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Abstract N6‐methyladenosine (m6A) is the most abundant modification of RNA in eukaryotic cells. Previous studies have shown that m6A is pivotal in diverse diseases especially cancer. m6A corelates with the initiation, progression, resistance, invasion, and metastasis of cancer. However, despite these insights, a comprehensive understanding of its specific roles and mechanisms within the complex landscape of cancer is still elusive. This review begins by outlining the key regulatory proteins of m6A modification and their posttranslational modifications (PTMs), as well as the role in chromatin accessibility and transcriptional activity within cancer cells. Additionally, it highlights that m6A modifications impact cancer progression by modulating programmed cell death mechanisms and affecting the tumor microenvironment through various cancer‐associated immune cells. Furthermore, the review discusses how microorganisms can induce enduring epigenetic changes and oncogenic effect in microorganism‐associated cancers by altering m6A modifications. Last, it delves into the role of m6A modification in cancer immunotherapy, encompassing RNA therapy, immune checkpoint blockade, cytokine therapy, adoptive cell transfer therapy, and direct targeting of m6A regulators. Overall, this review clarifies the multifaceted role of m6A modification in cancer and explores targeted therapies aimed at manipulating m6A modification, aiming to advance cancer research and improve patient outcomes.

Abstract Determination of prognosis in the triage process after traumatic brain injury (TBI) is difficult to achieve. Current severity measures like the Trauma and injury severity score (TRISS) and revised trauma score (RTS) rely on additional information from the Glasgow Coma Scale (GCS) and the Injury Severity Score (ISS) which may be inaccurate or delayed, limiting their usefulness in the rapid triage setting. We hypothesized that machine learning based estimations of GCS and ISS obtained through modeling of continuous vital sign features could be used to rapidly derive an automated RTS and TRISS. We derived variables from electrocardiograms (ECG), photoplethysmography (PPG), and blood pressure using continuous data obtained in the first 15 min of admission to build machine learning models of GCS and ISS (ML-GCS and ML-ISS). We compared the TRISS and RTS using ML-ISS and ML-GCS and its value using the actual ISS and GCS in predicting in-hospital mortality. Models were tested in TBI with systemic injury (head abbreviated injury scale (AIS) ≥ 1), and isolated TBI (head AIS ≥ 1 and other AIS ≤ 1). The area under the receiver operating characteristic curve (AUROC) was used to evaluate model performance. A total of 21,077 cases (2009–2015) were in the training set. 6057 cases from 2016 to 2017 were used for testing, with 472 (7.8%) severe TBI (GCS 3–8), 223 (3.7%) moderate TBI (GCS 9–12), and 5913 (88.5%) mild TBI (GCS 13–15). In the TBI with systemic injury group, ML-TRISS had similar AUROC (0.963) to TRISS (0.965) in predicting mortality. ML-RTS had AUROC (0.823) and RTS had AUROC 0.928. In the isolated TBI group, ML-TRISS had AUROC 0.977, and TRISS had AUROC 0.983. ML-RTS had AUROC 0.790 and RTS had AUROC 0.957. Estimation of ISS and GCS from machine learning based modeling of vital sign features can be utilized to provide accurate assessments of the RTS and TRISS in a population of TBI patients. Automation of these scores could be utilized to enhance triage and resource allocation during the ultra-early phase of resuscitation.

Introduction Tinnitus is a prevalent and disabling condition characterized by the perception of sound in the absence of external acoustic stimuli. The hyperactivity of the auditory pathway is a crucial factor in the development of tinnitus. This study aims to examine genetic expression variations in the dorsal cochlear nucleus (DCN) and inferior colliculus (IC) following the onset of tinnitus using transcriptomic analysis. The goal is to investigate the relationship between hyperactivity in the DCN and IC.Methods To confirm the presence of tinnitus behavior, we utilized the gap pre-pulse inhibition of the acoustic startle (GPIAS) response paradigm. In addition, we conducted auditory brainstem response (ABR) tests to determine the baseline hearing thresholds, and repeated the test one week after subjecting the rats to noise exposure (8–16 kHz, 126 dBHL, 2 h). Samples of tissue were collected from the DCN and IC in both the tinnitus and non-tinnitus groups of rats. We employed RNA sequencing and quantitative PCR techniques to analyze the changes in gene expression between these two groups. This allowed us to identify any specific genes or gene pathways that may be associated with the development or maintenance of tinnitus in the DCN and IC.Results Our results demonstrated tinnitus-like behavior in rats exposed to noise, as evidenced by GPIAS measurements. We identified 61 upregulated genes and 189 downregulated genes in the DCN, along with 396 upregulated genes and 195 downregulated genes in the IC. Enrichment analysis of the DCN revealed the involvement of ion transmembrane transport regulation, synaptic transmission, and negative regulation of neuron apoptotic processes in the development of tinnitus. In the IC, the enrichment analysis indicated that glutamatergic synapses and neuroactive ligand-receptor interaction pathways may significantly contribute to the process of tinnitus development. Additionally, protein-protein interaction (PPI) networks were constructed, and 9 hub genes were selected based on their betweenness centrality rank in the DCN and IC, respectively.Conclusions Our findings reveal enrichment of differential expressed genes (DEGs) associated with pathways linked to alterations in neuronal excitability within the DCN and IC when comparing the tinnitus group to the non-tinnitus group. This indicates an increased trend in neuronal excitability within both the DCN and IC in the tinnitus model rats. Additionally, the enriched signaling pathways within the DCN related to changes in synaptic plasticity suggest that the excitability changes may propagate to IC.New and Noteworthy Our findings reveal gene expression alterations in neuronal excitability within the DCN and IC when comparing the tinnitus group to the non-tinnitus group at the transcriptome level. Additionally, the enriched signaling pathways related to changes in synaptic plasticity in the differentially expressed genes within the DCN suggest that the excitability changes may propagate to IC.

Gut microbiota dysbiosis is involved in cholestatic liver diseases. However, the mechanisms remain to be elucidated. The purpose of this study was to examine the effects and mechanisms of Lactobacillus acidophilus (L. acidophilus) on cholestatic liver injury in both animals and humans. Bile duct ligation (BDL) was performed to mimic cholestatic liver injury in mice and serum liver function was tested. Gut microbiota were analyzed by 16S rRNA sequencing. Fecal bacteria transplantation (FMT) was used to evaluate the role of gut microbiota in cholestasis. Bile acids (BAs) profiles were analyzed by targeted metabolomics. Effects of L. acidophilus in cholestatic patients were evaluated by a randomized controlled clinical trial (NO: ChiCTR2200063330). BDL induced different severity of liver injury, which was associated with gut microbiota. 16S rRNA sequencing of feces confirmed the gut flora differences between groups, of which L. acidophilus was the most distinguished genus. Administration of L. acidophilus after BDL significantly attenuated hepatic injury in mice, decreased liver total BAs and increased fecal total BAs. Furthermore, after L. acidophilus treatment, inhibition of hepatic Cholesterol 7α-hydroxylase (CYP7α1), restored ileum Fibroblast growth factor 15 (FGF15) and Small heterodimer partner (SHP) accounted for BAs synthesis decrease, whereas enhanced BAs excretion was attributed to the increase of unconjugated BAs by enriched bile salt hydrolase (BSH) enzymes in feces. Similarly, in cholestasis patients, supplementation of L. acidophilus promoted the recovery of liver function and negatively correlated with liver function indicators, possibly in relationship with the changes in BAs profiles and gut microbiota composition. L. acidophilus treatment ameliorates cholestatic liver injury through inhibited hepatic BAs synthesis and enhances fecal BAs excretion.

Triptolide (TP) is the principal bioactive compound of Tripterygium wilfordii with significant anti-tumor, anti-inflammatory and immunosuppressive activities. However, its severe hepatotoxicity greatly limits its clinical use. The underlying mechanism of TP-induced liver damage is still poorly understood. Here, we estimate the role of the gut microbiota in TP hepatotoxicity and investigate the bile acid metabolism mechanisms involved. The results of the antibiotic cocktail (ABX) and fecal microbiota transplantation (FMT) experiment demonstrate the involvement of intestinal flora in TP hepatotoxicity. Moreover, TP treatment significantly perturbed gut microbial composition and reduced the relative abundances of Lactobacillus rhamnosus GG (LGG). Supplementation with LGG reversed TP-induced hepatotoxicity by increasing bile salt hydrolase (BSH) activity and reducing the increased conjugated bile acids (BA). LGG supplementation upregulates hepatic FXR expression and inhibits NLRP3 inflammasome activation in TP-treated mice. In summary, this study found that gut microbiota is involved in TP hepatotoxicity. LGG supplementation protects mice against TP-induced liver damage. The underlying mechanism was associated with the gut microbiota-BA-FXR axis. Therefore, LGG holds the potential to prevent and treat TP hepatotoxicity in the clinic.

Abstract Nature presents the most beautiful patterns through evolving. Here, a layered porous pattern in golden ratio (0.618) is reported from a type of mushroom ‐Dictyophora Rubrovalvata stipe (DRS). The hierarchical structure shows a mathematical correlation with the golden ratio. This unique structure leads to superior mechanical properties. The gradient porous structure from outside to innermost endows it with asymmetrical hydrophilicity. A mathematical model is then developed to predict and apply to 3D printed structures. The mushroom is then explored to repair gastric perforation because the stomach is a continuous peristaltic organ, and the perforated site is subject to repeated mechanical movements and pressure changes. At present, endoscopic clipping is ineffective in treating ulcerative perforation with fragile surrounding tissues. Although endoscopic implant occlusion provides a new direction for the treatment of gastric ulcers, but the metal or plastic occluder needs to be removed, requiring a second intervention. Decellularized DRS (DDRS) is found with asymmetric water absorption rate, super‐compressive elasticity, shape memory, and biocompatibility, making it a suitable occluder for the gastric perforation. The efficacy in blocking gastric perforation and promoting healing is confirmed by endoscopic observation and tissue analysis during a 2‐month study.

Abstract Background Interindividual variation characterizes the relief experienced by constipation-predominant irritable bowel syndrome (IBS-C) patients following linaclotide treatment. Complex bidirectional interactions occur between the gut microbiota and various clinical drugs. To date, no established evidence has elucidated the interactions between the gut microbiota and linaclotide. We aimed to explore the impact of linaclotide on the gut microbiota and identify critical bacterial genera that might participate in linaclotide efficacy. Methods IBS-C patients were administered a daily linaclotide dose of 290 µg over six weeks, and their symptoms were then recorded during a four-week posttreatment observational period. Pre- and posttreatment fecal samples were collected for 16S rRNA sequencing to assess alterations in the gut microbiota composition. Additionally, targeted metabolomics analysis was performed for the measurement of short-chain fatty acid (SCFA) concentrations. Results Approximately 43.3% of patients met the FDA responder endpoint after taking linaclotide for 6 weeks, and 85% of patients reported some relief from abdominal pain and constipation. Linaclotide considerably modified the gut microbiome and SCFA metabolism. Notably, the higher efficacy of linaclotide was associated with enrichment of the Blautia genus, and the abundance of Blautia after linaclotide treatment was higher than that in healthy volunteers. Intriguingly, a positive correlation was found for the Blautia abundance and SCFA concentrations with improvements in clinical symptoms among IBS-C patients. Conclusion The gut microbiota, especially the genus Blautia, may serve as a significant predictive microbe for symptom relief in IBS-C patients receiving linaclotide treatment. Trial registration: This trial was registered with the Chinese Clinical Trial Registry (Chictr.org.cn, ChiCTR1900027934).

Abstract Hereditary deafness is a common neurosensory disorder, and 148 non‐syndromic deafness genes have been identified to date. Gene therapy has been used to treat a variety of genetic diseases, but no gene therapy drug for hereditary deafness has been approved for clinical use. At present, several clinical trials of gene therapy for hereditary deafness are underway. However, few normative documents have been issued to guide the standardization of gene therapy for hearing loss, and this document is the first global gene therapy guideline for hereditary hearing loss. The guidelines were jointly developed and drafted by experienced audiologists, virologists and biologists who are vigorously involved in inner ear gene therapy research in the Hearing, Speech and Communication Subsociety of Biophysical Society of China, Audiology Development Foundation Of China and Audiology Subsociety of Jiangsu Medical Association. These guidelines cover preclinical research and clinical practice of gene therapy for hereditary deafness, including indications, key points of pre‐clinical research, patient selection criteria, pre‐clinical preparation, drug efficacy, drug safety evaluation criteria, ethical review, etc. We hope that the guidelines will promote the standardization of clinical practice related to gene therapy for hereditary deafness in China and around the world.

Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction. However, there are currently no effective pharmacological interventions for patients with noise-induced hearing loss. Here, we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss, and elucidate its underlying regulatory mechanisms. We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 dB for 4 hours. We found that tranylcypromine treatment led to the upregulation of Sestrin2 (SESN2) and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine. The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click, 4, 8, and 16 kHz frequencies compared with the noise exposure group treated with saline. These findings indicate that tranylcypromine treatment resulted in increased SESN2, light chain 3B, and lysosome-associated membrane glycoprotein 1 expression after noise exposure, leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3, thereby reducing noise-induced hair cell loss. Additionally, immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway. Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domain-containing 3 (NLRP3) production. In conclusion, our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2, which induced autophagy, thereby restricting NLRP3-related inflammasome signaling, alleviating cochlear hair cell loss, and protecting hearing function. These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.

Abstract Peutz–Jeghers Syndromeis a rare autosomal dominant genetic disease characterized by gastrointestinal hamartomatous polyps and skin and mucous membrane pigmentation. The pathogenesis of PJS remains unclear; however, it may be associated with mutations in the STK11 gene, and there is currently no effective treatment available. The gut microbiota plays an important role in maintaining intestinal homeostasis in the human body, and an increasing number of studies have reported a relationship between gut microbiota and human health and disease. However, relatively few studies have been conducted on the gut microbiota characteristics of patients with PJS. In this study, we analyzed the characteristics of the gut microbiota of 79 patients with PJS using 16 S sequencing and measured the levels of short-chain fatty acids in the intestines. The results showed dysbiosis in the gut microbiota of patients with PJS, and decreased synthesis of short-chain fatty acids. Bacteroides was positively correlated with maximum polyp length, while Agathobacter was negatively correlated with age of onset. In addition, acetic acid, propionic acid, and butyric acid were positively correlated with the age of onset but negatively correlated with the number of polyps. Furthermore, the butyric acid level was negatively correlated with the frequency of endoscopic surgeries. In contrast, we compared the gut microbiota of STK11-positive and STK11-negative patients with PJS for the first time, but 16 S sequencing analysis revealed no significant differences. Finally, we established a random forest prediction model based on the gut microbiota characteristics of patients to provide a basis for the targeted diagnosis and treatment of PJS in the future.

Abstract Background Iatrogenic facial nerve injury is one of the severest complications of middle ear surgery, this study aims to evaluate surgical management and prognosis in the era of improved surgical instruments. Methods Patients suffered from facial nerve paralysis after middle ear surgery between January 2000 and December 2019 were retrospectively collected. Demographic characters, primary disease and surgery, details of revision surgery were analyzed. Results Forty-five patients were collected, of whom 8 were injured at our center and 37 were transferred. For 8 patients injured at our center, seven (87.5%) ranked House-Brackmann (H-B) grade V and one (12.5%) ranked H-B VI before revision surgery; postoperatively, two (25.0%) patients recovered to H-B grade I, four (50.0%) recovered to H-B II, and the other two (25.0%) recovered to H-B III. For 37 patients transferred, thirteen (35.1%) ranked H-B grade V and 24 (64.9%) ranked H-B VI preoperatively, final postoperative grade ranked from H-B grade I to grade V, with H-B I 6 (16.2%) cases, H-B II 6 (16.2%) cases, H-B III 18 (48.6%) cases, H-B IV 5 (13.5%) cases and H-B V 2 (5.4%) cases. The most vulnerable site was tympanic segment (5, 62.5% and 27, 73.0% respectively). Twenty-one (46.7%) patients suffered from mild injury and 24 (53.3%) suffered from partial or complete nerve transection. For surgical management, twenty-one (46.7%) patients received decompression, nineteen (42.2%) received graft and 5 (11.1%) received anastomosis. Those decompressed within 2 months after paralysis had higher possibility of H-B grade I or II recovery (P = 0.026), those received graft within 6 months were more likely to get H-B grade III recovery (P = 0.041), and for patients underwent anastomosis within 6 months, all recovered to H-B grade III. Conclusions Tympanic segment is the vulnerable site. If facial nerve paralysis happens, high-resolution computed tomography could help identify the injured site. Timely treatment is important, decompression within 2 months after paralysis, graft and anastomosis within 6 months lead to better recovery.

Abstract Introduction Hepatocellular carcinoma (HCC) is one of the most serious cancers. Circular RNA (circRNA) has been reported to regulate the progression of HCC. Herein, the role of circ_0102543 in HCC tumorigenesis was investigated. Materials The expression levels of circ_0102543, microRNA‐942‐5p (miR‐942‐5p), and small glutamine rich tetratricopeptide repeat co‐chaperone beta (SGTB) were detected by quantitative real‐time PCR (qRT‐PCR). 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium Bromide (MTT) assay, thymidine analog 5‐ethynyl‐2'‐deoxyuridine (EDU) assay, transwell assay, and flow cytometry were conducted to explore the function of circ_0102543 in HCC cells and the regulatory mechanism among circ_0102543, miR‐942‐5p and SGTB in HCC cells. Western blot examined the related protein levels. Results The expression of circ_0102543 and SGTB was decreased in HCC tissues, while the expression of miR‐942‐5p was increased. Circ_0102543 acted as a sponge for miR‐942‐5p, and SGTB was the target of miR‐942‐5p. Circ_0102543 up‐regulation hindered tumor growth in vivo. In vitro experiments showed that overexpression of circ_0102543 significantly repressed the malignant behaviors of HCC cells, while co‐transfection of miR‐942‐5p partially attenuated these effects mediated by circ_0102543. In addition, SGTB knockdown increased the proliferation, migration, and invasion of HCC cells inhibited by miR‐942‐5p inhibitor. Mechanically, circ_0102543 regulated SGTB expression in HCC cells by sponging miR‐942‐5p. Conclusion Overexpression of circ_0102543 suppressed proliferation, migration, and invasion of HCC cells by regulating the miR‐942‐5p/SGTB axis, suggesting that circ_0102543/miR‐942‐5p/SGTB axis may be a potential therapeutic target for HCC.

Abstract Metastasis is the leading cause of death in hepatocellular carcinoma (HCC) patients, and autophagy plays a crucial role in this process by orchestrating epithelial–mesenchymal transition (EMT). Stromal interaction molecule 1 (STIM1), a central regulator of store‐operated calcium entry (SOCE) in nonexcitable cells, is involved in the development and spread of HCC. However, the impact of STIM1 on autophagy regulation during HCC metastasis remains unclear. Here, we demonstrate that STIM1 is temporally regulated during autophagy‐induced EMT in HCC cells, and knocking out (KO) STIM1 significantly reduces both autophagy and EMT. Interestingly, STIM1 enhances autophagy through both SOCE‐dependent and independent pathways. Mechanistically, STIM1 directly interacts with microtubule‐associated protein 1A/1B‐light chain 3B (LC3B) to form a complex via the sterile‐α motif (SAM) domain, which promotes autophagosome formation. Furthermore, deletion of the SAM domain of STIM1 abolishes its binding with LC3B, leading to a decrease in autophagy and EMT in HCC cells. These findings unveil a novel mechanism by which the STIM1/LC3B complex mediates autophagy and EMT in HCC cells, highlighting a potential target for preventing HCC metastasis.

Summary: The efficacy of COVID-19 vaccination relies on the induction of neutralizing antibodies, which can vary among vaccine recipients. In this study, we investigated the potential factors affecting the neutralizing antibody response by combining plasma and urine proteomics and gut microbiota analysis. We found that activation of the LXR/FXR pathway in plasma was associated with the production of ACE2-RBD-inhibiting antibodies, while urine proteins related to complement system, acute phase response signaling, LXR/FXR, and STAT3 pathways were correlated with neutralizing antibody production. Moreover, we observed a correlation between the gut microbiota and plasma and urine proteins, as well as the vaccination response. Based on the above data, we built a predictive model for vaccination response (AUC = 0.85). Our study provides insights into characteristic plasma and urine proteins and gut microbiota associated with the ACE2-RBD-inhibiting antibodies, which could benefit our understanding of the host response to COVID-19 vaccination.

Tinnitus is a phantom auditory sensation often accompanied by hearing loss, cognitive impairments, and psychological disturbances in various populations. Dysfunction of KCNQ2 and KCNQ3 channels—voltage-dependent potassium ion channels—in the cochlear nucleus can cause tinnitus. Despite the recognized significance of KCNQ2 and KCNQ3 channels in the auditory cortex, their precise relationship and implications in the pathogenesis of tinnitus remain areas of scientific inquiry. This study aimed to elucidate the pathological roles of KCNQ2 and KCNQ3 channels within the auditory cortex in tinnitus development and examine the therapeutic potential of mid-infrared photons for tinnitus treatment. We utilized a noise-induced tinnitus model combined with immunofluorescence, electrophysiological recording, and molecular dynamic simulation to investigate the morphological and physiological alterations after inducing tinnitus. Moreover, in vivo irradiation was administered to verify the treatment effects of infrared photons. Tinnitus was verified by deficits of the gap ratio with similar prepulse inhibition ratio and auditory brainstem response threshold. We observed an important enhancement in neuronal excitability in the auditory cortex using patch-clamp recordings, which correlated with KCNQ2 and KCNQ3 channel dysfunction. After irradiation with infrared photons, excitatory neuron firing was inhibited owing to increased KCNQ2 current resulting from structural alterations in the filter region. Meanwhile, deficits of the acoustic startle response in tinnitus animals were alleviated by infrared photons. Furthermore, infrared photons reversed the abnormal hyperexcitability of excitatory neurons in the tinnitus group. This study provided a novel method for modulating neuron excitability in the auditory cortex using KCNQ2 channels through a nonthermal effect. Infrared photons effectively mitigated tinnitus-related behaviors by suppressing abnormal neural excitability, potentially laying the groundwork for innovative therapeutic approaches for tinnitus treatment.

BackgroundClinicians working in intensive care units (ICUs) are immersed in a cacophony of alarms and a relentless onslaught of data. Within this frenetic environment, clinicians make high-stakes decisions using many data sources and are often oversaturated with information of varying quality. Traditional bedside monitors only depict static vital signs data, and these data are not easily viewable remotely. Clinicians must rely on separate nursing charts—handwritten or electric—to review physiological patterns, including signs of potential clinical deterioration. An automated physiological data viewer has been developed to provide at-a-glance summaries and to assist with prioritizing care for multiple patients who are critically ill. ObjectiveThis study aims to evaluate a novel vital signs viewer system in a level 1 trauma center by subjectively assessing the viewer’s utility in a high-volume ICU setting. MethodsICU attendings were surveyed during morning rounds. Physicians were asked to conduct rounds normally, using data reported from nurse charts and briefs from fellows to inform their clinical decisions. After the physician finished their assessment and plan for the patient, they were asked to complete a questionnaire. Following completion of the questionnaire, the viewer was presented to ICU physicians on a tablet personal computer that displayed the patient’s physiologic data (ie, shock index, blood pressure, heart rate, temperature, respiratory rate, and pulse oximetry), summarized for up to 72 hours. After examining the viewer, ICU physicians completed a postview questionnaire. In both questionnaires, the physicians were asked questions regarding the patient’s stability, status, and need for a higher or lower level of care. A hierarchical clustering analysis was used to group participating ICU physicians and assess their general reception of the viewer. ResultsA total of 908 anonymous surveys were collected from 28 ICU physicians from February 2015 to June 2017. Regarding physicians’ perception of whether the viewer enhanced the ability to assess multiple patients in the ICU, 5% (45/908) strongly agreed, 56.6% (514/908) agreed, 35.3% (321/908) were neutral, 2.9% (26/908) disagreed, and 0.2% (2/908) strongly disagreed. ConclusionsMorning rounds in a trauma center ICU are conducted in a busy environment with many data sources. This study demonstrates that organized physiologic data and visual assessment can improve situation awareness, assist clinicians with recognizing changes in patient status, and prioritize care.

M6A is essential for tumor occurrence and progression. The expression patterns of m6A regulators differ in various kinds of tumors. Transcriptomic expression statistics together with clinical data from a database were analyzed to distinguish patients with digestive tract tumors. Based on the expression patterns of diverse m6A regulators, patients were divided into several clusters. Survival analysis suggested significant differences in patient prognosis among the m6A clusters. The results showed overlapping of m6A expression patterns with energy metabolism and nucleotide metabolism. Functional analyses imply that m6A modifications in tumor cells probably drive metabolic reprogramming to sustain rapid proliferation of cancer cells. Our analysis highlights the m6A risk characterizes various kinds of metabolic features and predicts chemotherapy sensitivity in digestive tract tumors, providing evidence for m6A regulators as markers to predict patient outcomes.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disease that sometimes develops during pregnancy and is characterized by increased serum bile acid levels. Here the authors report that the gut microbiome species B. fragilis is enriched in patients with ICP and promotes ICP development in mice via inhibition of signalling though the bile acid receptor FXR.

Abstract Common biliary tract is ≈4 mm in diameter to deliver bile from liver to small intestine to help digestion. The abnormal narrowing leads to severe symptoms such as pain and nausea. Stents are an effective treatment. Compared with non‐degradable stents which require repeated removal, biodegradable stents have the advantage of reducing secondary injury related to endoscopic operation and patient burden. However, current biodegradable materials may cause tissue hyperplasia and the treatment method does not target etiology of stricture. So recurrence rates after biodegradable stent implantation are still high. Here, a biodegradable helical stent fabricated from biosynthetic P(3HB‐co‐4HB) is reported. Tunable properties can be acquired through altering culture substrates. Stent shows shape memory in various solvents. The stent has an optimized design with helical structure and outer track. The self‐expanding of helical structure and double drainage realized by outer track greatly improve drainage of bile. Importantly, stent‐loading triamcinolone acetonide can inhibit proliferation of fibroblasts and reduce incidence of restricture. Therapeutic effect is also demonstrated in minipigs with biliary stricture. The results of minipig experiments show that biliary duct in treatment group is unobstructed and tissue hyperplasia is effectively inhibited.

Abstract Secondary neurologic decline (ND) after traumatic brain injury (TBI) is independently associated with outcome, but robust predictors of ND are lacking. In this retrospective analysis of consecutive isolated TBI admissions to the R. Adams Cowley Shock Trauma Center between November 2015 and June 2018, we aimed to develop a triage decision support tool to quantify risk for early ND. Three machine learning models based on clinical, physiologic, or combined characteristics from the first hour of hospital resuscitation were created. Among 905 TBI cases, 165 (18%) experienced one or more ND events (130 clinical, 51 neurosurgical, and 54 radiographic) within 48 h of presentation. In the prediction of ND, the clinical plus physiologic data model performed similarly to the physiologic only model, with concordance indices of 0.85 (0.824–0.877) and 0.84 (0.812–0.868), respectively. Both outperformed the clinical only model, which had a concordance index of 0.72 (0.688–0.759). This preliminary work suggests that a data-driven approach utilizing physiologic and basic clinical data from the first hour of resuscitation after TBI has the potential to serve as a decision support tool for clinicians seeking to identify patients at high or low risk for ND.

Abstract Introduction With the spread of the epidemic worldwide, an increasing number of doctors abroad have observed the following atypical symptoms of coronavirus disease 2019 (COVID‐19): olfactory or taste disorders. Therefore, clarifying the incidence and clinical characteristics of olfactory and taste disorders in Chinese COVID‐19 patients is of great significance and urgency. Materials and Methods A retrospective study was conducted, which included 229 severe acute respiratory syndrome coronavirus 2 confirmed patients, through face‐to‐face interviews and telephone follow‐up. Following the completion of questionnaires, the patients participating in the study, were categorized according to the degree of olfactory and taste disorders experienced, and the proportion of each clinical type of patient with olfactory and taste disorders and the time when symptoms appeared were recorded. Results Among the 229 patients, 31 (13.54%) had olfactory dysfunction, and 44 (19.21%) had gustatory dysfunction. For the patients with olfactory dysfunction, 6 (19.35%) developed severe disease and became critically ill. Olfactory dysfunction appeared before the other symptoms in 21.43% of cases. The proportion of females with olfactory and gustatory dysfunction was higher than that of males (P

Abstract Background Wound closure in the complex body environment places higher requirements on suture’s mechanical and biological performance. In the scenario of frequent mechanical gastric motility and extremely low pH, single functional sutures have limitations in dealing with stomach bleeding trauma where the normal healing will get deteriorated in acid. It necessitates to advance suture, which can regulate wounds, resist acid and intelligently sense stomach pH. Methods Based on fish swim bladder, a double-stranded drug-loaded suture was fabricated. Its cytotoxicity, histocompatibility, mechanical properties, acid resistance and multiple functions were verified. Also, suture’s performance suturing gastric wounds and Achilles tendon was verified in an in vivo model. Results By investigating the swim bladder’s multi-scale structure, the aligned tough collagen fibrous membrane can resist high hydrostatic pressure. We report that the multi-functional sutures on the twisted and aligned collagen fibers have acid resistance and low tissue reaction. Working with an implantable “capsule robot”, the smart suture can inhibit gastric acid secretion, curb the prolonged stomach bleeding and monitor real-time pH changes in rabbits and pigs. The suture can promote stomach healing and is strong enough to stitch the fractured Achilles tendon. Conclusions As a drug-loaded absorbable suture, the suture shows excellent performance and good application prospect in clinical work.

Nonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, the authors show that disulfiram (DSF) reduces Clostridium-mediated 7α-dehydroxylation activity to suppress secondary bile acid biosynthesis and ameliorate NASH in mice, and validate DSF regulation of the gut-liver axis in healthy men in a self-controlled clinical trial.

Abstract Metastasis is the dominant cause of cancer-related mortality. Metastasis-associated with colon cancer protein 1 (MACC1) has been proven to play a critical role in cancer metastasis. However, the prometastatic role of MACC1 in regulating the pancreatic cancer (PC) metastatic phenotype remains elusive. Here, we report that MACC1 is highly expressed in The Cancer Genome Atlas (TCGA) and tissue microarray (TMA) and identified as a good indicator for poor prognosis. Overexpression or knockdown of MACC1 in PC cells correspondingly promoted or inhibited pancreatic cancer cell migration and invasion in a MET proto-oncogene receptor tyrosine kinase (MET)-independent manner. Notably, knockdown of MACC1 in PC cells markedly decreased the liver metastatic lesions in a liver metastasis model. Mechanistically, MACC1 binds to the epithelial-mesenchymal transition (EMT) regulator snail family transcriptional repressor 1 (SNAI1) to drive EMT via upregulating the transcriptional activity of SNAI1, leading to the transactivation of fibronectin 1 (FN1) and the trans-repression of cadherin 1 (CDH1). Collectively, our results unveil a new mechanism by which MACC1 drives pancreatic cancer cell metastasis and suggest that the MACC1-SNAI1 complex-mediated mesenchymal transition may be a therapeutic target in pancreatic cancer.

Forkhead box M1 (FOXM1) plays a critical role in development physiologically and tumorigenesis pathologically. However, insufficient efforts have been dedicated to exploring the regulation, in particular the degradation of FOXM1. Here, the ON-TARGETplus siRNA library targeting E3 ligases was used to screen potential candidates to repress FOXM1. Of note, mechanism study revealed that RNF112 directly ubiquitinates FOXM1 in gastric cancer, resulting in a decreased FOXM1 transcriptional network and suppressing the proliferation and invasion of gastric cancer. Interestingly, the well-established small-molecule compound RCM-1 significantly enhanced the interaction between RNF112 and FOXM1, which further promoted FOXM1 ubiquitination and subsequently exerted promising anticancer effects in vitro and in vivo. Altogether, we demonstrate that RNF112 suppresses gastric cancer progression by ubiquitinating FOXM1 and highlight the RNF112/FOXM1 axis serves as both prognosis biomarker and therapeutic target in gastric cancer.

Abstract Background Well-balanced interactions between gut microbiota and the immune system are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). Toll-like receptor 4 (TLR4) functions as a sensor mediating the crosstalk between the intestinal commensal microbiome and host immunity, but the influence of TLR4 on the shaping of intestinal microbiota and immune responses during colon inflammation remains poorly characterized. We investigated whether the different susceptibilities to colitis between wild-type (WT) and TLR4−/− mice were gut microbiota-dependent and aimed to identify the potential immunity modulation mechanism. Methods We performed antibiotic depletion of the microbiota, cohousing experiments, and faecal microbiota transplantation (FMT) in WT and TLR4−/− mice to assess the influence of TLR4 on intestinal microbial ecology. 16S rRNA sequencing was performed to dissect microbial discrepancies, and dysbiosis-associated immune perturbation was investigated by flow cytometry. Akkermansia muciniphila (A. muciniphila)-mediated immune modulation was confirmed through the T-cell transfer colitis model and bone marrow chimaera construction. Results TLR4−/− mice experienced enhanced susceptibility to DSS-induced colitis. 16S rRNA sequencing showed notable discrepancy in the gut microbiota between WT and TLR4−/− mice. In particular, A. muciniphila contributed most to distinguishing the two groups. The T-cell transfer colitis model and bone marrow transplantation (BMT) consistently demonstrated that A. muciniphila ameliorated colitis by upregulating RORγt+ Treg cell-mediated immune responses. Mucosal biopsies from human manifested parallel outcomes with colon tissue from WT mice, as evidenced by the positive correlation between TLR4 expression and intestinal A. muciniphila colonization during homeostasis. Conclusions Our results demonstrate a novel protective role of TLR4 against intestinal inflammation, wherein it can modulate A. muciniphila-associated immune responses. These findings provide a new perspective on host-commensal symbiosis, which may be beneficial for developing potential therapeutic strategies. Video abstract. Graphical Abstract

Abstract Inner ear disorders are a cluster of diseases that cause hearing loss in more than 1.5 billion people worldwide. However, the presence of the blood-labyrinth barrier (BLB) on the surface of the inner ear capillaries greatly hinders the effectiveness of systemic drugs for prevention and intervention due to the low permeability, which restricts the entry of most drug compounds from the bloodstream into the inner ear tissue. Here, we report the finding of a novel receptor, low-density lipoprotein receptor-related protein 1 (LRP1), that is expressed on the BLB, as a potential target for shuttling therapeutics across this barrier. As a proof-of-concept, we developed an LRP1-binding peptide, IETP2, and covalently conjugated a series of model small-molecule compounds to it, including potential drugs and imaging agents. All compounds were successfully delivered into the inner ear and inner ear lymph, indicating that targeting the receptor LRP1 is a promising strategy to enhance the permeability of the BLB. The discovery of the receptor LRP1 will illuminate developing strategies for crossing the BLB and for improving systemic drug delivery for inner ear disorders.

Tinnitus is closely associated with cognition functioning. In order to clarify the central reorganization of tinnitus in patients with vestibular schwannoma (VS), this study explored the aberrant dynamics of electroencephalogram (EEG) microstates and their correlations with tinnitus features in VS patients. Clinical and EEG data were collected from 98 VS patients, including 76 with tinnitus and 22 without tinnitus. Microstates were clustered into four categories. Our EEG microstate analysis revealed that VS patients with tinnitus exhibited an increased frequency of microstate C compared to those without tinnitus. Furthermore, correlation analysis demonstrated that the Tinnitus Handicap Inventory (THI) score was negatively associated with the duration of microstate A and positively associated with the frequency of microstate C. These findings suggest that the time series and syntax characteristics of EEG microstates differ significantly between VS patients with and without tinnitus, potentially reflecting abnormal allocation of neural resources and transition of functional brain activity. Our results provide a foundation for developing diverse treatments for tinnitus in VS patients.

Aiming at the difficulty in identifying early faults and compound faults of gearboxes under strong noise background，a method of extracting fault features based on the combination of improved symplectic geometry mode decomposition （ISGMD） and minimum entropy deconvolution （MED） is proposed. Firstly，the signal is preprocessed by minimum entropy deconvolution to highlight the fault impact component in the signal. Then，the fault enhancement signal is adaptively decomposed into several symplectic geometric components through improved symplectic geometric modal decomposition，and the sensitive symplectic geometric component with the largest kurtosis value is selected according to the maximum kurtosis criterion. Finally，an envelope analysis of the selected sensitive symplectic geometric components can effectively extract the fault features of the gearbox. The effectiveness of the method is verified by experimental.

Abstract Background Gastric cancer (GC) is one of the most pernicious tumors that seriously harm human healthcare. GC metastasis is one of the prime cause of failed cancer treatment, but correlation between N6-methyladenosine (m6A) and GC metastasis was less reported. Methods Methylated RNA immunoprecipitation sequencing (MeRIP-seq) of GC tissues was conducted. Quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry (IHC) were taken to determine the expression of ALKBH5 in GC tissues and cell lines. RNA-seq together with MeRIP-qRT-PCR was used to screen the target gene of ALKBH5. RNA pulldown, mass spectrometry and RNA immunoprecipitation (RIP) were used to search the “reader” protein of target gene. The mechanism was also validated via a tail vein injection method for lung metastasis model. Results Decreased expression of ALKBH5 was detected in GC samples, and it was correlated with clinical tumor distal metastasis and lymph node metastasis. ALKBH5 interference promoted metastasis of GC cells and this effect was closely related to the demethylase activity of ALKBH5. PKMYT1, as a downstream target of ALKBH5, promoted invasion and migration in GC. Caused by ALKBH5 knockdown or its demethylase activity mutation, upregulated expression of PKMYT1 indicated that ALKBH5 modulates expression of PKMYT1 in an m6A-dependent manner. IGF2BP3 helped stabilize the mRNA stability of PKMYT1 via its m6A modification site. Conclusions This study established an ALKBH5-PKMYT1-IGF2BP3 regulation system in metastasis, representing a new therapeutic target for GC metastasis.

Abstract With the development of blue laser endoscopy (BLE) technique, it's often used to diagnose early gastric cancer (EGC) by the morphological changes of blood vessels through BLE. However, EGC is still not obvious to identify, resulting in a high rate of missed diagnosis. Molecular imaging can show the changes in early tumors at molecular level, which provides a possibility for diagnosing EGC. Therefore, developing a probe that visually monitors blood vessels of EGC under BLE is particularly necessary. Herein, a bis‐pyrene (BP) based nanoprobe (BP‐FFVLK‐(PEG)‐RGD, M1) is designed, which can target angiogenesis and self‐assemble into fibers in situ, resulting in stable and long‐term retention in tumor. Moreover, M1 probe can emit yellow‐green fluorescence for imaging under BLE. M1 probe is confirmed to steadily remain in tumor for up to 96 hours in mice transplanted subcutaneously. In addition, the M1 probe is able to target angiogenesis for molecular imaging of isolated human gastric cancer tissue under BLE. Finally, M1 probe i.v. injected into primary gastric cancer model rabbits successfully highlighted the tumor site under BLE, which is confirmed by pathological analysis. It's the first time to develop a probe for diagnosing EGC by visualizing angiogenesis under BLE, showing great clinical significance.

Aiming at the safety problem of grip force of the different surgical instruments with the same opening & closing angle in minimally invasive surgical robot，which is controlled by using the same master manipulator，the end-effector grip force of the surgical instrument is studied，a mathematical model is established to solve the end-effector grip force. The influences of the nonlinear friction among the steel cable and the guide pulleys，the motion coupling between the finger and wrist joints，and the creep deformation of the steel cable on the guide pulleys on the grip force are considered in the model. The mapping relationship between the motor current and the end-effector grip force under the corresponding opening & closing angle is obtained. At the same time，the grip force of the clamping suture needle is analyzed，and the relationships of the grip force and the motor current，and the pulling force of the suture needle and the motor current are obtained. The grip force model is simulated and researched by Matlab，the curves of the grip forces with/without friction and creep deformation，and the grip force and the pulling force of the suture needle are especially given. The simulation results show that the mathematical model of the grip force is closer to the actual situation，which provides a theoretical basis for effective and safe grip force control in future.

Subjective tinnitus is the most common type of tinnitus, which is the manifestation of pathological activities in the brain. It happens in a substantial portion of the general population and brings significant burden to the society. Severe subjective tinnitus can lead to depression and insomnia and severely affects patients’ quality of life. However, due to poor understanding of its etiology and pathogenesis, treatment of subjective tinnitus remains challenging. In recent decades, a growing number of studies have shown that subjective tinnitus is related to lesion-induced neural plasticity of auditory and non-auditory central systems. This article reviews cellular mechanisms of neural plasticity in subjective tinnitus to provide further understanding of its pathogenesis.

Heparanase is highly implicated in tumor metastasis due to its capacity to cleave heparan sulfate and, consequently, remodel the extracellular matrix underlying epithelial and endothelial cells. In striking contrast, only little attention was given to its close homolog, heparanase 2 (Hpa2), possibly because it lacks heparan sulfate-degrading activity typical of heparanase. We subjected sections of gastric carcinoma to immunostaining and correlated Hpa2 immunoreactivity with clinical records, including tumor grade, stage and patients' status. We over-expressed Hpa2 in gastric carcinoma cell lines and examined their tumorigenic properties in vitro and in vivo. We also evaluated the expression of Hpa2 by gastric carcinoma cells following inhibition of the proteasome, leading to proteotoxic stress, and the resulting signaling responsible for Hpa2 gene regulation. Here, we report that gastric cancer patients exhibiting high levels of Hpa2 survive longer. Similarly, mice administrated with gastric carcinoma cells engineered to over-express Hpa2 produced smaller tumors and survived longer than mice administrated with control cells. This was associated with increased phosphorylation of AMP-activated protein kinase (AMPK), a kinase that is situated at the center of a tumor suppressor network. We also found that MG132, an inhibitor of the proteasome that results in proteotoxic stress, prominently enhances Hpa2 expression. Notably, Hpa2 induction by MG132 appeared to be mediated by AMPK, and AMPK was found to induce the expression of Hpa2, thus establishing a loop that feeds itself where Hpa2 enhances AMPK phosphorylation that, in turn, induces Hpa2 expression, leading to attenuation of gastric tumorigenesis. These results indicate that high levels of Hpa2 in some tumors are due to stress conditions that tumors often experience due to their high rates of cell proliferation and high metabolic demands. This increase in Hpa2 levels by the stressed tumors appears critically important for patient outcomes.

BackgroundMicroRNAs (miRNAs) play a vital role in tuberculosis (TB). Vitamin D receptor (VDR), an miRNA target gene, and its ligand, vitamin D3 (VitD3), have been reported to exert protective effects against TB. However, whether miRNAs can affect the progression of TB by targeting VDR has not been reported.Materials and methodsResearch subjects were selected according to defined inclusion criteria. A clinical database of 360 samples was established, including the subjects’ demographic information, miRNA expression profiles and cellular experimental results. Two candidate miRNAs, miR-27a-3p, and miR-30b-5p, were identified by a high-throughput sequencing screen and validated by qRT–PCR assays. Univariate and multivariate statistical analyses were performed. VDR and NF-kB p65 protein levels were detected by Western blot assays. Proinflammatory cytokine expression levels were detected by enzyme-linked immunosorbent assay (ELISA). Luciferase assays and fluorescence-activated cell sorting (FACS) were further applied to elucidate the detailed mechanisms.ResultsDifferential miRNA expression profiles were obtained, and miR-27a-3p and miR-30b-5p were highly expressed in patients with TB. These results showed that the two miRNAs were able to induce M1 macrophage differentiation and inhibit M2 macrophage differentiation. Further experiments showed that the two miRNAs decreased the VDR protein level and increased proinflammatory cytokine secretion by macrophages. Mechanistically, the miRNAs targeted the 3′ untranslated region (3′UTR) of the VDR mRNA and thereby downregulated VDR protein levels by post-transcriptional regulation. Then, due to the reduction in VDR protein levels, the NF-kB inflammatory cytokine signaling pathway was activated, thus promoting the progression of TB.ConclusionOur study not only identified differentially expressed miRNAs between the TB and control groups but also revealed that miR-27a-3p and miR-30b-5p regulate proinflammatory cytokine secretion and macrophage differentiation through VDR in macrophages. Thus, these two miRNAs influence the progression of TB.

Abnormal auditory cortex (AC) neuronal activity is thought to be a primary cause of the auditory disturbances perceived by individuals suffering from tinnitus. The present study was designed to test that possibility by evaluating auditory cortical characteristics (volume, curvature, surface area, thickness) and surface-based functional metrics in chronic tinnitus patients. In total, 63 chronic tinnitus patients and 36 age-, sex- and education level-matched healthy control (HC) patients were enrolled in this study. Hearing levels in these two groups were comparable, and following magnetic resonance imaging (MRI) of these individuals, the DPABISurf software was used to compute cerebral cortex curvature, thickness, and surface area as well as surface-based functional metrics. The Tinnitus Handicap Inventory (THI), Tinnitus Handicap Questionary (THQ), and Visual Analogue Scales (VAS) were used to gauge participant tinnitus severity, while correlation analyses were conducted to evaluate associations between these different analyzed parameters. A significant increase in the regional homogeneity (ReHo) of the right secondary AC was detected in the tinnitus group relative to the HC group. There were also significant reductions in the cortical volume and surface area of the right secondary AC in the tinnitus group relative to the HC group (all P < 0.05). In addition, significant negative correlations between tinnitus pitch and the cortical area and volume of the right secondary AC were observed in the tinnitus group.

Gene therapy for curing congenital human diseases is promising, but the feasibility and safety need to be further evaluated. In this study, based on a pig model that carries the c.740T>C (L247S) mutation in MITF with an inheritance pattern and clinical pathology that mimics Waardenburg syndrome 2A (WS2A), we corrected the point mutation by the CRISPR-Cas9 system in the mutant fibroblast cells using single-stranded oligodeoxynucleotide (ssODN) and long donor plasmid DNA as the repair template. By using long donor DNA, precise correction of this point mutation was achieved. The corrected cells were then used as the donor cell for somatic cell nuclear transfer (SCNT) to produce piglets, which exhibited a successfully rescued phenotype of WS2A, including anophthalmia and hearing loss. Furthermore, engineered base editors (BEs) were exploited to make the correction in mutant porcine fibroblast cells and early embryos. The correction efficiency was greatly improved, whereas substantial off-targeting mutations were detected, raising a safety concern for their potential applications in gene therapy. Thus, we explored the possibility of precise correction of WS2A-causing gene mutation by the CRISPR-Cas9 system in a large-animal model, suggesting great prospects for its future applications in treating human genetic diseases.

Abstract Background The endoglycosidase heparanase which degrades heparan sulfate proteoglycans, exerts a pro-inflammatory mediator in various inflammatory disorders. However, the function and underlying mechanism of heparanase in acute pancreatitis remain poorly understood. Here, we investigated the interplay between heparanase and the gut microbiota in the development of acute pancreatitis. Methods Acute pancreatitis was induced in wild-type and heparanase-transgenic mice by administration of caerulein. The differences in gut microbiota were analyzed by 16S ribosomal RNA sequencing. Antibiotic cocktail experiment, fecal microbiota transplantation, and cohousing experiments were used to assess the role of gut microbiota. Results As compared with wild-type mice, acute pancreatitis was exacerbated in heparanase-transgenic mice. Moreover, the gut microbiota differed between heparanase-transgenic and wild-type mice. Heparanase exacerbated acute pancreatitis in a gut microbiota-dependent manner. Specially, the commensal Parabacteroides contributed most to distinguish the differences between wild-type and heparanase-transgenic mice. Administration of Parabacteroides alleviated acute pancreatitis in wild-type and heparanase-transgenic mice. In addition, Parabacteroides produced acetate to alleviate heparanase-exacerbated acute pancreatitis through reducing neutrophil infiltration. Conclusions The gut–pancreas axis played an important role in the development of acute pancreatitis and the acetate produced by Parabacteroides may be beneficial for acute pancreatitis treatment. Video abstract

Endoscopic submucosal dissection (ESD) is a common procedure to treat early and precancerous gastrointestinal lesions. Via submucosal injection, a liquid cushion is created to lift and separate the lesion and malignant part from the muscular layer where the formed indispensable space is convenient for endoscopic incision. Saline is a most common submucosal injection liquid, but the formed liquid pad lasts only a short time, and thus repeated injections increase the potential risk of adverse events. Hydrogels with high osmotic pressure and high viscosity are used as an alternate; however, with some drawbacks such as tissue damage, excessive injection resistance, and high cost. Here, we reported a nature derived hydrogel of gelatin-oxidized alginate (G-OALG). Based on the rheological analysis and compare to commercial endoscopic mucosal resection (EMR) solution (0.25% hyaluronic acid, HA), a designed G-OALG hydrogel of desired concentration and composition showed higher performances in controllable gelation and injectability, higher viscosity and more stable structures. The G-OALG gel also showed lower propulsion resistance than 0.25% HA in the injection force assessment under standard endoscopic instruments, which eased the surgical operation. In addition, the G-OALG hydrogel showed good in vivo degradability biocompatibility. By comparing the results acquired via ESD to normal saline, the G-OALG shows great histocompatibility and excellent endoscopic injectability, and enables create a longer-lasting submucosal cushion. All the features have been confirmed in the living both pig and rat models. The G-OALG could be a promising submucosal injection agent for esophageal ESD.

Abstract Background lncRNA may be involved in the occurrence, metastasis, and chemical reaction of hepatocellular carcinoma (HCC) through various pathways associated with autophagy. Therefore, it is urgent to reveal more autophagy-related lncRNAs, explore these lncRNAs’ clinical significance, and find new targeted treatment strategies. Methods The corresponding data of HCC patients and autophagy genes were obtained from the TCGA database, and the human autophagy database respectively. Based on the co-expression and Cox regression analysis to construct prognostic prediction signature. Results Finally, a signature containing seven autophagy-related lncRNAs (PRRT3-AS1, RP11-479G22.8, RP11-73M18.8, LINC01138, CTD-2510F5.4, CTC-297N7.9, RP11-324I22.4) was constructed. Based on the risk score of signature, Overall survival (OS) curves show that the OS of high-risk patients is significantly lower than that of low-risk patients (P = 2.292e−10), and the prognostic prediction accuracy of risk score (AUC = 0.786) is significantly higher than that of ALBI (0.532), child_pugh (0.573), AFP (0.5751), and AJCC_stage (0.631). Moreover, multivariate Cox analysis and Nomogram of risk score are indicated that the 1-year and 3-year survival rates of patients are obviously accuracy by the combined analysis of the risk score, child_pugh, age, M_stage, and Grade (The AUC of 1- and 3-years are 0.87, and 0.855). Remarkably, the 7 autophagy-related lncRNAs may participate in Spliceosome, Cell cycle, RNA transport, DNA replication, and mRNA surveillance pathway and be related to the biological process of RNA splicing and mRNA splicing. Conclusion In conclusion, the 7 autophagy-related lncRNAs might be promising prognostic and therapeutic targets for HCC.

Tinnitus is an unpleasant symptom characterized by detective hearing without the actual sound input. Despite numerous studies elucidating a variety of pathomechanisms inducing tinnitus, the pathophysiology of tinnitus is not fully understood. The genes that are closely associated with this subtype of the auditory hallucination that could be utilized as potential treatment targets are still unknown. In this study, we explored the transcriptional profile changes of the auditory cortex after noise-induced tinnitus in rats using high throughput sequencing and verification of the detected genes using quantitative PCR (qPCR). Tinnitus models were established by analyzing startle behaviors through gap pre-pulse inhibition (PPI) of the acoustic startle. Two hundred and fifty-nine differential genes were identified, of which 162 genes were up-regulated and 97 genes were down-regulated. Analysis of the pathway enrichment indicated that the tinnitus group exhibited increased gene expression related to neurodegenerative disorders such as Huntington’s disease and Amyotrophic lateral sclerosis. Based on the identified genes, networks of protein–protein interaction were established and five hub genes were identified through degree rank, including Fos, Nr4a1, Nr4a3, Egr2, and Egr3. Therein, the Fos gene ranked first with the highest degree after noise exposure, and may be a potential target for the modulation of noise-induced tinnitus.

Objective: Sufferers of tinnitus, especially of the prolonged type, frequently suffer from comorbid depression and anxiety. From the perspective of the network model, this comorbidity is thought to be an interacting system of these two symptoms. In our study, we conducted a network analysis of depression and anxiety comorbidity in tinnitus sufferers, aiming to identify the central and bridge symptoms and make informed suggestions for clinical interventions and psychotherapy. Method: A total of 566 tinnitus sufferers were enrolled in our study. The Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder 7-Item Questionnaire (GAD-7) were selected to evaluate depression and anxiety symptoms, respectively, followed by network analysis to construct the interacting networks. Results: The findings identified six edges of strongest regularized partial correlations in this network. Of these, three were depression symptoms and three were anxiety symptoms. The anxiety symptoms “Unable to control worry” and “Relaxation difficulty” and the depression symptom “Feeling depressed or hopeless” had the highest expected influence centrality. The analysis results also revealed three bridge symptoms: “Afraid something awful might happen”, “Feeling of worthlessness”, and “Trouble concentrating”. As for “Suicidal ideation”, the direct relations between this symptom and “Afraid something awful might happen” and “Feeling depressed or hopeless” were the strongest. Conclusions: The central and bridge symptoms of the interacting network of depression and anxiety symptoms in tinnitus sufferers can be considered a significant transdiagnostic intervention target for the management of this comorbidity. In particular, clinical prevention and psychotherapy should be implemented, targeting the symptoms that have the strongest associations with suicidal ideation.

TMC1 p.M418K mutation is homologous to that in Beethoven mice, which may induce autosomal dominant non-syndromic progressive hearing loss. Previously, we generated an induced pluripotent stem cells (iPSCs) line (CPGHi001-A) from a hearing loss patient with the TMC1 c.1253 T > A (p.M418K) mutation. Here we genetically corrected the TMC1 c.1253 T > A mutation using CRISPR/Cas9 technology to generate an isogenic control, CPGHi001-A-1. The resulting iPSCs had a normal karyotype, showed pluripotency by immunofluorescence staining, and differentiated into the three germ layers in vitro.

Abstract Background Huntington’s disease (HD) is a neurodegenerative disease that involves a complex combination of psychiatric, cognitive and motor impairments. Synaptic dysfunction has been implicated in HD pathogenesis. However, the mechanisms have not been clearly delineated. Synaptic vesicular zinc is closely linked to modulating synaptic transmission and maintaining cognitive ability. It is significant to assess zinc homeostasis for further revealing the pathogenesis of synaptic dysfunction and cognitive impairment in HD. Results Histochemical staining by autometallography indicated that synaptic vesicular zinc was decreased in the hippocampus, cortex and striatum of N171-82Q HD transgenic mice. Analyses by immunohistochemistry, Western blot and RT-PCR found that the expression of zinc transporter 3 (ZnT3) required for transport of zinc into synaptic vesicles was obviously reduced in these three brain regions of the HD mice aged from 14 to 20 weeks and BHK cells expressing mutant huntingtin. Significantly, dual-luciferase reporter gene and chromatin immunoprecipitation assays demonstrated that transcription factor Sp1 could activate ZnT3 transcription via its binding to the GC boxes in ZnT3 promoter. Moreover, mutant huntingtin was found to inhibit the binding of Sp1 to the promoter of ZnT3 and down-regulate ZnT3 expression, and the decline in ZnT3 expression could be ameliorated through overexpression of Sp1. Conclusions This is first study to reveal a significant loss of synaptic vesicular zinc and a decline in ZnT3 transcriptional activity in the HD transgenic mice. Our work sheds a novel mechanistic insight into pathogenesis of HD that mutant huntingtin down-regulates expression of ZnT3 through inhibiting binding of Sp1 to the promoter of ZnT3 gene, causing disruption of synaptic vesicular zinc homeostasis. Disrupted vesicular zinc ultimately leads to early synaptic dysfunction and cognitive deficits in HD. It is also suggested that maintaining normal synaptic vesicular zinc concentration is a potential therapeutic strategy for HD.

Abstract Background Point-of-care transthoracic echocardiography (POC-TTE) is essential in shock management, allowing for stroke volume (SV) and cardiac output (CO) estimation using left ventricular outflow tract diameter (LVOTD) and left ventricular velocity time integral (VTI). Since LVOTD is difficult to obtain and error-prone, the body surface area (BSA) or a modified BSA (mBSA) is sometimes used as a surrogate (LVOTDBSA, LVOTDmBSA). Currently, no models of LVOTD based on patient characteristics exist nor have BSA-based alternatives been validated. Methods Focused rapid echocardiographic evaluations (FREEs) performed in intensive care unit patients over a 3-year period were reviewed. The age, sex, height, and weight were recorded. Human expert measurement of LVOTD (LVOTDHEM) was performed. An epsilon-support vector regression was used to derive a computer model of the predicted LVOTD (LVOTDCM). Training, testing, and validation were completed. Pearson coefficient and Bland-Altman were used to assess correlation and agreement. Results Two hundred eighty-seven TTEs with ideal images of the LVOT were identified. LVOTDCM was the best method of SV measurement, with a correlation of 0.87. LVOTDmBSA and LVOTDBSA had correlations of 0.71 and 0.49 respectively. Root mean square error for LVOTDCM, LVOTDmBSA, and LVOTDBSA respectively were 13.3, 37.0, and 26.4. Bland-Altman for LVOTDCM demonstrated a bias of 5.2. LVOTDCM model was used in a separate validation set of 116 ideal images yielding a linear correlation of 0.83 between SVHEM and SVCM. Bland Altman analysis for SVCM had a bias of 2.3 with limits of agreement (LOAs) of − 24 and 29, a percent error (PE) of 34% and a root mean square error (RMSE) of 13.9. Conclusions A computer model may allow for SV and CO measurement when the LVOTD cannot be assessed. Further study is needed to assess the accuracy of the model in various patient populations and in comparison to the gold standard pulmonary artery catheter. The LVOTDCM is more accurate with less error compared to BSA-based methods, however there is still a percentage error of 33%. BSA should not be used as a surrogate measure of LVOTD. Once validated and improved this model may improve feasibility and allow hemodynamic monitoring via POC-TTE once it is validated.

Objective: The aim of this study was to improve muscle flaps and to evaluate surgical outcomes with the use of a novel specialized retractor, which is a surgical instrument used to locate and shape a bony seat for minimally invasive cochlear implantation. Methods: 50 patients aged 1–75 years with sensorineural hearing loss who required cochlear implantation were recruited. A small incision (

Abstract Background Aberrant expression of circular RNAs contributes to the initiation and progression of cancers, but the underlying mechanism remains elusive. Methods RNA-seq and qRT-PCR were performed to screen differential expressed circRNAs between gastric cancer tissues and adjacent normal tissues. Candidate circRNA (circMRPS35) was screened out and validated by qRT-PCR. Cell proliferation and invasion ability were determined by CCK-8 and cell invasion assays. RNA-seq, GO-pathway, RNA pull-down and ChIRP were further applied to search for detailed mechanism. Results Here, a novel circRNA named circMRPS35, was screened out by RNA-seq in gastric cancer tissues, whose expression is related to clinicopathological characteristics and prognosis in gastric cancer patients. Biologically, circMRPS35 suppresses the proliferation and invasion of gastric cancer cells in vitro and in vivo. Mechanistically, circMRPS35 acts as a modular scaffold to recruit histone acetyltransferase KAT7 to the promoters of FOXO1 and FOXO3a genes, which elicits acetylation of H4K5 in their promoters. Particularly, circMRPS35 specifically binds to FOXO1/3a promoter regions directly. Thus, it dramatically activates the transcription of FOXO1/3a and triggers subsequent response of their downstream target genes expression, including p21, p27, Twist1 and E-cadherin, resulting in the inhibition of cell proliferation and invasion. Moreover, circMRPS35 expression positively correlates with that of FOXO1/3a in gastric cancer tissues. Conclusions Our findings not only reveal the pivotal roles of circMRPS35 in governing histone modification in anticancer treatment, but also advocate for triggering circMRPS35/KAT7/FOXO1/3a pathway to combat gastric cancer.

ObjectiveMindfulness-based interventions have been widely demonstrated to be effective in reducing stress, alleviating mood disorders, and improving quality of life; however, the underlying mechanisms remained to be fully understood. Along with the advanced research in the microbiota-gut-brain axis, this study aimed to explore the impact of gut microbiota on the effectiveness and responsiveness to mindfulness-based cognitive therapy (MBCT) among high trait anxiety populations.DesignA standard MBCT was performed among 21 young adults with high trait anxiety. A total of 29 healthy controls were matched for age and sex. The differences in gut microbiota between the two groups were compared. The changes in fecal microbiota and psychological indicators were also investigated before and after the intervention.ResultsCompared with healthy controls, we found markedly decreased bacterial diversity and distinctive clusters among high trait anxiety populations, with significant overgrowth of bacteria such as Streptococcus, Blautia, and Romboutsia, and a decrease in genera such as Faecalibacterium, Coprococcus_3, and Lachnoclostridium. Moreover, MBCT attenuated trait anxiety and depression, improved mindfulness and resilience, and increased the similarity of gut microbiota to that of healthy controls. Notably, a high presence of intestinal Subdoligranulum pre-MBCT was associated with increased responsiveness to MBCT. Decreases in Subdoligranulum post-MBCT were indicative of ameliorated trait anxiety. The tryptophan metabolism pathways were significantly over-represented among high responders compared to low responders.ConclusionThe significantly increased diversity post-MBCT added evidence to gut-brain communication and highlighted the utility of mycobiota-focused strategies for promoting the effectiveness and responsiveness of the MBCT to improve trait anxiety.Clinical Trial Registrationchictr.org.cn, ChiCTR1900028389.

Purpose: Tinnitus is a common but obscure auditory disease to be studied. This study will determine whether the connectivity features in electroencephalography (EEG) signals can be used as the biomarkers for an efficient and fast diagnosis method for chronic tinnitus.Methods: In this study, the resting-state EEG signals of tinnitus patients with different tinnitus locations were recorded. Four connectivity features [including the Phase-locking value (PLV), Phase lag index (PLI), Pearson correlation coefficient (PCC), and Transfer entropy (TE)] and two time-frequency domain features in the EEG signals were extracted, and four machine learning algorithms, included two support vector machine models (SVM), a multi-layer perception network (MLP) and a convolutional neural network (CNN), were used based on the selected features to classify different possible tinnitus sources.Results: Classification accuracy was highest when the SVM algorithm or the MLP algorithm was applied to the PCC feature sets, achieving final average classification accuracies of 99.42 or 99.1%, respectively. And based on the PLV feature, the classification result was also particularly good. And MLP ran the fastest, with an average computing time of only 4.2 s, which was more suitable than other methods when a real-time diagnosis was required.Conclusion: Connectivity features of the resting-state EEG signals could characterize the differentiation of tinnitus location. The connectivity features (PCC and PLV) were more suitable as the biomarkers for the objective diagnosing of tinnitus. And the results were helpful for clinicians in the initial diagnosis of tinnitus.