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Antioxidants represent a potential therapy for cerebral ischemia–reperfusion injury (CIRI). Compounds which exhibit both direct and indirect antioxidative activity may potentially exert improved effects. Hence, we aimed to assess whether the dual antioxidant DH-217, a derivative of DHAP clinically used to treat coronary heart disease, can reduce oxidative stress damage and elucidate the underlying mechanism. Hydrogen peroxide (H2O2)-induced and Middle Cerebral Artery Occlusion (MCAO)-induced damages were used to imitate oxidative stress. The antioxidation of DH-217 was determined by MTT, ROS, colony and DPPH assay. Besides, immunofluorescence, Real-Time PCR Analyses, western blotting and si-RNA/Plasmid-induced protein expression were used for mechanism validation. DPPH scavenging assay evidenced DH-217 was a well free radical scavenger. Cell survival assay also showed that DH-217 had a significant cytoprotection through direct and indirect clearance mechanisms. Further, it clearly inhibited oxidative stress-induced IkappaB kinase beta (IKKβ) phosphorylation and increased heme oxygenase-1 (HO-1) expression. Significantly, these antioxidant beneficial effects were reversed by HO-1 inhibitor, si-nuclear erythroid 2-related factor 2 (Nrf2) and IKKβ plasmid. Meanwhile, DH-217 had a good neuroprotective effect on CIRI rats. The dual antioxidant DH-217 has potential reference value for drug development of CIRI. Furthermore, inhibition of IKKβ phosphorylation and activation of Nrf2/HO-1 could be a promising antioxidant pathway. Dual antioxidant DH-217 not only has the ability of directly scavenging ROS, but also can clear it by targeting IKKβ/Nrf2/HO-1 signal axis. Inhibition of IKKβ phosphorylation and activation of Nrf2/HO-1 may be a promising antioxidant pathway for CIRI. [ABSTRACT FROM AUTHOR]

Geometry and topology of decision regions are closely related with classification performance and robustness against adversarial attacks. In this paper, we use differential geometry to theoretically explore the geometrical and topological properties of decision regions produced by deep neural networks (DNNs). The goal is to obtain some geometrical and topological properties of decision boundaries for given DNN models, and provide some principled guidance to design and regularization of DNNs. First, we present the curvatures of decision boundaries in terms of network parameters, and give sufficient conditions on network parameters for producing flat or developable decision boundaries. Based on the Gauss-Bonnet-Chern theorem in differential geometry, we then propose a method to compute the Euler characteristics of compact decision boundaries, and verify it with experiments. [ABSTRACT FROM AUTHOR]

With the increasing clinical focus on the safety of bilateral cochlear implantation (CI) and the potential risk of bilateral vestibular dysfunction, evaluating vestibular end-organ function in patients with vestibular malformations with accompanying abnormalities has been strongly recommended. To identify the vestibular-evoked myogenic potential (VEMP) values among children with sensorineural hearing loss (SNHL) with vestibular malformation and assess the effectiveness of VEMP testing for inner ear malformations (IEM) diagnosis. This study included 96 children (192 ears), including those with vestibular malformations (48 ears), large vestibular aqueduct syndrome (LVAS) (50 ears), and SNHL without IEM (94 ears; control group). All groups underwent ocular and cervical VEMP (oVEMP and cVEMP, respectively) testing. The response rates, VEMP parameters, and wave characteristics were compared. The cVEMP response rates were 37.5 %, 64 %, and 58.51 % and the oVEMP response rates were 42.86 %, 78.95 %, and 77.27 % in the vestibular malformation, LVAS, and control groups, respectively, and significantly differed between groups (cVEMP: X 2 = 18.228, P< 0.001) (oVEMP: X 2 = 7.528, P = 0.023). Significant inter-group differences were observed for the cVEMP and oVEMP latency and amplitude (P < 0.05). The LVAS group's waveform exhibited a prolonged latency and increased amplitude compared with that of the other groups. Patients with SNHL were highly susceptible to otolith dysfunction, regardless of comorbid vestibular malformation presence. Measuring VEMPs is an effective and rapid evaluation technique for vestibular function and could provide a basis for vestibular rehabilitation training. • Studies of characteristics of VEMPs waveform in severe SNHL and vestibular malformations are limited. • Vestibular-evoked myogenic potential (VEMP) testing is an effective and rapid method for measuring saccule and utricle function. • The cVEMP and oVEMP response rate of the vestibular malformation group was significantly low. • Patients with SNHL were highly susceptible to otolith dysfunction. • Results of VEMP testing could improve the classification of vestibular malformations and allow further characterization of IEM subsets. [ABSTRACT FROM AUTHOR]

The online version of the original article can be found at https://doi.org/10.1007/s11064-022-03783-x. Correction to: Dual Antioxidant DH-217 Mitigated Cerebral Ischemia-Reperfusion Injury by Targeting IKK /Nrf2/HO-1 Signal Axis In the original version of the above article, after forwarding the article to online publication, author found that there is a spell error in one of the co-author names. [Extracted from the article]

Objective: The objectives of this study are twofold: first, to visualize the structure of malformed cochleae through image reconstruction; and second, to develop a predictive model for postoperative outcomes of cochlear implantation (CI) in patients diagnosed with cochlear hypoplasia (CH) and incomplete partition (IP) malformation. Methods: The clinical data from patients diagnosed with cochlear hypoplasia (CH) and incomplete partition (IP) malformation who underwent cochlear implantation (CI) at Beijing Tongren Hospital between January 2016 and August 2020 were collected. Radiological features were analyzed through 3D segmentation of the cochlea. Postoperative auditory speech rehabilitation outcomes were evaluated using the Categories of Auditory Performance (CAP) and the Speech Intelligibility Rating (SIR). This study aimed to investigate the relationship between cochlear parameters and postoperative outcomes. Additionally, a predictive model for postoperative outcomes was developed using the K-nearest neighbors (KNN) algorithm. Results: In our study, we conducted feature selection by using patients' imaging and audiological attributes. This process involved methods such as the removal of missing values, correlation analysis, and chi-square tests. The findings indicated that two specific features, cochlear volume (V) and cochlear canal length (CDL), significantly contributed to predicting the outcomes of hearing and speech rehabilitation for patients with inner ear malformations. In terms of hearing rehabilitation, the KNN classification achieved an accuracy of 93.3%. Likewise, for speech rehabilitation, the KNN classification demonstrated an accuracy of 86.7%. Conclusion: The measurements obtained from the 3D reconstruction model hold significant clinical relevance. Despite the considerable variability in cochlear morphology across individuals, radiological features remain effective in predicting cochlear implantation (CI) prognosis for patients with inner ear malformations. The utilization of 3D segmentation techniques and the developed predictive model can assist surgeons in conducting preoperative cochlear structural measurements for patients with inner ear malformations. This, in turn, can offer a more informed perspective on the anticipated outcomes of cochlear implantation. [ABSTRACT FROM AUTHOR]

As the penetration of renewable energy sources (RES) significantly increases, their inherent uncertainty has brought about a paradigm shift in distribution system planning and operation. The existing planning methodologies usually consider the uncertainty during the investment and day-ahead stages while neglecting the interactive power fluctuations during the intraday stage, resulting in planning schemes with a risk of inadequate regional stability. In light of this, this paper proposes a novel adaptive robust distribution system planning approach that integrates local uncertainty management (LUM) to provide a comprehensive and refined consideration of uncertainty. First, we introduce the concept of LUM that can effectively address the deviations between predicted and actual power of RES and load. Second, we propose the adaptive robust planning model for the distribution system, in which the investment and day-ahead operation are considered in the first stage, while LUM is considered in the second stage to maintain the local stability of interactive power. The proposed model can actively manage uncertainties of RES and load demand, reaching the optimal balance between the investment cost, operational cost, and LUM cost. Finally, by employing the column-and-constraint generation (C&CG), the adaptive robust planning model is decoupled into a master min problem and a slaver max-min problem, after which the max-min problem is converted into a single mixed-integer linear programming (MILP) problem through the strong duality theory and big-M method. The effectiveness of the proposed model is demonstrated using a real-world distribution system located in Fujian Province, China. The simulation results indicate that the proposed model achieves a quantitative decrease of approximately 10% in total cost compared to deterministic planning. Sensitivity analysis is also conducted to reveal the trade-off between economic cost and robustness level. • Local uncertainty management (LUM) is incorporated into distribution system planning. • A three-stage framework is developed for the planning problem incorporating LUM. • An adaptive robust distribution system planning model incorporating LUM is proposed. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a highly heterogeneous clinical syndrome and an important cause of mortality in critically ill patients, with limited treatment options currently available. Chalcone, an essential secondary metabolite found in edible or medicinal plants, exhibits good antioxidant activity and simple structure for easy synthesis. In our study, we synthesized a novel chalcone derivative, compound 27 (C27). We hypothesized that C27 could be a potential treatment for acute respiratory distress syndrome (ARDS). Therefore, the protective effects of C27 on lung epithelial cells during ALI and the underlying molecular mechanisms were investigated. In vivo, Intratracheal instillation of LPS (10 mg/kg) was used to induce acute lung injury in mice. In vitro, the bronchial epithelial cell line (Beas-2b) was treated with 30 μM tert-butyl hydroperoxide (t-BHP) to simulate oxidative stress. Our findings demonstrate that pretreatment with C27 reduces LPS-induced oxidative destruction and cellular apoptosis in lung tissues of mice. Furthermore, it significantly attenuates t-BHP-induced cellular reactive oxygen species (ROS) generation, mitochondrial damage, and apoptosis in vitro. Mechanistically, the signaling pathway involving Nrf2-Keap1 and the downstream antioxidative proteins were activated by C27 in vivo. Additionally, PI3K inhibitor LY294002 and Nrf2 inhibitor ML385 abolished the effect of C27 in vitro, indicating that the protective effect of C27 is mediated via the PI3K/AKT/Nrf2-Keap1 pathway. Our study provides evidence that C27 protects against LPS-induced ALI by mitigating oxidative stress via activation of the PI3K/AKT/Nrf2-Keap1 signaling pathway. Therefore, we hypothesize that C27 represents a viable alternative for ALI therapy. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a continuum of pulmonary changes caused by various lung insults. Previously, we synthesized a series of nordihydroguaiaretic acid analogs; of these, compound 3a exhibited excellent antioxidant capacity in a murine model of middle cerebral artery occlusion. However, it remains unclear whether compound 3a can modulate lipopolysaccharide (LPS)-induced ALI. ALI was induced via tracheal LPS administration, and the pathological changes were assessed. The level of inflammation was verified by immunofluorescence and immunohistochemical analyses. Apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling assays and Western blotting. Changes in the levels of mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) pathway proteins were assessed by immunofluorescence assays and Western blotting. In vitro , RAW 264.7 cells were treated with compound 3a prior to LPS challenge, and the intracellular level of inflammation was assessed by quantitative PCR (qPCR). Relevant proteins were detected via immunofluorescence assays and Western blotting. Mice developed extensive lung inflammation by 24 h after LPS challenge. Histological examination revealed signs typical of ALI. Preadministration of compound 3a markedly ameliorated the histopathological changes and reduced fluid exudation into the alveolar space. Compound 3a also greatly reduced the levels of inflammation and apoptosis both in vivo and in vitro. Moreover, compound 3a markedly reduced phosphorylation of MAPK/NF-κB pathway-related proteins and p65 translocation, consistent with the in vitro observations. In summary, administration of compound 3a prior to LPS suppressed ALI via inhibition of the MAPK/NF-κB pathway. • Compound 3a alleviated pathological alternations, edema extent and pulmonary inflammation in LPS-induced ALI in vivo. • Compound 3a protected RAW 264.7 cells from LPS-induced damage. • Compound 3a inhibited MAPK/NF-κB pathways in both cells and mice. [ABSTRACT FROM AUTHOR]

Nucleotide-binding leucine-rich repeat-containing receptor 12 (NLRP12), a highly conserved protein containing an N-terminal pyrin domain (PYD), a nucleotide-binding domain and a C-terminal leucine-rich repeat region, belongs to the nucleotide-binding oligomerization domain-like receptor-containing PYD (NLRP) family and is a cytoplasmic sensor that plays a negative role in inflammation. NLRP12 is involved in multiple disease processes, including formation of inflammasomes and regulation of both canonical and noncanonical inflammatory signaling pathways. NLRP12 and pathogenic infections are closely linked, and alterations in NLRP12 expression and activity are associated with inflammatory diseases. In this review, we begin with a summary of the mechanisms of negative regulation by NLRP12. We then underscore the important roles of NLRP12 in the onset and progression of inflammation, infectious disease, host defense, carcinogenesis and COVID-19. Finally, we highlight factors that influence NLRP12 activity, including synthetic and naturally derived agonists, and are regarded as potential therapeutic agents to overcome inflammatory diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel curcumin analogs with stability and low toxicity were designed. • Most compounds obtained by green synthesis exhibited obvious antioxidant activity. • Nrf2 pathway activator sAc15 showed excellent protective activity against CIRI. Antioxidants with high efficacy and low toxicity have the potential to treat cerebral ischemia reperfusion injury (CIRI). Dienone monocarbonyl curcumin analogs (DMCA) capable of overcoming the instability and pharmacokinetic defects of curcumin possess notable antioxidant activity but are found to be significantly toxic. In this study, a novel skeleton of the monoenone monocarbonyl curcumin analogue sAc possessing reduced toxicity and improved stability was designed on the basis of the DMCA skeleton. Moreover, 32 sAc analogs were obtained by applying a green, simple, and economical synthetic method. Multiple sAc analogs with an antioxidant protective effect in PC12 cells were screened using an H 2 O 2 -induced oxidative stress damage model, and quantitative evaluation of structure–activity relationship (QSAR) model with regression coefficient of R2 = 0.918921 was built through random forest algorithm (RF). Among these compounds, the optimally active compound sAc15 elicited a potent protective effect on cell growth of PC12 cells by effectively eliminating ROS generation in response to oxidative stress injury by activating the Nrf2/HO-1 antioxidant signaling pathway. In addition, sAc15 exhibited good protection against CIRI in the mice middle cerebral artery occlusion (MCAO) model. In this paper, we provide a novel class of antioxidants and a potential compound for stroke treatment. [ABSTRACT FROM AUTHOR]