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Abstract Background Tauopathies are a group of age-related neurodegenerative diseases characterized by the accumulation of pathologically hyperphosphorylated tau protein in the brain, leading to prion-like aggregation and propagation. They include Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick’s disease (PiD). Currently, reliable diagnostic biomarkers that directly reflect the capability of propagation and spreading of misfolded tau aggregates in peripheral tissues and body fluids are lacking. Methods We utilized the seed-amplification assay (SAA) employing ultrasensitive real-time quaking-induced conversion (RT-QuIC) to assess the prion-like seeding activity of pathological tau in the skin of cadavers with neuropathologically confirmed tauopathies, including AD, PSP, CBD, and PiD, compared to normal controls. Results We found that the skin tau-SAA demonstrated a significantly higher sensitivity (75–80%) and specificity (95–100%) for detecting tauopathy, depending on the tau substrates used. Moreover, the increased tau-seeding activity was also observed in biopsy skin samples from living AD and PSP patients examined. Analysis of the end products of skin-tau SAA confirmed that the increased seeding activity was accompanied by the formation of tau aggregates with different physicochemical properties related to two different tau substrates used. Conclusions Overall, our study provides proof-of-concept that the skin tau-SAA can differentiate tauopathies from normal controls, suggesting that the seeding activity of misfolded tau in the skin could serve as a diagnostic biomarker for tauopathies.

Abstract Basic science educators play a significant role in medical and health professions curricula, particularly in the biomedical science components. Although the shift from basic scientists to educators seems promising, no study has yet explored the transition process from the perspective of basic scientists themselves, especially in the early stages of their transition. An anonymous survey with voluntary participation was administered to all basic scientists in National University of Singapore (NUS) Yong Loo Lin School of Medicine. The survey aimed to identify the perceived challenges faced by basic scientists transitioning to basic science educators in medical and health professions education. This study consisted of Likert scale questions, followed by one multiple-choice question and two open-ended questions. Twenty-one basic scientists either postdoctoral fellows or instructors, completed the study. The study found that gaps in clinical content and experience, along with teaching pedagogy and training were among the major concerns for basic scientists aspiring to be basic science educators. These challenges and shortcomings could potentially be addressed by providing them with clinical shadowing opportunities, education mentorship and teaching training. Since most respondents lacked teaching experience, the results might differ if the majority had been involved in teaching within medical and health professions education. Nonetheless, it is important to understand and acknowledge the challenges and concerns experienced by basic scientists and examine how they can navigate them in the process of their transition to teaching medical and health professions. This also provides opportunities for personal reflection and development so that basic science educators will be more prepared for greater challenges and the ever-changing demands of contemporary medical and health professions education.

Abstract Pancreatic cancer is among the most immune-resistant tumor types due to its unique tumor microenvironment and low cancer immunogenicity. Single-agent immune modulators have thus far proven clinically ineffective. However, a growing body of evidence suggests that combination of these modulators with other strategies could unlock the potential of immunotherapy in pancreatic cancer. Herein, we describe the case of a 59-year-old male with metastatic pancreatic ductal adenocarcinoma, referred to our center to receive immunotherapy (serplulimab, a novel anti-PD-1 antibody) combined with chemotherapy (gemcitabine/nab-paclitaxel). During the initial three treatment cycles, the patient was assessed as having stable disease (SD) according to RECIST 1.1 criteria. However, following two additional cycles of combination therapy, the primary tumor mass increased from 4.9 cm to 13.2 cm, accompanied by the development of new lung lesions, ascites, and pelvic metastases. He succumbed to respiratory failure one month later. Retrospective analysis revealed that the patient had MDM4 amplification, identified as a high-risk factor for hyperprogressive disease (HPD). To our knowledge, this is the first reported case of HPD in pancreatic cancer with multiple metastases treated using combination therapy. We investigated the potential mechanisms and reviewed the latest literature on predictive factors for HPD. These findings suggest that while chemotherapy combined with immunotherapy may hold promise for treating pancreatic cancer, it is imperative to identify and closely monitor patients with high-risk factors for HPD when using immunotherapy.

In order to assess the potential for implementing the 1-hydroxyethylidene-1，1-diphosphonic acid (HEDP) copper plating process in engineering applications， copper coatings were prepared on the surfaces of A3 steel substrates using HEDP plating method and cyanide plating method.The macroscopic and microscopic morphologies， deposition rates， dispersion abilities， and deep plating capabilities of the copper coatings produced by the two processes were compared.Additionally， the coating adhesion and hydrogen embrittlement performance of the HEDP copper plating layer were characterized.Results showed that the HEDP copper plating layer exhibited fine crystallization with a dense distribution of grain grooves and undulations.The cyanide copper plating layer， on the other hand， displayed a granular structure with grains of varying sizes.At a current density of 1.0 A/dm2， the deposition rate of the HEDP copper coating reached 0.19 μm/min， which was 35.7%higher than the 0.14 μm/min deposition rate observed in the cyanide copper plating process.The dispersion and deep plating capabilities of both the HEDP and cyanide copper plating processes were found to be comparable.Additionally， the HEDP copper plating layer demonstrated good adhesion to the steel substrate and qualified hydrogen embrittlement performance.

Abstract Background Seed amplification assays (SAA) enable the amplification of pathological misfolded proteins, including α-synuclein (αSyn), in both tissue homogenates and body fluids of Parkinson’s disease (PD) patients. SAA involves repeated cycles of shaking or sonication coupled with incubation periods. However, this amplification scheme has limitations in tracking protein propagation due to repeated fragmentation. Methods We introduced a modified form of SAA, known as Quiescent SAA (QSAA), and evaluated biopsy and autopsy samples from individuals clinically diagnosed with PD and those without synucleinopathies (control group). Brain biopsy samples were obtained from 14 PD patients and 6 controls without synucleinopathies. Additionally, skin samples were collected from 214 PD patients and 208 control subjects. Data were analyzed from April 2019 to May 2023. Results QSAA successfully amplified αSyn aggregates in brain tissue sections from mice inoculated with pre-formed fibrils. In the skin samples from 214 PD cases and 208 non-PD cases, QSAA demonstrated high sensitivity (90.2%) and specificity (91.4%) in differentiating between PD and non-PD cases. Notably, more αSyn aggregates were detected by QSAA compared to immunofluorescence with the pS129-αSyn antibody in consecutive slices of both brain and skin samples. Conclusion We introduced the new QSAA method tailored for in situ amplification of αSyn aggregates in brain and skin samples while maintaining tissue integrity, providing a streamlined approach to diagnosing PD with individual variability. The integration of seeding activities with the location of deposition of αSyn seeds advances our understanding of the mechanism underlying αSyn misfolding in PD.

The temperature control of the air-cooled proton exchange membrane fuel cell (PEMFC) is important for effective and safe operation. To develop a practical and precise controller, this study combines the Radial Basis Function (RBF) neural network with Back Propagation neural network adaptive Proportion Integration Differentiation (BP-PID), and then a metaheuristic algorithm is used to optimize the parameters of RBF-BP-PID for further improvement in temperature control. First, an air-cooled PEMFC system model is established. To match the simulation data with the experimental data, Teaching Learning Based Optimization–Differential Evolution (TLBO-DE) is proposed to identify the unknown parameters, and the maximum relative error is

Abstract To address the challenges posed by imbalanced and limited battlefield data, which typically results in complex models prone to overfitting during training, we introduce a novel diffusion model grounded in Wasserstein distance (WDiffusion) tailored for the multi-categorical and multivariate characteristics inherent to intent recognition data. Subsequently, we propose a streamlined tactical intent recognition framework predicated on gate recurrent unit (GRU), designed to enhance model responsiveness, and train it on an innovative dataset. Comparative experimental analyses corroborate that the synthetic data generated via WDiffusion significantly outperforms other prevalent generation models. Furthermore, the WDiffusion-GRU model achieves a recognition accuracy of 97.09%, surpassing current aerial target intent recognition models by more than 1.07%. This advancement maintains high recognition precision while substantially curtailing model parameters, thereby amplifying the agility and reliability of battlefield commanders’ decision-making processes.

ObjectiveTo summarize typical situations of illegal addition， the illegal drug addition to ordinary food sold online that claimed to reduce weight was investigated， and its typical external characteristics analyzed.MethodsHigh throughput screening method and liquid chromatography tandem mass spectrometry method that could detect multiple types of compounds simultaneously and quantification accurately were developed. The packaging information， typical ingredients， gifts， production enterprises， and other external typical characteristics of the product were sorted out， and the correlation between detection results and external typical characteristics was analyzed.Results22.09% （19/86） of the weight loss claiming samples purchased online added drugs， and the drug addition behavior showed characteristics such as escape addition， combination addition， and main and auxiliary addition. There were certain correlations between drug addition and external typical features. Typical ingredients， gifts， trial products， products involving OEM， and products labeled with liability insurance had a higher probability of drug addition.ConclusionTypical situations analysis and summarization that are prone to illegal addition ， and we expected to give consumers moderate consumption advices and provide precise guidance for the regulation of illegal added products.

Abstract Improving the performance of proton exchange membrane fuel cells (PEMFCs) requires deep understanding of the reactive transport processes inside the catalyst layers (CLs). In this study, a particle-overlapping model is developed for accurately describing the hierarchical structures and oxygen reactive transport processes in CLs. The analytical solutions derived from this model indicate that carbon particle overlap increases ionomer thickness, reduces specific surface areas of ionomer and carbon, and further intensifies the local oxygen transport resistance (R other). The relationship between R other and roughness factor predicted by the model in the range of 800-1600 s m-1 agrees well with the experiments. Then, a multiscale model is developed by coupling the particle-overlapping model with cell-scale models, which is validated by comparing with the polarization curves and local current density distribution obtained in experiments. The relative error of local current density distribution is below 15% in the ohmic polarization region. Finally, the multiscale model is employed to explore effects of CL structural parameters including Pt loading, I/C, ionomer coverage and carbon particle radius on the cell performance as well as the phase-change-induced (PCI) flow and capillary-driven (CD) flow in CL. The result demonstrates that the CL structural parameters have significant effects on the cell performance as well as the PCI and CD flows. Optimizing the CL structure can increase the current density and further enhance the heat-pipe effect within the CL, leading to overall higher PCI and CD rates. The maximum increase of PCI and CD rates can exceed 145%. Besides, the enhanced heat-pipe effect causes the reverse flow regions of PCI and CD near the CL/PEM interface, which can occupy about 30% of the CL. The multiscale model significantly contributes to a deep understanding of reactive transport and multiphase heat transfer processes inside PEMFCs.

Abstract Background Pseudoachalasia is a rare disease that behaves similarly to achalasia (AC), making it sometimes difficult to differentiate. Case presentation We report a case of 49-year-old male with adenocarcinoma of the gastroesophageal junction misdiagnosed as achalasia. No obvious abnormalities were found in his initial examinations including upper digestive endoscopy, upper gastrointestinal imaging and chest computed tomography (CT). During the subsequent introduced-peroral endoscopic myotomy (POEM), it was found that the mucosal layer and the muscular layer had severe adhesion, which did not receive much attention, delayed the clear diagnosis and effect treatment, and ultimately led to a poor prognosis for the patient. Conclusions This case suggests that when patients with AC found mucosal and muscular adhesions during POEM surgery, the possibility should be considered that the lesion may be caused by a malignant lesion.

Objective: Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal rapidly progressive neurodegenerative disorder with no effective therapeutic interventions. We aimed to identify potential genetically-supported drug targets for sCJD by integrating multi-omics data. Methods: Multi-omics-wide association studies, Mendelian randomization, and colocalization analyses were employed to explore potential therapeutic targets using expression, single-cell expression, DNA methylation, and protein quantitative trait locus data from blood and brain tissues. Outcome data was from a case-control genome-wide association study, which included 4110 sCJD patients and 13,569 controls. Further investigations encompassed druggability, potential side effects, and associated biological pathways of the identified targets. Results: Integrative multi-omics analysis identified 23 potential therapeutic targets for sCJD, with five targets (STX6, XYLT2, PDIA4, FUCA2, KIAA1614) having higher levels of evidence. One target (XYLT2) shows promise for repurposing, two targets (XYLT2, PDIA4) are druggable, and three (STX6, KIAA1614, and FUCA2) targets represent potential future breakthrough points. The expression level of STX6 and XYLT2 in neurons and oligodendrocytes was closely associated with an increased risk of sCJD. Brain regions with high expression of STX6 or causal links to sCJD were often those areas commonly affected by sCJD. Conclusions: Our study identified five potential therapeutic targets for sCJD. Further investigations are warranted to elucidate the mechanisms underlying the new targets for developing disease therapies or initiate clinical trials.

ABSTRACT In recent years, most studies on the gut microbiome have primarily focused on feces samples, leaving the microbial communities in the intestinal mucosa relatively unexplored. To address this gap, our study employed shotgun metagenomics to analyze the microbial compositions in normal rectal mucosa and matched feces from 20 patients with colonic polyps. Our findings revealed a pronounced distinction of the microbial communities between these two sample sets. Compared with feces, the mucosal microbiome contains fewer genera, with Burkholderia being the most discriminating genus between feces and mucosa, highlighting its significant influence on the mucosa. Furthermore, based on the microbial classification and KEGG Orthology (KO) annotation results, we explored the association between rectal mucosal microbiota and factors such as age, gender, BMI, and polyp risk level. Notably, we identified novel biomarkers for these phenotypes, such as Clostridium ramosum and Enterobacter cloacae in age. The mucosal microbiota showed an enrichment of KO pathways related to sugar transport and short chain fatty acid metabolism. Our comprehensive approach not only bridges the knowledge gap regarding the microbial community in the rectal mucosa but also underscores the complexity and specificity of microbial interactions within the human gut, particularly in the Chinese population.IMPORTANCEThis study presents a system-level map of the differences between feces and rectal mucosal microbial communities in samples with colorectal cancer risk. It reveals the unique microecological characteristics of rectal mucosa and its potential influence on health. Additionally, it provides novel insights into the role of the gut microbiome in the pathogenesis of colorectal cancer and paves the way for the development of new prevention and treatment strategies.

Melasma, a prevalent pigmentary disorder, is characterized by its complex etiology, propensity for recurrence, and resistance to treatment. However, there is currently no research on melasma through bibliometrics and visualisation. This study analyses the hotspots and trends in the field based on 2,709 publications from the Web of Science Core Collection (WOSCC). We carried out bibliometric analyses using Citespace software for different countries/regions, institutions, authors, and keywords. References were also analysed using VoSviewer. The results indicate that overall, there has been an increase in publications related to melasma since 2014. According to the analysis of the collaborative network diagram, the United States, Egyptian Knowledge Bank, and Benjakul Soottawat are the most contributing countries, institutions, and authors, respectively. Reference and keyword analyses have identified the pathogenesis and treatment of melasma as a prevalent topic in recent years. And how to find new treatment options and more effective therapeutic drugs is a future research trend. This is the first bibliometric and visual analysis of melasma-related literature to explore research hotspots and trends.

ObjectiveMetagenomic next-generation sequencing (mNGS) was used to analyze the etiological distribution of refractory pneumonia in children. We compared its efficacy in pathogen diagnosis against traditional methods to provide a basis for clinical adjustment and treatment.MethodsA total of 60 children with refractory pneumonia treated at the Department of Respiratory Medicine, Children’s Hospital Affiliated with the Capital Institute of Paediatrics, from September 2019 to December 2021 were enrolled in this study. Clinical data (including sex, age, laboratory tests, complications, and discharge diagnosis) and lower respiratory tract specimens were collected, including bronchoalveolar lavage fluid (BALF), deep sputum, pleural effusion, lung abscess puncture fluid, traditional respiratory pathogens (culture, acid-fast staining, polymerase chain reaction, serological testing, etc.), and mNGS detection methods were used to determine the distribution of pathogens in children with refractory pneumonia and to compare the positive rate and diagnostic efficiency of mNGS and traditional pathogen detection for different types of pathogens.ResultsAmong the 60 children with refractory pneumonia, 43 specimens were positive by mNGS, and 67 strains of pathogens were detected, including 20.90% (14 strains) of which were Mycoplasma pneumoniae, 11.94% (8 strains) were Streptococcus pneumoniae, 7.46% (5 strains) were cytomegalovirus, and 5.97% (4 strains) were Candida albicans. Thirty-nine strains of Mycoplasma pneumoniae (41.03%, 16 strains), Streptococcus pneumoniae (10.26%, 4 strains), Candida albicans (7.69%, 3 strains), and Aspergillus (5.13%, 2 strains) were detected using traditional methods. The positive rate of mNGS detection was 90.48%, and the positive rate of the traditional method was 61.90% (p = 0.050), especially for G+ bacteria. The positive rate of mNGS was greater than that of traditional methods (p 0.05). Due to the small sample size, statistical analysis could not be conducted on viral infections.ConclusionmNGS has higher overall efficacy than traditional methods for the etiological diagnosis of refractory pneumonia in children. The application of mNGS can significantly improve the detection rate of pathogens in children with refractory pneumonia. The sensitivity and negative predictive value of mNGS for detecting G+ bacteria are greater than those of other methods, and it can exclude the original suspected pathogenic bacteria. Unnecessary antibiotic use was reduced, but there was no statistically significant difference in G- bacteria, fungi, or Mycoplasma/Chlamydia.