Repetitive Transcranial Magnetic Stimulation (rTMS) Improves Cognitive Impairment and Intestinal Microecological Dysfunction Induced by High-Fat Diet in Rats.

Consuming a high-fat diet (HFD) is widely recognized to cause obesity and result in chronic brain inflammation that impairs cognitive function. Repetitive transcranial magnetic stimulation (rTMS) has shown effectiveness in both weight loss and cognitive improvement, although the exact mechanism is still unknown. Our study examined the effects of rTMS on the brain and intestinal microecological dysfunction. rTMS successfully reduced cognitive decline caused by an HFD in behavioral assessments involving the Y maze and novel object recognition. This was accompanied by an increase in the number of new neurons and the transcription level of genes related to synaptic plasticity (spindlin 1, synaptophysin, and postsynaptic protein-95) in the hippocampus. It was reached that rTMS decreased the release of high mobility group box 1, activation of microglia, and inflammation in the brains of HFD rats. rTMS also reduced hypothalamic hypocretin levels and improved peripheral blood lipid metabolism. In addition, rTMS recovered the HFD-induced gut microbiome imbalances, metabolic disorders, and, in particular, reduced levels of the microvirus. Our research emphasized that rTMS enhanced cognitive abilities, resulting in positive impacts on brain inflammation, neurodegeneration, and the microbiota in the gut, indicating the potential connection between the brain and gut, proposing that rTMS could be a new approach to addressing cognitive deficits linked to obesity.

SMARCA5 reprograms AKR1B1-mediated fructose metabolism to control leukemogenesis.

A significant variation in chromatin accessibility is an epigenetic feature of leukemia. The cause of this variation in leukemia, however, remains elusive. Here, we identify SMARCA5, a core ATPase of the imitation switch (ISWI) chromatin remodeling complex, as being responsible for aberrant chromatin accessibility in leukemia cells. We find that SMARCA5 is required to maintain aberrant chromatin accessibility for leukemogenesis and then promotes transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1. Higher levels of AKR1B1 are associated with a poor prognosis in leukemia patients and promote leukemogenesis by reprogramming fructose metabolism. Moreover, pharmacological inhibition of AKR1B1 has been shown to have significant therapeutic effects in leukemia mice and leukemia patient cells. Thus, our findings link the aberrant chromatin state mediated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming and shed light on the essential role of AKR1B1 in leukemogenesis, which may provide therapeutic strategies for leukemia.

Analysis of Body Mass Index and Clinicopathological Factors in Patients with Papillary Thyroid Carcinoma.

Objective: To analyze the correlation between body mass index (BMI) and clinicopathological factors of papillary thyroid cancer (PTC). Methods: The clinical data of patients with PCT who were hospitalized in the Department of Thyroid Surgery of the Affiliated Hospital of Guizhou Medical University from March 2023 to September 2023 were retrospectively collected, including age, gender, height, weight, BMI, v-raf murine sarcoma viral oncogene homolog B (BRAF) gene mutation, tumor size, multifocus, Hashimoto's thyroiditis, lymph node metastasis and other clinicopathological factors. According to the World Health Organization (WHO) definition for Asian population, BMI≥25kg/m2 was obese group, 23≤BMI≤24.9kg/m2 was overweight group, 18.5≤BMI≤22.9kg/m2 was normal weight group, and BMI≤18.5kg/m2 was low weight group. The clinicopathological factors of overweight and obese patients with PTC were analyzed. Results: A total of 164 PTC patients were included, with an average BMI of (24.44±3.57) kg/m2. Age of overweight and obese PTC patients (Z=1.978, p=0.083); Gender of overweight and obese PTC patients (χ2 value: 11.570, p=0.004); Tumor size in overweight and obese PTC patients (Z=0.894, p=0.411); BRAF gene mutation in overweight and obese PTC patients (χ2 value: 1.452, p =0.623); Multifocal lesions were found in overweight and obese patients (χ2 value: 1.653, p =0.201). Hashimoto's thyroiditis was found in overweight and obese PTC patients (χ2 value: 1.147, p=0.298). Overweight and obese patients with PTC had lymph node metastasis (χ2 value: 1.690, p =0.251). Conclusion: Overweight and obesity in PTC patients are correlated with male, but not with age, tumor size, BRAF mutation, multifocality, Hashimoto's thyroiditis and lymph node metastasis.

Multi-instance learning based artificial intelligence model to assist vocal fold leukoplakia diagnosis: A multicentre diagnostic study.

OBJECTIVE: To develop a multi-instance learning (MIL) based artificial intelligence (AI)-assisted diagnosis models by using laryngoscopic images to differentiate benign and malignant vocal fold leukoplakia (VFL). METHODS: The AI system was developed, trained and validated on 5362 images of 551 patients from three hospitals. Automated regions of interest (ROI) segmentation algorithm was utilized to construct image-level features. MIL was used to fusion image level results to patient level features, then the extracted features were modeled by seven machine learning algorithms. Finally, we evaluated the image level and patient level results. Additionally, 50 videos of VFL were prospectively gathered to assess the system's real-time diagnostic capabilities. A human-machine comparison database was also constructed to compare the diagnostic performance of otolaryngologists with and without AI assistance. RESULTS: In internal and external validation sets, the maximum area under the curve (AUC) for image level segmentation models was 0.775 (95 % CI 0.740-0.811) and 0.720 (95 % CI 0.684-0.756), respectively. Utilizing a MIL-based fusion strategy, the AUC at the patient level increased to 0.869 (95 % CI 0.798-0.940) and 0.851 (95 % CI 0.756-0.945). For real-time video diagnosis, the maximum AUC at the patient level reached 0.850 (95 % CI, 0.743-0.957). With AI assistance, the AUC improved from 0.720 (95 % CI 0.682-0.755) to 0.808 (95 % CI 0.775-0.839) for senior otolaryngologists and from 0.647 (95 % CI 0.608-0.686) to 0.807 (95 % CI 0.773-0.837) for junior otolaryngologists. CONCLUSIONS: The MIL based AI-assisted diagnosis system can significantly improve the diagnostic performance of otolaryngologists for VFL and help to make proper clinical decisions.

Improving prediction of tacrolimus concentration using a combination of population pharmacokinetic modeling and machine learning in chinese renal transplant recipients.

Aims: The population pharmacokinetic (PPK) model-based machine learning (ML) approach offers a novel perspective on individual concentration prediction. This study aimed to establish a PPK-based ML model for predicting tacrolimus (TAC) concentrations in Chinese renal transplant recipients. Methods: Conventional TAC monitoring data from 127 Chinese renal transplant patients were divided into training (80%) and testing (20%) datasets. A PPK model was developed using the training group data. ML models were then established based on individual pharmacokinetic data derived from the PPK basic model. The prediction performances of the PPK-based ML model and Bayesian forecasting approach were compared using data from the test group. Results: The final PPK model, incorporating hematocrit and CYP3A5 genotypes as covariates, was successfully established. Individual predictions of TAC using the PPK basic model, postoperative date, CYP3A5 genotype, and hematocrit showed improved rankings in ML model construction. XGBoost, based on the TAC PPK, exhibited the best prediction performance. Conclusion: The PPK-based machine learning approach emerges as a superior option for predicting TAC concentrations in Chinese renal transplant recipients.

Mimicking the retinal neuron functions by a photoresponsive single transistor with double-gate.

To realize a low-cost neuromorphic visual system, employing an artificial neuron capable of mimicking the retinal neuron functions is essential. A photoresponsive single transistor (1T) neuron composed of a vertical silicon nanowire (Si-NW) is proposed. Similar to retinal neurons, various photoresponsive characteristics of the 1T neuron can be modulated by light intensity as well as wavelength, and have a high responsivity to green light like the human eye. The device is designed with a cylindrical surrounding double-gate (CSDG) structure, enclosed by an independently controlled outer gate and inner gate. The outer gate has the function of selectively inhibiting neuron activity, which can mimic lateral inhibition of amacrine cells to ganglion cells. And the inner gate can be utilized for the adjustment of the firing threshold voltage, which can be used to mimic the regulation of photoresponsivity by horizontal cells for adaptive visual perception. Furthermore, a myelination function that controls the speed of information transmission is obtained according to the inherent asymmetric source/drain structure of vertical Si-NW. This work can enable photoresponsive neuronal function using only a single transistor, providing a promising hardware implementation for building miniaturized neuromorphic vision systems with low cost.

Corrigendum to "Anti-tumor effect and mechanism of the total biflavonoid extract from S doederleinii on human cervical cancer cells in vitro and in vivo" [Heliyon 10(2) January 2024 e24778].

[This corrects the article DOI: 10.1016/j.heliyon.2024.e24778.].

MEK/ERK signaling drives the transdifferentiation of supporting cells into functional hair cells by modulating the Notch pathway.

Loss of cochlear hair cells (HCs) leads to permanent hearing loss in mammals, and regenerative medicine is regarded as an ideal strategy for hearing recovery. Limited genetic and pharmaceutical approaches for HC regeneration have been established, and the existing strategies cannot achieve recovery of auditory function. A promising target to promote HC regeneration is MEK/ERK signaling because dynamic shifts in its activity during the critical stages of inner ear development have been observed. Here, we first showed that MEK/ERK signaling is activated specifically in supporting cells (SCs) after aminoglycoside-induced HC injury. We then selected 4 MEK/ERK signaling inhibitors, and PD0325901 (PD03) was found to induce the transdifferentiation of functional supernumerary HCs from SCs in the neonatal mammalian cochlear epithelium. We next found that PD03 facilitated the generation of HCs in inner ear organoids. Through genome-wide high-throughput RNA sequencing and verification, we found that the Notch pathway is the downstream target of MEK/ERK signaling. Importantly, delivery of PD03 into the inner ear induced mild HC regeneration in vivo. Our study thus reveals the importance of MEK/ERK signaling in cell fate determination and suggests that PD03 might serve as a new approach for HC regeneration.

New insights into the influences of firework combustion on molecular composition and formation of sulfur- and halogen-containing organic compounds.

Firework (FW) events occur during various festivals worldwide and substantially negatively influence both air quality and human health. However, the effects of FWs on the chemical properties and formation of organic aerosols are far from clear. In this study, fine particulate matter (PM2.5) samples were collected in a suburban area in Qingdao, China during the Chinese Spring Festival. The concentrations of chemical species (especially carbonaceous components) in PM2.5 were measured using a combination of several state-of-the-art techniques. Our results showed that mass concentrations of water-soluble sulfate, potassium and chloride ions, and organic carbon drastically increased and became the predominant components in PM2.5 during FW events. Correspondingly, both the number and fractional contributions of sulfur (S)-containing subgroups (e.g., CHOS and CHONS compounds) and some chlorine (Cl)-containing organic (e.g., CHOSCl and CHONSCl) compounds identified using ultrahigh-resolution Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR MS) increased. The S- and Cl-containing compounds unique to the FW display period were identified, and their chemical characterization, sources, and formation mechanisms were elucidated by combining FT-ICR MS and quantum chemical calculations. Our results suggest that FW emissions play notable roles in both primary and secondary organic aerosol formation, especially for CHOS- and Cl-containing organic compounds.

Efficacy of acupuncture-related therapy in the treatment of primary dysmenorrhea: A network meta-analysis of randomized controlled trials.

Objectives: In order to compare and rank the most effective acupuncture therapy for primary dysmenorrhea and provide evidence-based medical support for clinical treatment of this disease. Methods: A comprehensive search was conducted on China National Knowledge Infrastructure (CNKI), Wanfang Database, Information Chinese Journal Service Platform (VIP), China Biomedical Literature Service System (SinoMed), PubMed, Web of Science, Embase, and Cochrane Library databases from their inception to May 1, 2023. The Cochrane Collaboration Risk of Bias Tool was used to evaluate bias risk, and the GeMTC package of Stata 15.1 software and R 4.3.1 software was used to perform network Meta-analysis. Results: 70 studies were included, including 5772 patients with primary dysmenorrhea, involving 25 kinds of acupuncture techniques commonly used in clinic. The quality of the included literature was low, most of them did not mention the registration information of clinical trial centers, and the specific sample size estimation method was unclear. Some literature did not explain the specific random method, distribution concealment and blindness, so there was a certain publication bias and small sample effect. Results showed that for improving the clinical effective rate, the top three treatments were salt-separated moxibustion, massotherapy + acupoint patching, acupuncture + heat-sensitive moxibustion. In terms of reducing the visual analogue scale(VAS), the top three treatments were massotherapy + acupoint patching, acupuncture + acupoint patching and warm acupuncture. In terms of alleviating cox menstrual symptom scale (CMSS), the top three treatments were acupuncture + acupoint patching, acupoint patching and point embedding. In relieving TCM symptom score, the top three treatments were acupoint patching + heat-sensitive moxibustion, acupoint patching and moxibustion. Conclusion: Different acupuncture therapies have more advantages than oral analgesics in improving the clinical effective rate, reducing VAS score, reducing CMSS score, and alleviating TCM symptom score. Among them, massage therapy + acupoint patching, acupuncture + acupoint patching and acupoint patching may be the best solutions for the treatment of primary dysmenorrhea. However, more large-sample, multi-center and high-quality randomized controlled trials are needed to demonstrate.

Entrepreneurial fear of failure among college students: A scoping review of literature from 2010 to 2023.

Entrepreneurial fear of failure (EFoF) is a psychological barrier to college entrepreneurship. Current research on EFoF among college students is at an emerging stage, and relevant evidence, such as the factors influencing EFoF, remains unclear and unsystematic. Most EFoF studies treat college students as general entrepreneurs, neglecting their unique social identities and situational contexts that influence their EFoF, such as parents and education. It is essential to provide a thorough and organized review to comprehensively understand the role of the EFoF in college student entrepreneurship. A scoping review was conducted following the PRISMA-ScR protocol to offer a broad exploration and mapping of the literature. This review identified 35 studies published from 2010 to 2023 through a rigorous search and sift across five prominent databases. Descriptive and thematic analyses revealed 1) the characteristics of the included studies, 2) the exogenous and endogenous factors that influence college students' EFoF, 3) the outcomes of EFoF on college students, and 4) research gaps. By mapping and synthesizing the literature, this scoping review contributes to the theory by providing a comprehensive overview of EFoF among college students and identifying research gaps, which illuminates future research directions. The findings also offer practical insights for entrepreneurship practitioners, including college student entrepreneurs, policymakers, and educators, to better understand the role of EFoF among college students, thus effectively promoting the development of college student entrepreneurship.

Multi-Instance Learning for Vocal Fold Leukoplakia Diagnosis Using White Light and Narrow-Band Imaging: A Multicenter Study.

OBJECTIVES: Vocal fold leukoplakia (VFL) is a precancerous lesion of laryngeal cancer, and its endoscopic diagnosis poses challenges. We aim to develop an artificial intelligence (AI) model using white light imaging (WLI) and narrow-band imaging (NBI) to distinguish benign from malignant VFL. METHODS: A total of 7057 images from 426 patients were used for model development and internal validation. Additionally, 1617 images from two other hospitals were used for model external validation. Modeling learning based on WLI and NBI modalities was conducted using deep learning combined with a multi-instance learning approach (MIL). Furthermore, 50 prospectively collected videos were used to evaluate real-time model performance. A human-machine comparison involving 100 patients and 12 laryngologists assessed the real-world effectiveness of the model. RESULTS: The model achieved the highest area under the receiver operating characteristic curve (AUC) values of 0.868 and 0.884 in the internal and external validation sets, respectively. AUC in the video validation set was 0.825 (95% CI: 0.704-0.946). In the human-machine comparison, AI significantly improved AUC and accuracy for all laryngologists (p < 0.05). With the assistance of AI, the diagnostic abilities and consistency of all laryngologists improved. CONCLUSIONS: Our multicenter study developed an effective AI model using MIL and fusion of WLI and NBI images for VFL diagnosis, particularly aiding junior laryngologists. However, further optimization and validation are necessary to fully assess its potential impact in clinical settings. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Advances in Material-Assisted Electromagnetic Neural Stimulation.

Bioelectricity plays a crucial role in organisms, being closely connected to neural activity and physiological processes. Disruptions in the nervous system can lead to chaotic ionic currents at the injured site, causing disturbances in the local cellular microenvironment, impairing biological pathways, and resulting in a loss of neural functions. Electromagnetic stimulation has the ability to generate internal currents, which can be utilized to counter tissue damage and aid in the restoration of movement in paralyzed limbs. By incorporating implanted materials, electromagnetic stimulation can be targeted more accurately, thereby significantly improving the effectiveness and safety of such interventions. Currently, there have been significant advancements in the development of numerous promising electromagnetic stimulation strategies with diverse materials. This review provides a comprehensive summary of the fundamental theories, neural stimulation modulating materials, material application strategies, and pre-clinical therapeutic effects associated with electromagnetic stimulation for neural repair. It offers a thorough analysis of current techniques that employ materials to enhance electromagnetic stimulation, as well as potential therapeutic strategies for future applications.

Clinical efficacy and safety of combined anti-BCMA and anti-CD19 CAR-T cell therapy for relapsed/refractory multiple myeloma: a systematic review and meta-analysis.

Background: The low rates of durable response against relapsed/refractory multiple myeloma (RRMM) in recent studies prompt that chimeric antigen receptor (CAR)-T cell therapies are yet to be optimized. The combined anti-BCMA and anti-CD19 CAR-T cell therapy showed high clinical efficacy in several clinical trials for RRMM. We here conducted a meta-analysis to confirm its efficacy and safety. Methods: We collected data from Embase, Web of Science, PubMed, CNKI, Wanfang and Cochrane databases up to April 2023. We extracted and evaluated data related to the efficacy and safety of combined anti-BCMA and anti-CD19 CAR-T cell therapies in RRMM patients. The data was then analyzed using RevMan5.4 and StataSE-64 software. PROSPERO number was CRD42023455002. Results: Our meta-analysis included 12 relevant clinical trials involving 347 RRMM patients who were treated with combined anti-BCMA and anti-CD19 CAR-T cell therapies. For efficacy assessment, the pooled overall response rate (ORR) was 94% (95% CI: 91%-98%), the complete response rate (CRR) was 50% (95% CI: 29%-71%), and the minimal residual disease (MRD) negativity rate within responders was 73% (95% CI: 66%-80%). In terms of safety, the pooled all-grade cytokine release syndrome (CRS) rate was 98% (95% CI: 97%-100%), grade≥3 CRS rate was 9% (95% CI: 4%-14%), and the incidence of neurotoxicity was 8% (95% CI: 4%-11%). Of hematologic toxicity, neutropenia was 82% (95% CI: 75%-89%), anemia was 71% (95% CI: 53%-90%), thrombocytopenia was 67% (95% CI: 40%-93%) and infection was 42% (95% CI: 9%-76%). The median progression-free survival (PFS) was 12.97 months (95% CI: 6.02-19.91), and the median overall survival (OS) was 26.63 months (95% CI: 8.14-45.11). Conclusions: As a novel immunotherapy strategy with great potential, the combined anti-BCMA and anti-CD19 CAR-T cell therapy showed high efficacy in RRMM, but its safety needs further improvement. This meta-analysis suggests possible optimization of combined CAR-T therapy. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023455002.

Boron dopant- and nitrogen defect-decorated C3N5 porous nanostructure as an efficient sulfur host for lithium-sulfur batteries.

Active site implantation and morphology manipulation are efficient protocols for boosting the electrochemical performance of carbon nitrides. As a promising sulfur host for lithium-sulfur batteries (LSBs), in this study, C3N5 porous nanostructure incorporated with both boron (B) atoms and nitrogen (N) defects was constructed (denoted as ND-B-C3N5) using a two-step strategy, i.e., pyrolysis of the mixture of 3-amino-1,2, 4-triazole and boric acid to obtain B-doped C3N5 porous nanostructure and then KOH etching under hydrothermal condition to generate N defects. The doped B atoms in the C3N5 porous nanostructure are in the form of B-N bonds and grafted B-O bonds. N defects are primarily created at the CN-C positions of the triazine unit, leaving behind some N vacancies and cyano groups. Benefiting from the involvement of B dopants and N defects, the optimized ND-B-C3N5-12 sample exhibits ameliorative conductivity, mass transport, lithium polysulfides (LiPSs) adsorption ability, diffusion of Li+ ions, Li2S deposition capacity, sulfur redox polarization, and a reversible solid-solid sulfur redox process. Consequently, the ND-B-C3N5-12/S cathode delivers accelerated redox performance of polysulfides for LSBs, revealing capacities of 1091 ± 44 and 753 ± 20 mAh/g at 0.2C for the initial and 300th cycles, respectively. The ND-B-C3N5-12/S cathode is also endowed with desired sulfur redox activity and stability at 2C for 1000 cycles, holding an initial discharging capacity of 788 ± 24 mAh/g and a low decay rate of 0.05 % per cycle.

Pivotal Evaluation of Novel Dedicated Venous Stent for Iliofemoral Venous Obstruction: A Prospective Cohort Study.

PURPOSE: The purpose was to evaluate the clinical outcomes of a dedicated venous stent with the tripartite composite segments for the treatment of iliofemoral venous obstruction (IVO) in a mixed cohort of nonthrombotic iliac vein lesion (NIVL) and post-thrombotic syndrome (PTS) over a period of 12 months. METHODS: The Grency Trial is a prospective, multicenter, single-arm, open-label, pivotal study, which was conducted at 18 large tertiary hospitals in China from August 2019 to October 2020. A total of 133 hospitalized patients were screened and 110 patients with clinical, etiology, anatomical, and pathophysiology clinical class (CEAP) clinical grade C>3 and iliac vein stenosis >50% or occlusion, including 72 patients with NIVL and 38 patients with PTS, were implanted with Grency venous stents. Primary endpoint was stent patency at 12 months follow-up, and secondary outcomes were technical success; improvement in venous clinical severity score (VCSS) at 3, 6, and 12 month follow-up; and rates of clinical adverse events. RESULTS: Among 110 patients who were implanted with Grency venous stents, 107 patients completed the 12 month follow-up. All 129 stents were successfully implanted in 110 limbs. Twelve-month primary patency rate was 94.39% [95% confidence interval [CI]=88.19%-97.91%] overall, and 100% [94.94%-100%] and 83.33% [67.19%-93.63%] in the NIVL and PTS subgroups, respectively. Venous clinical severity score after iliac vein stenting improved significantly up to 12 months follow-up. There were 3 early major adverse events (1 intracerebral hemorrhage and 2 stent thrombosis events related to anticoagulation therapy), and 7 late major adverse events (1 cardiovascular death, 1 intracranial hemorrhage with uncontrolled hypertension, and 5 in-stent restenosis cases without stent fractures or migration). CONCLUSIONS: The Grency venous stent system appeared excellent preliminary safe and effective for IVO treatment. Further large-scale studies with longer-term follow-up are needed to evaluate long-term patency and durability of stent. CLINICAL IMPACT: The design of venous stents for iliofemoral venous obstruction (IVO) must address engineering challenges distinct from those encountered in arterial stenting. The Grency venous stent, a nitinol self-expanding stent specifically tailored for IVO, features a composite structure designed to meet the stent requirements of various iliac vein segments. The Grency Trial is a prospective, multicenter, single-arm, open-label pivotal study aimed at evaluating the efficacy and safety of the Grency stent system. Following a 12-month follow-up period, the Grency venous stent system has demonstrated both safety and efficacy in treating iliofemoral venous outflow obstruction.