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We sought to assess cognitive benefits of a community-based multidomain intervention for improving cognition among older adults at risk of cognitive decline (COMBAT).A two-armed cluster-randomized controlled trial.Community-dwelling older adults aged 60 years or older and were at risk of cognitive decline (n = 209).In this 9-month intervention study, 10 community hospitals in Beijing, China, were randomized (1:1) to receive either a multidomain intervention of meditation, cognitive training, exercise, and nutrition counseling or usual care. The intervention was delivered with weekly 1-hour group training sessions and weekly home homework.Primary outcome was change in cognition as measured by a composite Z score of seven cognitive tests. Secondary outcomes included subjective cognitive abilities, positive and negative affective experiences, physical activity, and dietary habits. Assessments were administered at baseline, end of the intervention, and 1 year after completing the intervention (1-year follow-up).Immediately after the intervention, the intervention group showed significant enhancement in cognitive performance (p = 0.026). The between-group difference in the Z score of change of cognition was 0.20 (95% CI: 0.053, 0.35), with a Hedges' g of 0.40 (95% CI: 0.29, 0.50). However, this cognitive benefit was not significant at 1-year follow-up.This multidomain intervention was effective to improve cognition for at-risk individuals. Long-term effects on cognitive function and individual differences in response to the intervention deserve further investigation.

What is known and objective: The regimen of nivolumab plus ipilimumab(NI) has been recommended by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology-Malignant Pleural Mesothelioma (Version 1.2022) and Chinese Guidelines for the Clinical Diagnosis and Treatment of Malignant Pleural Mesothelioma (2021 edition) as the first-line treatment for Malignant Pleural Mesothelioma (MPM). But whether immunotherapy has a financial advantage over conventional chemotherapy (pemetrexed plus cisplatin/carboplatin, C) is uncertain. Methods: Based on survival and safety data from the CheckMate 743 clinical trial (NCT02899299), a partitioned survival model was constructed using TreeAge Pro2022 software. The model cycle was set to 1 month and the study period was 10 years. The output indicators included total cost, quality-adjusted life year (QALY) and incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were used to assess the robustness of the results, considering only direct medical costs. Results and discussion: The ICER for group NI vs. Group C was $375,656/QALY in all randomized patients, $327,943/QALY in patients with epithelioid histology, and $115,495/QALY in patients with non-epithelioid histology. The ICERs of all three different populations all exceeded the willingness-to-pay threshold (three times the per capita gross domestic product of China in 2021). The results of univariate sensitivity analysis showed that the price of pemetrexed and nivolumab had great influence on the analysis results. The results of the probabilistic sensitivity analysis show that the probability of the NI scheme being more economical in all three different populations was 0. What is new and conclusion: From the perspective of Chinese payers, in patients with unresectable MPM, NI has no economic advantage over C.

Aim of the study To evaluate the efficacy and preliminary outcomes of using a postauricular-groove approach without endoscopic assistance for the excision of parotid tumors. Case series Patients who underwent parotidectomy using a postauricular-groove incision were selected for this study. For patients in which parotidectomy was difficult, namely, for tumors located in the deep lobe area, the parotid gland sternocleidomastoid space was fully utilized, and the tumor was resected from the posterior plane. A total of fifty-eight patients with parotid tumor were enrolled and divided into superior lobe group (n=46) and deep lobe group (n=12). The difference in operation time (94 vs 119 min) and postoperative drainage (20.18 vs 45.33 mL) was statistically significant between the tumors in the superficial and deep lobes. However, postoperative cosmetic VAS score was 10 (extremely satisfied) for all patients. The incidence of transient facial nerve paralysis was comparable (8.7% vs 16.7%), and all of them resolved spontaneously within 3 months. No recurrence of tumors was found in either group in the median follow-up interval of 26.45 months (range 22.2-35.3 months), which was comparable to the result using the conventional “S” approach. Conclusion After making full use of the parotid gland sternocleidomastoid space, the postauricular-groove approach demonstrated satisfactory facial nerve protection, as well as easy maneuverability without the risk of surgical complications for tumors located in the deep lobe area. Importantly, the postauricular-groove approach showed excellent cosmetic outcomes for all patients and should be considered an alternative approach for parotidectomy of selected cases.

IntroductionDetermination of pediatric Crohn's disease (CD) remains a major diagnostic challenge. However, the rapidly emerging field of artificial intelligence has demonstrated promise in developing diagnostic models for intractable diseases.MethodsWe propose an artificial neural network model of 8 gene markers identified by 4 classification algorithms based on Gene Expression Omnibus database for diagnostic of pediatric CD.ResultsThe model achieved over 85% accuracy and area under ROC curve value in both training set and testing set for diagnosing pediatric CD. Additionally, immune infiltration analysis was performed to address why these markers can be integrated to develop a diagnostic model.ConclusionThis study supports further clinical facilitation of precise disease diagnosis by integrating genomics and machine learning algorithms in open-access database.

Background and Objectives Individuals with subjective cognitive decline (SCD) who perform normally on objective cognitive tests may have an increased risk of pathological cognitive decline and progression to Alzheimer’s disease (AD) and related dementia (ADRD). Working memory is widely regarded as an early sign of pathological cognitive decline. We tested the hypothesis that older adults with SCD already exhibit aberrant neurocognitive processing underlying working memory. Research Design and Methods Electroencephalography (EEG) was recorded during a delayed match-to-sample (DMS) task and an eyes-closed resting condition in cognitively healthy community-dwelling older adults who were assigned to the SCD or Control group. Results The SCD and Control groups showed comparable performance on the neuropsychological tests and DMS task. The SCD group showed an enhanced right frontal target-related P300 effect during working memory retrieval and higher frontal theta power during rest. Higher theta power was associated with worse working memory performance and greater left frontal nontarget-related positivity across all older adults. Discussion and Implications Our findings suggest that older people with SCD have subtle pathophysiological changes in working memory–related potentials and intrinsic theta power, which has important implications for predicting risks and early interventions in older adults in the preclinical stage of ADRD.

Aim: This study aimed to evaluate the cost-effectiveness of pembrolizumab compared with that of chemotherapy in the second-line treatment of locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) patients with a combined positive score ≥10. Methods: A Markov model was established to compare the lifetime costs and quality-adjusted life years (QALYs) of different treatment options. Sensitivity analysis was performed to test the stability of the model. Results: The increased utility and cost of pembrolizumab were 0.442 QALYs and US$11,826.79 compared with those of chemotherapy. The incremental cost–effectiveness ratio was US$26,757.45/QALY, which was less than the threshold of three-times the GDP per capita. The prices of paclitaxel and pembrolizumab were the most important influencing factors. Conclusion: Pembrolizumab is a cost-effective second-line treatment of ESCC.

Cisplatin-related ototoxicity is a critical side effect of chemotherapy and can lead to irreversible hearing loss. This study aimed to assess the potential effect of the DNA methyltransferase (DNMT) inhibitor RG108 on cisplatin-induced ototoxicity. Immunohistochemistry, apoptosis assay, and auditory brainstem response (ABR) were employed to determine the impacts of RG108 on cisplatin-induced injury in murine hair cells (HCs) and spiral ganglion neurons (SGNs). Rhodamine123 and TMRM were utilized for mitochondrial membrane potential (MMP) assessment. Reactive oxygen species (ROS) amounts were evaluated by Cellrox green and Mitosox-red probes. Mitochondrial respiratory function evaluation was performed by determining oxygen consumption rates (OCRs). The results showed that RG108 can markedly reduce cisplatin induced damage in HCs and SGNs, and alleviate apoptotic rate by protecting mitochondrial function through preventing ROS accumulation. Furthermore, RG108 upregulated BCL-2 and downregulated APAF1, BAX, and BAD in HEI-OC1 cells, and triggered the PI3K/AKT pathway. Decreased expression of low-density lipoprotein receptor-related protein 1 (LRP1) and high methylation of the LRP1 promoter were observed after cisplatin treatment. RG108 treatment can increase LRP1 expression and decrease LRP1 promoter methylation. In conclusion, RG108 might represent a new potential agent for preventing hearing loss induced by cisplatin via activating the LRP1-PI3K/AKT pathway.

In recent years, cross-cultural research on the modulation of basic cognitive processes by culture has intensified – also from an aging perspective. Despite this increased research interest, only a few cross-culturally normed non-verbal stimulus sets are available to support cross-cultural cognitive research in younger and older adults. Here we present the ORCA (Official Rating of Complex Arrangements) picture database, which includes a total of 720 object–scene compositions sorted into 180 quadruples (e.g., two different helmets placed in two different deserts). Each quadruple contains visually and semantically matched pairs of objects and pairs of scenes with varying degrees of semantic fit between objects and scenes. A total of 95 younger and older German and Chinese adults rated every object–scene pair on object familiarity and semantic fit between object and scene. While the ratings were significantly correlated between cultures and age groups, small but significant culture and age differences emerged. Object familiarity was higher for older adults than younger adults and for German participants than for Chinese participants. Semantic fit was rated lower by German older adults and Chinese younger adults as compared to German younger adults and Chinese older adults. Due to the large number of stimuli, our database is particularly well suited for cognitive and neuroscientific research on cross-cultural and age-related differences in perception, attention, and memory.

Zhiwei Zheng,1,&ast; Cui Yang,2,&ast; Chun Cai,1 Huide Zhu1 1Department of Pharmacy, Cancer Hospital of Shantou University Medical College, Shantou, 515041, People’s Republic of China; 2Department of Obstetrics and Gynecology Shantou Central Hospital, Shantou, 515000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huide ZhuDepartment of Pharmacy, Cancer Hospital of Shantou University Medical College, Shantou, 515041, People’s Republic of ChinaTel +86 075488555844-1140Fax +86 0754 88555844Email zhuhuide_2009@163.comBackground: Recent studies have revealed that the presence of systemic inflammation is associated with poor survival for esophageal squamous cell carcinoma. We aimed to investigate prognostic values of preoperative neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) in resectable esophageal squamous cell carcinoma.Methods: A cohort of 167 resectable ESCC patients was retrospectively reviewed between January 2017 and September 2020. The best cut-off value of NLR and PLR was selected by plotting the receiver operating characteristic curve. All reviewed patients were divided into high NLR/PLR or low NLR/PLR group to evaluate prognostic factors.Results: Among the 167 patients, 34 (20.36%) were women and 133 (79.64%) were men. The mean age was 62.64 ± 7.91 years, with an age range from 44 to 85 years. All patients were divided into low NLR (< 2.20) or high NLR (≥ 2.20) group (AUC=62.5% with the sensitivity of 61.8% and specificity 60.9%, P=0.025), low PLR (< 110) or high PLR (≥ 110) group (AUC=59.6% with the sensitivity of 82.4% and specificity 35.3%, P=0.083). High NLR and PLR were associated with a larger tumor diameter (P< 0.05), while high NLR was also associated with poor tumor classification (P=0.022). There was a positive correlation between NLR and PLR (r = 0.614, P < 0.001). High NLR and PLR were significantly associated with poor disease-free survival. Multivariate analyses identified NLR as a prognostic factor in resectable ESCC.Conclusion: The NLR and PLR predict disease-free survival in resectable esophageal squamous cell carcinoma.Keywords: neutrophil lymphocyte ratio, platelet lymphocyte ratio, disease-free survival, resectable esophageal squamous cell carcinoma

We classify the symplectic automorphism groups for cubic fourfolds. The main inputs are the global Torelli theorem for cubic fourfolds and the classification of the fixed-point sublattices of the Leech lattice. Among the highlights of our results, we note that there are 34 possible groups of symplectic automorphisms, with 6 maximal cases. The six maximal cases correspond to 8 non-isomorphic, and isolated in moduli, cubic fourfolds; six of them previously identified by other authors. Finally, the Fermat cubic fourfold has the largest possible order (174,960) for the automorphism group (non-necessarily symplectic) among all smooth cubic fourfolds., Comment: 41 pages; minor update following some comments from S. Mukai and G. Ouchi

Previously, we have demonstrated that thermal-assisted techniques can accelerate the extraction of inert platinum group metals (PGMs), while they still have several concerns about difficulty of temperature control in actual extraction contactors and safety risks arising from heating organic solvents. In this study, we report a complexation-distribution separated extraction process for the accelerated extraction of inert PGMs. This extraction method includes two steps: (1) complexation of PGMs with extractants in aqueous solution and (2) distribution of the formed complex from the aqueous phase to organic one. We separately investigated the complexation and distribution processes for typical inert PGMs such as Ru(III) and Rh(III) in the presence of water-soluble N,N,N',N'-tetra-alkylpyridinediamide ligands (PDA) and bis(trifluoromethylsulfonyl)amide (Tf2N-) counteranions. As a result, the water-soluble complexes of Ru(III) and Rh(III) with PDA can be formed in 0.5 M HNO3(aq) within 3 h under heating at 356 K. The formed complexes were extracted to the 1-octanol layer containing Tf2N- within 5 min at room temperature, where this hydrophobic anion plays an important role to promote extraction of PGMs as an anionic phase-transfer catalyst (PTC). Consequently, we successfully established and demonstrated the complexation-distribution separated extraction process for the accelerated extraction of inert PGMs using a water-soluble ligand and anionic PTC.

Mnemonic training can improve episodic memory function, the most aging-sensitive functional domain in older adults. However, it remains unclear whether memory training gains can be maintained over time. In this meta-analysis, we aimed to investigate the long-term effects (pretest to follow-up) of mnemonic training in improving memory among older adults. Eligible studies were randomized controlled trials of mnemonic training with follow-up assessments (ranging from 0.5 to 32 months, median follow-up duration = 4 months) in healthy older adults (aged ≥ 50 years) without known cognitive impairment. Twenty-one studies, with a total of 4,149 participants, were identified. The three-level meta-analyses indicated that the immediate (pre- to post-test) and long-term effect sizes on episodic memory were 0.408 and 0.418 (Hedges'

Phenotypic resistance to fluoroquinolones due to mutational changes in the gyrA and parC genes is common among clinical Vibrio strains; the plasmid-mediated quinolone resistance (PMQR) qnrVC genes were also suggested to play a role in enhancing resistance development. This study investigated the prevalence of qnrVC genes in foodborne Vibrio strains collected in Shenzhen, China, during the period August 2015 and April 2017. A total of 1811 foodborne Vibrio strains were collected, mostly (73.8%) from shrimp samples and 20.2% of these strains were resistant to ciprofloxacin. Investigation of resistance mechanisms showed that mutations in the gyrA and parC genes were commonly associated with ciprofloxacin resistance. The presence of qnrVC genes was shown to enhance ciprofloxacin MIC in Vibrio strains and 69.7% of Vibrio strains that harbored target mutations also carried qnrVC genes, yet only 27.5% of the isolates not harboring such mutations carried the qnrVC genes. A total of 141 strains were found to carry the qnrVC alleles, with qnrVC5 and qnrVC1 being the most common types. Fourteen qnrVC variant genes that contained novel mutations were detectable, with 12 (85.7%) involving qnrVC5-like alleles. For the first time, we found a variant that was likely formed by the recombination of qnrVC1 and qnrVC5. The genetic context of the qnrVC genes found in this study was highly variable, with most being accompanied by mobile genetic elements and other resistance genes. The increasing prevalence of qnrVC genes in Vibrio and its contribution on mediating the development of ciprofloxacin resistance need to be further investigated.

Objective: Sugemalimab is approved in China as a first-line treatment in combination with chemotherapy for metastatic nonsquamous non-small cell lung cancer (NSCLC). This study aims to evaluate the cost-effectiveness of first-line additional sugemalimab in combination with chemotherapy vs. chemotherapy from the perspective of the Chinese healthcare system.Materials and methods: A three-state Markov model was designed to evaluate the costs and quality-adjusted life years (QALYs) of first-line sugemalimab combination with chemotherapy vs. chemotherapy over a 10-year period. Data on clinical outcomes were obtained from GEMSTONE-302 clinical trials. Costs and health utilities were collected from local databases and published literature. The uncertainty of the model parameters was explored through sensitivity analysis.Results: Compared to chemotherapy, sugemalimab treatment for NSCLC resulted in an extra 0.50 QALYs at an additional cost of $73627.99, with an incremental cost-effectiveness ratio (ICER) of 148354.07/QALY at the willingness-to-pay (WTP) threshold of $37663.26/QALY. One-way sensitivity analysis indicated that the primary motivator in this model was the cost of sugemalimab. However, none of the parameters significantly affected the model’s results.Conclusion: Sugemalimab combination therapy is not economically advantageous for the first-line management of metastatic non-squamous NSCLC, according to the Chinese healthcare system.

The role of rituximab in the first-line treatment of low-tumour-burden follicular lymphoma (LTB-FL) has been supported by a large number of data. However, whether rituximab biosimilars have the same efficacy and safety as the reference drug (MabThera) is still controversial.Electronic databases and the ClinicalTrail.gov website were extensively searched using relevant search criteria. The risk of bias of the included studies was assessed using the RoB 2 assessment scale, and the RevMan 5.4 statistical software was used for meta-analysis.A total of 1223 patients were included in four clinical randomized controlled trials. There was no statistical difference in efficacy between biosimilars and MabThera groups (the objective response rate: RR = 1.00, 95% CI: 0.93-1.08, p = 0.92; the progression-free survival: RR = 1.04, 95% CI: 0.96-1.12, p = 0.30; the overall survival: RR = 1.00, 95% CI: 0.98-1.03, p = 0.76; the serious adverse events: RR = 1.15, 95% CI: 0.69-1.89, p = 0.59; the infusion-related reaction: RR = 0.91, 95% CI: 0.77-1.09, p = 0.32). In terms of safety, there was also no significant difference between two groups.Our study concluded that the efficacy and safety of rituximab biosimilars in the treatment of LTB-FL are highly similar to those of the original drug.

Curcumin is a natural medicine with a wide range of anti-tumour activities. However, due to β-diketone moiety, curcumin exhibits poor stability and pharmacokinetics which significantly limits its clinical applications. In this article, two types of dicarbonyl curcumin analogues with improved stability were designed through the calculation of molecular stability by density functional theory. Twenty compounds were synthesised, and their anti-tumour activity was screened. A plurality of analogues had significantly stronger activity than curcumin. In particular, compound B2 ((2E,2'E)-3,3'-(1,4-phenylene)bis(1-(2-chlorophenyl)prop-2-en-1-one)) exhibited excellent anti-lung cancer activity

As a general sensory disorder, hearing loss was a major concern worldwide. Autophagy is a common cellular reaction to stress that degrades cytoplasmic waste through the lysosome pathway. Autophagy not only plays major roles in maintaining intracellular homeostasis but is also involved in the development and pathogenesis of many diseases. In the auditory system, several studies revealed the link between autophagy and hearing protection. In this review, we aimed to establish the correlation between autophagy and hair cells (HCs) from the aspects of ototoxic drugs, aging, and acoustic trauma and discussed whether autophagy could serve as a potential measure in the protection of HCs.

Carbapenem-resistant and hypervirulent K. pneumoniae (CR-HvKP) strains that have emerged recently have caused infections of extremely high mortality in various countries. In this study, we discovered a conjugative plasmid that encodes carbapenem resistance and hypervirulence in a clinical ST86 K2 CR-HvKP, namely 17ZR-91. The conjugative plasmid (p17ZR-91-Vir-KPC) was formed by fusion of a non-conjugative pLVPK-like plasmid and a conjugative blaKPC-2-bearing plasmid and is present dynamically with two other non-fusion plasmids. Conjugation of p17ZR-91-Vir-KPC to other K. pneumoniae enabled them to rapidly express the carbapenem resistance and hypervirulence phenotypes. More importantly, genome analysis provided direct evidence that p17ZR-91-Vir-KPC could be directly transmitted from K2 CR-HvKP strain, 17ZR-91, to ST11 clinical K. pneumoniae strains to convert them into ST11 CR-HvKP strains, which explains the evolutionary mechanisms of recently emerged ST11 CR-HvKP strains., Carbapenem-resistant and hypervirulent Klebsiella pneumoniae strains are emerging. Here Xie et al. show that these phenotypes are carried on a plasmid formed from the fusion of a virulence plasmid with a conjugative plasmid.

Data-driven models have been widely developed and achieved impressive results in streamflow prediction. However, the existing data-driven models mostly focus on the selection of input features and the adjustment of model structure, and less on the impact of spatial connectivity on daily streamflow prediction. In this paper, a basin network based on graph-structured data is constructed by considering the spatial connectivity of different stations in the real basin. Furthermore, a novel graph neural network model, variational Bayesian edge-conditioned graph convolution model, which consists of edge-conditioned convolution networks and variational Bayesian inference, is proposed to assess the spatial connectivity effects on daily streamflow forecasting. The proposed graph neural network model is applied to forecast the next-day streamflow of a hydrological station in the Yangtze River Basin, China. Six comparative models and three comparative experimental groups are used to validate model performance. The results show that the proposed model has excellent performance in terms of deterministic prediction accuracy (NSE ≈ 0.980, RMSE≈1362.7 and MAE ≈ 745.8) and probabilistic prediction reliability (ICPC≈0.984 and CRPS≈574.1), which demonstrates that establishing appropriate connectivity and reasonably identifying connection relationships in the basin network can effectively improve the deterministic and probabilistic forecasting performance of the graph convolutional model.

BackgroundThis study aimed to analyze the economics of pembrolizumab plus chemotherapy as first-line treatment in patients with esophageal squamous cell carcinoma (ESCC) and programmed cell death-Ligand 1 (PD-L1) combined positive score (CPS) of 10 or more in China.MethodsBased on the advanced ESCC of the KEYNOTE-590 clinical trial data, a Markov model was performed to simulate the clinical course and evaluate the patient's total lifetime, total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) for pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil) vs. chemotherapy alone in first-line treatment of ESCC and PD-L1 CPS of 10 or more. Utility values and direct costs related to the treatments were gathered from the published literature data. One-way and probabilistic sensitivity analyses were conducted to check the stability of the model.ResultsThe baseline analysis indicated that the incremental effectiveness and cost of pembrolizumab plus chemotherapy vs. chemotherapy alone added 1.23 QALYs and resulted in an incremental cost of $51,320.22, which had an ICER of $41,805.12/QALY, higher than the willingness-to-pay (WTP) threshold of China ($37,663.26/QALY). The sensitivity analysis demonstrated that the ICERs were most sensitive to the cycle of pembrolizumab used and the cost of pembrolizumab.ConclusionThe result of our present analysis suggests that the addition of pembrolizumab plus chemotherapy as first-line treatment might not be cost-effective for patients with ESCC and PD-L1 CPS of 10 or more in China.

This study evaluated the cost-effectiveness of nivolumab plus chemotherapy (NC) or ipilimumabA partitioned survival model was constructed from the perspective of the US third-party payers and Chinese healthcare system. Health states and transition probabilities were modeled based on the survival data from the CheckMate-648 clinical trial (NCT03143153). The time horizon for the model was 10 years. Only direct medical costs were considered. One-way and probabilistic sensitivity analyses were conducted to assess the robustness of the results.In the United States, nivolumab plus ipilimumab (NI) led to an incremental cost-effectiveness ratio (ICER) of $155,159.82/quality-adjusted life year (QALY) and $104,297.07/QALY gained in the overall population and in patients with tumor cell programmed death-ligand 1 (PD-L1) expression of ⩾1% (subgroup), respectively. The ICER for the subgroup was between the willingness-to-pay (WTP) threshold values of $100,000/QALY and $150,000/QALY, and the other case was higher than $150,000/QALY. NC led to an ICER of $518,062.85/QALY and $193,169.49/QALY gained in the overall population and the subgroup, respectively. Both ICERs were significantly higher than the WTP threshold of $150,000/QALY. In China, the ICERs for patients treated with the addition of nivolumab were$90,000/QALY in all cases, significantly exceeding the WTP threshold of $37,654/QALY.NI is more cost-effective than NC or chemotherapy alone for treating advanced ESCC with PD-L1 expression ⩾1% in the United States. Chemotherapy alone is the only cost-effective option in China.

Cingulin, a cytoplasmic element of tight junctions (TJs), is involved in maintenance of the integrity of epithelial and endothelial cells. However, the role of cingulin in the development of auditory organs remains unclear. Zebrafish is popular as a model organism for hearing research. Using the whole mount in situ hybridization (WISH) experiment, we detected the expression of cingulin b in the posterior lateral line system (PLLs) of zebrafish. We traced the early development progress of zebrafish PLLs from 36 hpf to 72 hpf, and found that inhibition of cingulin b by target morpholinos resulted in severe developmental obstruction, including decreased number of neuromasts, reduced proliferative cells in the primordium, and repressed hair cell differentiation in the neuromasts. To examine the potential mechanism of cingulin b in the development of zebrafish PLL neuromasts, we performed RNA-seq analysis to compare the differently expressed genes (DEGs) between cingulin b knockdown samples and the controls. The KEGG enrichment analysis revealed that MAPK signaling pathway and cellular senescence were the key pathways with most DEGs in cingulin b-MO morphants compared to the Control-MO embryos. Furthermore, quantitative RT-PCR analysis confirmed the findings by RNA-seq that the transcript levels of cell cycle negative regulators such as tp53 and cdkn1a, were remarkably upregulated after inhibition of cingulin b. Our results therefore indicated an important role of cingulin b in the development of auditory organs, and MAPK signaling pathway was inhibited while cellular senescence pathway was activated after downregulation of cingulin b. We bring forward new insights of cingulin by exploring its function in auditory system.

Background Noise-induced hearing loss represents a commonly diagnosed type of hearing disability, severely impacting the quality of life of individuals. The current work is aimed at assessing the effects of DNA methylation on noise-induced hearing loss. Methods Blocking DNA methyltransferase 1 (DNMT1) activity with a selective inhibitor RG108 or silencing DNMT1 with siRNA was used in this study. Auditory brainstem responses were measured at baseline and 2 days after trauma in mice to assess auditory functions. Whole-mount immunofluorescent staining and confocal microcopy of mouse inner ear specimens were performed to analyze noise-induced damage in cochleae and the auditory nerve at 2 days after noise exposure. Results The results showed that noise exposure caused threshold elevation of auditory brainstem responses and cochlear hair cell loss. Whole-mount cochlea staining revealed a reduction in the density of auditory ribbon synapses between inner hair cells and spiral ganglion neurons. Inhibition of DNA methyltransferase activity via a non-nucleoside specific pharmacological inhibitor, RG108, or silencing of DNA methyltransferase-1 with siRNA significantly attenuated ABR threshold elevation, hair cell damage, and the loss of auditory synapses. Conclusions This study suggests that inhibition of DNMT1 ameliorates noise-induced hearing loss and indicates that DNMT1 may be a promising therapeutic target. Graphical abstract

To make a dual-direction silicon-controlled rectifier (SCR) that is highly robust in a high-voltage environment, a gate-controlled dual-direction SCR (GC-DDSCR) device is proposed. After analyzing the working principle of the device through the equivalent circuit and 2-D device simulation, the electro-static discharge (ESD) characteristics of the device are verified through the transmission line pulse (TLP) test. The failure current of the GC-DDSCR structure is greatly improved to 14.19 A compared with only 3.53 A of the same size traditional dual-direction SCR (TDDSCR) structure. The trigger voltage and the holding voltage of the GC-DDSCR are 24.23 and 20.15 V, respectively. In addition, this article explains the principle of GC-DDSCR devices with high protection capability. That is, because the device has a polysilicon gate electrode shorted to the anode (cathode), the electric field effect generated by the gate promotes carrier movement in the SCR path. Thus, the electric field force promotes the opening of the SCR path of the device and the direction of the electric field force is always consistent with the current direction. The overall failure capability of the device is effectively improved.