impulse control, leading to attenuate the moderating effect of gain and loss contexts on altruistic punishment. Our findings emphasize that DLPFC is closely related to altruistic punishment and provide causal neuroscientific evidence.
RESUMO
Polymer memristors represent a highly promising avenue for the advancement of next-generation computing systems. However, the intrinsic structural heterogeneity characteristic of most polymers often results in organic polymer memristors displaying erratic resistive switching phenomena, which in turn lead to diminished production yields and compromised reliability. In this study, a 2D conjugated polymer, named PBDTT-BPQTPA, is synthesized by integrating the coplanar bis(thiophene)-4,8-dihydrobenzo[1,2-b:4,5-b]dithiophene (BDTT) as an electron-donating unit with a quinoxaline derivative serving as an electron-accepting unit. The incorporation of triphenylamine groups at the quinoxaline termini significantly enhances the polymer's conjugation and planarity, thereby facilitating more efficient charge transport. The fabricated polymer memristor with the structure of Al/PBDTT-BPQTPA/ITO exhibits typical non-volatile resistive switching behavior under high voltage conditions, along with history-dependent memristive properties at lower voltages. The unique memristive behavior of the device enables the simulation of synaptic enhancement/inhibition, learning algorithms, and memory operations. Additionally, the memristor demonstrates its capability for executing logical operations and handling decimal calculations. This study offers a promising and innovative approach for the development of artificial neuromorphic computing systems.