Adenosine mediates the amelioration of social novelty deficits during rhythmic light treatment of 16p11.2 deletion female mice.

Non-invasive brain stimulation therapy for autism spectrum disorder (ASD) has shown beneficial effects. Recently, we and others demonstrated that visual sensory stimulation using rhythmic 40 Hz light flicker effectively improved cognitive deficits in mouse models of Alzheimer's disease and stroke. However, whether rhythmic visual 40 Hz light flicker stimulation can ameliorate behavioral deficits in ASD remains unknown. Here, we show that 16p11.2 deletion female mice exhibit a strong social novelty deficit, which was ameliorated by treatment with a long-term 40 Hz light stimulation. The elevated power of local-field potential (LFP) in the prefrontal cortex (PFC) of 16p11.2 deletion female mice was also effectively reduced by 40 Hz light treatment. Importantly, the 40 Hz light flicker reversed the excessive excitatory neurotransmission of PFC pyramidal neurons without altering the firing rate and the number of resident PFC neurons. Mechanistically, 40 Hz light flicker evoked adenosine release in the PFC to modulate excessive excitatory neurotransmission of 16p11.2 deletion female mice. Elevated adenosine functioned through its cognate A1 receptor (A1R) to suppress excessive excitatory neurotransmission and to alleviate social novelty deficits. Indeed, either blocking the A1R using a specific antagonist DPCPX or knocking down the A1R in the PFC using a shRNA completely ablated the beneficial effects of 40 Hz light flicker. Thus, this study identified adenosine as a novel neurochemical mediator for ameliorating social novelty deficit by reducing excitatory neurotransmission during 40 Hz light flicker treatment. The 40 Hz light stimulation warrants further development as a non-invasive ASD therapeutics.

Nephrectomy and high-salt diet inducing pulmonary hypertension and kidney damage by increasing Ang II concentration in rats.

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.

Discovery of Covalent Lead Compounds Targeting 3CL Protease with a Lateral Interactions Spiking Neural Network.

Covalent drugs exhibit advantages in that noncovalent drugs cannot match, and covalent docking is an important method for screening covalent lead compounds. However, it is difficult for covalent docking to screen covalent compounds on a large scale because covalent docking requires determination of the covalent reaction type of the compound. Here, we propose to use deep learning of a lateral interactions spiking neural network to construct a covalent lead compound screening model to quickly screen covalent lead compounds. We used the 3CL protease (3CL Pro) of SARS-CoV-2 as the screen target and constructed two classification models based on LISNN to predict the covalent binding and inhibitory activity of compounds. The two classification models were trained on the covalent complex data set targeting cysteine (Cys) and the compound inhibitory activity data set targeting 3CL Pro, respected, with good prediction accuracy (ACC > 0.9). We then screened the screening compound library with 6 covalent binding screening models and 12 inhibitory activity screening models. We tested the inhibitory activity of the 32 compounds, and the best compound inhibited SARS-CoV-2 3CL Pro with an IC50 value of 369.5 nM. Further assay implied that dithiothreitol can affect the inhibitory activity of the compound to 3CL Pro, indicating that the compound may covalently bind 3CL Pro. The selectivity test showed that the compound had good target selectivity to 3CL Pro over cathepsin L. These correlation assays can prove the rationality of the covalent lead compound screening model. Finally, covalent docking was performed to demonstrate the binding conformation of the compound with 3CL Pro. The source code can be obtained from the GitHub repository (https://github.com/guzh970630/Screen_Covalent_Compound_by_LISNN).

Graphical Presentations in Systemic Anticancer Treatment Network Meta-Analyses: A Systematic Review.

Network meta-analysis (NMA) draws conclusions about indirect comparisons of randomized clinical trials and is considered high-level evidence. Most NMA publications make use of network plots to portray results. Network plots are complex graphics that can have many visual attributes to portray useful information, such as node size, color, and graph layout. We analyzed the network plots from 162 NMAs of systemic anticancer therapy efficacy using a set of 16 attributes. Our review showed that the current state of network plot data visualizations within the NMA space lacks diversity and does not make use of many of the visual attributes available to convey information. More thoughtful design choices should be placed behind these important visualizations, which can carry clinical significance and help derive treatment plans for patients.

Palladium-Catalyzed Defluorinative Alkylation of gem-Difluoroalkenes with Cyclopropanols: Stereoselective Synthesis of γ-Fluorinated γ,δ-Unsaturated Ketones.

A palladium-catalyzed defluorinative alkylation of gem-difluoroalkenes with cyclopropyl alcohols was developed. A range of γ-fluorinated γ,δ-unsaturated ketones were constructed in good yields with excellent stereoselectivities. In addition, by base-mediated intramolecular nucleophilic vinylic substitution (SNV), the products could be further transformed to 2,5-dimethylenetetrahydrofurans and analogues with excellent stereoselectivities.

Design, synthesis and biological evaluation of novel 3C-like protease inhibitors as lead compounds against SARS-CoV-2.

Background: The epidemic caused by SARS-CoV-2 swept the world in 2019. The 3C-like protease (3CLpro) of SARS-CoV-2 plays a key role in viral replication, and its inhibition could inhibit viral replication. Materials & methods: The virtual screen based on receptor-ligand pharmacophore models and molecular docking were conducted to obtain the novel scaffolds of the 3CLpro. The molecular dynamics simulation was also carried out. All compounds were synthesized and evaluated in biochemical assays. Results: The compound C2 could inhibit 3CLpro with a 72% inhibitory rate at 10 µM. The covalent docking showed that C2 could form a covalent bond with the Cys145 in 3CLpro. Conclusion: C2 could be a potent lead compound of 3CLpro inhibitors against SARS-CoV-2.

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Predictive accuracy of wideband absorbance in children with large vestibular aqueduct syndrome: A single-center retrospective study.

Objectives: This study aimed to assess the clinical significance of Wideband Absorbance (WBA) in children with Large Vestibular Aqueduct Syndrome (LVAS), which could potentially serve as diagnostic and predictive markers for LVAS in children. Design: This was a single-center retrospective case-control study. Audiological measurements and Wideband Acoustic Immittance (WAI) were performed. Propensity score matching (PSM) was considered to treat group imbalance. The Receiver Operating Characteristic (ROC) curves and area under the ROC curve (AUC) were used to evaluate the sensitivity and specificity of WBA. Study sample: Participants included 42 children with LVAS and 163 normal children aged 6 months -11 years recruited from clinical audiology settings between 2019 and 2021. Results: The WBA at Tympanometric Peak Pressure (WBATPP) and Ambient Pressure (WBAA) in the LVAS group were significantly lower than those of the control group at 1259-2000 Hz but higher at 4000-6349 Hz (p < 0.05, power >0.8). The WBAA (1587 Hz) AUC value was 0.805, identifying a score ≤0.565 as indicative of a LVAS risk. Conclusions: WBA holds promise in distinguishing LVAS from the normal condition and warrants further exploration as a tool to examine the influence of inner ear pressure on acoustic energy transmission in the middle ear.

Targeting the TGF-ß signaling pathway: an updated patent review (2021-present).

INTRODUCTION: The TGF-ß signaling pathway is a complex network that plays a crucial role in regulating essential biological functions and is implicated in the onset and progression of multiple diseases. This review highlights the recent advancements in developing inhibitors targeting the TGF-ß signaling pathway and their potential therapeutic applications in various diseases. AREA COVERED: The review discusses patents on active molecules related to the TGF-ß signaling pathway, focusing on three strategies: TGF-ß activity inhibition, blocking TGF-ß receptor binding, and disruption of the signaling pathway using small molecule inhibitors. Combination therapies and the development of fusion proteins targeting multiple pathways are also explored. The literature search was conducted using the Cortellis Drug Discovery Intelligence database, covering patents from 2021 onwards. EXPERT OPINION: The development of drugs targeting the TGF-ß signaling pathway has made significant progress in recent years. However, addressing challenges such as specificity, systemic toxicity, and patient selection is crucial for their successful clinical application. Targeting the TGF-ß signaling pathway holds promise as a promising approach for the treatment of various diseases.

Integrated approach of network pharmacology, molecular docking, and clinical observations in evaluating the efficacy and safety of Bufei Huoxue capsules for pulmonary hypertension associated with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a persistent and progressive disorder characterized by airway or alveolar abnormalities, commonly leading to pulmonary hypertension (PH). This clinical observational study investigates the therapeutic mechanisms of Bufei Huoxue capsules (BHC) in treating PH in patients with COPD-linked PH (COPD-PH) using network pharmacology and molecular docking methods, and assesses the therapeutic efficacy and safety of BHCs. The active compounds and their target proteins in BHCs were sourced from the Traditional Chinese Medicine Systems Pharmacology database, with additional target proteins derived from the GeneCards and OMIM databases. An active network was constructed using Cytoscape 3.7.1, and interaction networks were established. Intersecting targets underwent Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using the Metascape database. Network pharmacology and molecular docking studies demonstrated favorable binding affinities of BHC active ingredients, such as quercetin, bavachalcone, and isobavachin, for key targets including PTGS1, ESR1, and PTGS2. Gene Ontology enrichment analysis highlighted the involvement of these targets in processes such as the positive regulation of locomotion, the transmembrane receptor protein tyrosine kinase signaling pathway, and peptidyl-tyrosine phosphorylation. KEGG pathway analysis indicated their roles in pathways related to cancer, AGE-RAGE signaling in diabetic complications, and prostate cancer. BHCs exhibit therapeutic effects on COPD-PH through multi-component, multi-target, and multi-pathway interactions. This clinical observational study confirms the efficacy and safety of BHCs in improving cardiac and pulmonary functions, enhancing exercise tolerance, and elevating the quality of life in patients with COPD-PH.

Gadolinium-enhanced MRI reveals dynamic development of endolymphatic hydrops in Ménières disease / Ressonância magnética com gadolínio revela o desenvolvimento dinâmico da hidropsia endolinfática na doença de Ménière

Abstract Introduction: Meniere's disease is associated with impaired hearing, tinnitus, vertigo, and aural fullness. Many anatomical studies have suggested idiopathic endolymphatic hydrops as the pathological basis of Meniere's disease, which now can be visualized by using gadolinium -enhanced magnetic resonance imaging of the inner ear. Objective: To investigate the development of endolymphatic hydrops in Meniere's disease by monitoring the vestibules and cochleae of affected patients. Methods: Inner ears of 178 patients with definite unilateral Meniere's disease diagnosis were visualized by 3-dimensional fluid-attenuated inversion recovery and three-dimensional real inversion recovery magnetic resonance imaging following bilateral gadolinium intratympanic injection. The scans were used to evaluate the presence and degree of endolymphatic hydrops in the vestibules and cochlear structures, including the cochlear apical turn, the cochlear middle turn, and the cochlear basal turn. The correlation of endolymphatic hydrops occurrence between the various parts of the inner ear was determined. Results: Symptomatic endolymphatic hydrops was detected on the affected side in all patients, whereas asymptomatic endolymphatic hydrops was detected on the unaffected contra-lateral side in 32 patients (18.0%). On the affected side, the cochlear apical turn and the cochlear middle turn demonstrated significantly higher rates of endolymphatic hydrops than the cochlear basal turn and the vestibule. The severity of endolymphatic hydrops gradually decreased from the cochlear apical turn to the cochlear basal turn. On the contra lateral side, the incidence and degree of the detected asymptomatic endolymphatic hydrops were significantly greater in the cochleae than in the vestibules (p < 0.05), with no significant difference detected between the cochlear turns. Conclusion: Progression of endolymphatic hydrops appears to be directional, initiated in the cochlea. The order of endolymphatic hydrops severity gradually decreases from the cochlear apical turn to the cochlear basal turn and then to the vestibule. Endolymphatic hydrops in the vestibule is associated with symptomatic Meniere's disease.

Resumo Introdução: A doença de Ménière está associada a deficiência auditiva, zumbido, vertigem e plenitude auricular. Muitos estudos anatômicos sugerem hidropsia endolinfática idiopática como a base patológica da doença, que agora pode ser visualizada através de estudo por imagem da orelha interna por ressonância magnética com gadolínio. Objetivo: Investigar o desenvolvimento da hidropsia endolinfática na doença de Ménière com monitoramento dos vestíbulos e das cócleas dos pacientes afetados. Métodos: Orelhas internas de 178 pacientes com diagnóstico definitivo de doença de Ménière unilateral foram visualizados através de imagem de recuperação de inversão atenuada por fluidos em ressonância magnética tridimensional, 3-D FLAIR, e por inversão real após injeção intratimpânica bilateral de gadolínio. Os exames foram usados para avaliar a presença e o grau de hidropsia endolinfática nos vestíbulos e nas estruturas cocleares, inclusive o giro coclear apical, o giro coclear médio e o giro coclear basal. A correlação da ocorrência de hidropsia endolinfática entre as várias partes da orelha interna foi determinada. Resultados: Hidropsia endolinfática sintomática foi detectada no lado afetado em todos os pacientes, enquanto hidropsia endolinfática assintomática foi detectada no lado contralateral não afetado em 32 pacientes (18,0%). No lado afetado, o giro apical da cóclea e o giro coclear médio demonstraram taxas significativamente mais altas de hidropsia endolinfática do que o giro basal e o vestíbulo. A gravidade da hidropsia endolinfática diminuiu gradualmente do giro apical da cóclea para o giro basal. No lado contralateral, a incidência e o grau da hidropsia endolinfática assintomática detectada foram significantemente maiores nas cócleas do que nos vestíbulos (p < 0,05), sem diferença significante entre os giros cocleares. Conclusões: A progressão da hidropsia endolinfática parece ser direcional, iniciando-se na cóclea. A sua ordem da gravidade diminui gradualmente do giro apical da cóclea para o giro basal e, em seguida, para o vestíbulo. A hidropsia endolinfática no vestíbulo está associada à doença de Ménière sintomática.