Mid1 promotes synovitis in rheumatoid arthritis via ubiquitin-dependent post-translational modification.

INTRODUCTION: Current anti-rheumatic drugs are primarily modulating immune cell activation, yet their effectiveness remained suboptimal. Therefore, novel therapeutics targeting alternative mechanisms, such as synovial activation, is urgently needed. OBJECTIVES: To explore the role of Midline-1 (Mid1) in synovial activation. METHODS: NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were used to establish a subcutaneous xenograft model. Wild-type C57BL/6, Mid1-/-, Dpp4-/-, and Mid1-/-Dpp4-/- mice were used to establish a collagen-induced arthritis model. Cell viability, cell cycle, qPCR and western blotting analysis were used to detect MH7A proliferation, dipeptidyl peptidase-4 (DPP4) and Mid1 levels. Co-immunoprecipitation and proteomic analysis identified the candidate protein of Mid1 substrates. Ubiquitination assays were used to determine DPP4 ubiquitination status. RESULTS: An increase in Mid1, an E3 ubiquitin ligase, was observed in human RA synovial tissue by GEO dataset analysis, and this elevation was confirmed in a collagen-induced mouse arthritis model. Notably, deletion of Mid1 in a collagen-induced arthritis model completely protected mice from developing arthritis. Subsequent overexpression and knockdown experiments on MH7A, a human synoviocyte cell line, unveiled a previously unrecognized role of Mid1 in synoviocyte proliferation and migration, the key aspects of synovial activation. Co-immunoprecipitation and proteomic analysis identified DPP4 as the most significant candidate of Mid1 substrates. Mechanistically, Mid1 promoted synoviocyte proliferation and migration by inducing ubiquitin-mediated proteasomal degradation of DPP4. DPP4 deficiency led to increased proliferation, migration, and inflammatory cytokine production in MH7A, while reconstitution of DPP4 significantly abolished Mid1-induced augmentation of cell proliferation and activation. Additionally, double knockout model showed that DPP4 deficiency abolished the protective effect of Mid1 defect on arthritis. CONCLUSION: Overall, our findings suggest that the ubiquitination of DPP4 by Mid1 promotes synovial cell proliferation and invasion, exacerbating synovitis in RA. These results reveal a novel mechanism that controls synovial activation, positioning Mid1 as a promising target for therapeutic intervention in RA.

Precision Medicine in Rheumatic Diseases: Unlocking the Potential of Antibody-Drug Conjugates.

In the era of precision medicine, antibody-drug conjugates (ADCs) have emerged as a cutting-edge therapeutic strategy. These innovative compounds combine the precision of monoclonal antibodies with the potent cell-killing or immune-modulating abilities of attached drug payloads. This unique strategy not only reduces off-target toxicity but also enhances the therapeutic effectiveness of drugs. Beyond their well established role in oncology, ADCs are now showing promising potential in addressing the unmet needs in the therapeutics of rheumatic diseases. Rheumatic diseases, a diverse group of chronic autoimmune diseases with varying etiologies, clinical presentations, and prognoses, often demand prolonged pharmacological interventions, creating a pressing need for novel, efficient, and low-risk treatment options. ADCs, with their ability to precisely target the immune components, have emerged as a novel therapeutic strategy in this context. This review will provide an overview of the core components and mechanisms behind ADCs, a summary of the latest clinical trials of ADCs for the treatment of rheumatic diseases, and a discussion of the challenges and future prospects faced by the development of next-generation ADCs. SIGNIFICANCE STATEMENT: There is a lack of efficient and low-risk targeted therapeutics for rheumatic diseases. Antibody-drug conjugates, a class of cutting-edge therapeutic drugs, have emerged as a promising targeted therapeutic strategy for rheumatic disease. Although there is limited literature summarizing the progress of antibody-drug conjugates in the field of rheumatic disease, updating the advancements in this area provides novel insights into the development of novel antirheumatic drugs.

A novel adaptive filter with a heart-rate-based reference signal for esophageal pressure signal denoising.

Esophageal pressure (Peso) is one of the most common and minimally invasive methods used to assess the respiratory and lung mechanics in patients receiving mechanical ventilation. However, the Peso measurement is contaminated by cardiogenic oscillations (CGOs), which cannot be easily eliminated in real-time. The field of study dealing with the elimination of CGO from Peso signals is still in the early stages of its development. In this study, we present an adaptive filtering-based method by constructing a reference signal based on the heart rate and sine function to remove CGOs in real-time. The proposed technique is tested using clinical data acquired from 20 patients admitted to the intensive care unit. Lung compliance ( QUOTE ) and esophageal pressure swings (△Pes) are used to evaluate the performance and efficiency of the proposed technique. The CGO can be efficiently suppressed when the constructional reference signal contains the fundamental, and second and third harmonic frequencies of the heart rate signal. The analysis of the data of 8 patients with controlled mechanical ventilation reveals that the standard deviation/mean of the QUOTE is reduced by 28.4-79.2% without changing the QUOTE and the △Pes measurement is more accurate, with the use of our proposed technique. The proposed technique can effectively eliminate the CGOs from the measured Peso signals in real-time without requiring additional equipment to collect the reference signal.

Self-Assembly of Cluster-Mediated 3D Catenanes with Size-Specific Recognition Behavior.

Although interlocked three-dimensional molecules display unique properties associated with their spatial structures, their synthesis and study of their host-guest properties remain challenging. We report the formation of a novel [2]catenane, [Et4N]@[(Tp*WS3Cu3Cl)2(cis-bpype)3]2(OTf)5 ([Et4N][1](OTf)5), by self-assembly of the cluster node [Tp*WS3Cu3Cl]+ and the organic linker (Z)-1,2-diphenyl-1,2-bis(4-(pyridin-4-yl)phenyl)ethene (cis-bpype). Single-crystal X-ray and NMR analyses established that [1]4+ is formed by the interpenetration of two cluster-organic cages. Unique cation-in-cation host-guest complexes were observed with this catenane. The crystalline, empty catenane was formed by taking advantage of the electrostatic repulsion-induced weak binding of the host. Encapsulation experiments also reveal that the empty catenane can adaptively encapsulate cations such as [Et4N]+ and [Pr4N]+ in the cross cavity but is unable to encapsulate [Bu4N]+ and [Me4N]+, although the size of the latter is compatible with that of the cavity. Theoretical calculations and volume analysis allow to unravel the ingenious role of catenane structures and the interplay between electrostatic repulsion and attractive noncovalent interactions for size-specific recognition behavior in host-guest systems involving species with similar electric charges.

Health-Related Quality of Life and Influencing Factors in Coronary Heart Disease Based on the Scale QLICD-CHD (V2.0): A Cross-Sectional Study.

Purpose: Coronary heart disease (CHD) is difficult to cure, so more attention should be paid to improving patients' health-related quality of life (HRQoL). This paper focuses on identifying factors that affect HRQoL. Patients and Methods: Overall, 189 in-patients with coronary heart disease were investigated at the Affiliated Hospital of Guangdong Medical University between 2015 and 2016. The scale Quality of Life Instruments for Chronic Diseases-Coronary heart disease (QLICD-CHD V2.0) was used to evaluate HRQoL and collect demographic information. Medical records were applied to collect patients' clinical indicators. A simple correlation analysis, Student's t-test, and a one-way analysis of variance were first performed to filter factors that might associate with HRQoL, and multiple linear regression was applied to finally identify related factors. Results: Findings from multiple linear regression showed that the total score was related to family economy, treatment, indirect bilirubin, and albumin with regression coefficient B=5.209, -6.615, 0.378, and 0.548, respectively. The physical functions were related to treatment, albumin, globular proteins, chloride, and red blood cell count with B=-9.031, 1.000, 0.612, 1.320, and 5.161, respectively. The psychological function was in association with family economy, clinical course, serum phosphorus, and percentage of lymphocyte population with B=7.487, 6.411, -16.458, and 0.090, respectively. The social function was associated with family economy, blood urea nitrogen, serum creatinine, and platelet distribution width with B=7.391, 1.331, -0.060, and -0.929, respectively. The special module was in association with treatment, indirect bilirubin, and serum calcium with B=-7.791, 0.414, and 23.017, respectively. Conclusion: Clinical indicators including albumin, globular proteins, chloride, red blood cell count, serum phosphorus, percentage of lymphocyte population, blood urea nitrogen, serum creatinine, platelet distribution width, indirect bilirubin, and serum calcium, as well as socio-demographic factors including the family economy, clinical course, and treatment, may affect coronary heart disease patients' HRQoL.

Determinants of gastric cancer screening attendance in Southeastern China: a cross-sectional study.

OBJECTIVES: This study aimed to identify the determinants of gastric cancer screening attendance among individuals aged 40 years in a region with high gastric cancer in China. DESIGN: An anonymous, cross-sectional survey was conducted between October 2021 and March 2022. SETTING: A self-administered online survey was conducted in Fujian Province in Southeastern China. PARTICIPANTS: People aged 40 years living in five selected cities in Fujian Province with no history of cancer. MAIN OUTCOME MEASURES: Gastric cancer screening attendance was measured with the question 'Have you ever been screened for gastric cancer in the past'. RESULTS: In total, 2547 complete responses were obtained. The mean age of respondents was 47.72±7.20 years, and 59.8% were men. A total of 42.6% of participants reported that they had undergone gastric cancer screening. The result of multivariable logistic regression analysis showed that participants with a first-degree relative affected with gastric cancer (OR=2.02, 95% CI: 1.58 to 2.59) and high perceived susceptibility of gastric cancer (OR=2.03, 95% CI: 1.58 to 2.59) were the strongest facilitators for screening attendance. Other factors positively associated with screening attendance were age 51-60 years (OR=1.69, 95% CI: 1.31 to 2.18), living in urban regions (OR=1.27, 95% CI: 1.05 to 1.55), friends/neighbours/colleagues with gastric cancer (OR=1.30, 95% CI: 1.07 to 1.58), history of chronic gastric disease (OR=1.90, 95% CI: 1.57 to 2.30), perceived high cost (OR=1.28, 95% CI: 1.01 to 1.61) and physician recommendation (OR=1.71, 95% CI: 1.36 to 2.16). On the other hand, factors negatively associated with screening attendance included perceived barriers, namely screening is only necessary when symptoms present (OR=0.71, 95% CI: 0.58 to 0.87) and perceived appointment for gastroscopy screening is difficult and time-consuming (OR=0.75, 95% CI: 0.60 to 0.94). No significant association was found between knowledge level and participation in screening. CONCLUSION: This study highlights important individual-level factors and barriers to gastric cancer screening. Strategies targeting under-screened populations and eliminating patient-perceived barriers to gastric cancer screening are essential.

Medical Image Classification Using Light-weight CNN with Spiking Cortical Model Based Attention Module.

In the field of disease diagnosis where only a small dataset of medical images may be accessible, the light-weight convolutional neural network (CNN) has become popular because it can help to avoid the over-fitting problem and improve computational efficiency. However, the feature extraction capability of the light-weight CNN is inferior to that of the heavy-weight counterpart. Although the attention mechanism provides a feasible solution to this problem, the existing attention modules, such as the squeeze and excitation module and the convolutional block attention module, have insufficient non-linearity, thereby influencing the ability of the light-weight CNN to discover the key features. To address this issue, we have proposed a spiking cortical model based global and local (SCM-GL) attention module. The SCM-GL module analyzes the input feature maps in parallel and decomposes each map into several components according to the relation between pixels and their neighbors. The components are weighted summed to obtain a local mask. Besides, a global mask is produced by discovering the correlation between the distant pixels in the feature map. The final attention mask is generated by combining the local and global masks, and it is multiplied by the original map so that the important components can be highlighted to facilitate accurate disease diagnosis. To appreciate the performance of the SCM-GL module, this module and some mainstream attention modules have been embedded into the popular light-weight CNN models for comparison. Experiments on the classification of brain MR, chest X-ray, and osteosarcoma image datasets demonstrate that the SCM-GL module can significantly improve the classification performance of the evaluated light-weight CNN models by enhancing the ability of discovering the suspected lesions and it is generally superior to state-of-the-art attention modules in terms of accuracy, recall, specificity and F1 score.

Multi-dimensional psychosocial factors influencing the willingness to receive a COVID-19 vaccine booster: A survey among the public in Mainland China.

This study aimed to investigate multi-dimensional psychological and social factors that influence the willingness to receive a COVID-19 vaccine booster in China. A nationwide cross-sectional online survey was conducted between March and April 2022. A total of 6375 complete responses were received. The majority were of age 18 to 40 years old (80.0%) and college-educated (49.2%). In total, 79% responded extremely willing to receive a COVID-19 vaccine booster. By demographics, younger age, females, higher education, and participants with the lowest income reported higher willingness. Having a very good health status (odds ratio [OR] 3.56, 95% confidence interval [CI] 2.92-4.34) and a higher score of vaccine confidence (OR 3.50, 95% CI 2.98-4.11) were associated with an increased willingness to receive a booster shot. Experiencing no side effects with primary COVID-19 vaccination (OR 2.46, 95% CI 1.89-3.20) and higher perceived susceptibility of COVID-19 infection (OR 2.38, 95% CI 1.92-2.95) were also associated with an increased willingness to receive a booster shot. A variety of psychosocial factors, namely having no chronic diseases, lower perceived concern over the safety of a booster shot, higher perceived severity of COVID-19 infection, and a higher level of institutional trust, were also significantly associated with greater willingness to get a booster shot. In conclusion, the present study adds evidence to the significant role of psychosocial factors in predicting COVID-19 vaccine booster acceptance and provides insights to design interventions to increase booster uptake in certain targeted demographic groups.

High-risk population's knowledge of risk factors and warning symptoms and their intention toward gastric cancer screening in Southeastern China.

Background: As the incidence of gastric cancer (GC) increases sharply in adults aged over 40 years, screening of this high-risk population is important. This study aimed to explore knowledge level of GC related risk factors and symptoms, and to identify influencing factors associated with intention toward GC screening among people aged 40 years old and above in China. Methods: A cross-sectional, web-based survey was conducted among people aged 40 years old and above between October 2021 and March 2022 in Southeastern China. The participants' knowledge was assessed by a series of questions about risk factors (24-item scale) and warning symptoms (14-item scale). Results: A total of 2547 complete responses were received. The mean age was 47.72 (±7.20) years and near 60% were male. Respondents had a moderate level of knowledge about risk factors and warning symptoms of GC. The total mean knowledge score was 23.9 (±9.8) out of a possible score of 38. Majority (80%) of respondents reported intention to be screened for GC in the next 5 years. The most influential predictors of screening intention were income level (OR = 2.13, 95% CI: 1.36-3.32), perceived benefits (OR = 1.99, 95% CI: 1.33-2.73), perceived severity (OR = 1.68, 95% CI: 1.20-2.34), ever took GC screening (OR = 1.63, 95% CI: 1.28-2.08), perceived poor overall health (OR = 1.59, 95% CI: 1.19-2.11), and perceived barriers (OR = 1.56, 95% CI: 1.17-2.09). Other significant factors were ever diagnosed with chronic gastric diseases, total knowledge score, and cues-to-action. The major reasons for not willing to take screening were "endoscopy is uncomfortable" (29.6%), "worry about screening results" (23.6%), and "have no symptoms" (21.3%). Conclusion: High-risk population aged 40 years and above expressed high intention to receive GC screening. Intervention to improve health promotion and reduce the barriers to uptake of GC screening among high-risk populations in China is warranted.

Development of a diagnostic assay by three-tube multiplex real-time PCR for simultaneous detection of nine microorganisms causing acute respiratory infections.

Acute respiratory infections are widespread in vulnerable populations of all ages and are characterized by a variety of symptoms. The underlying infection can be caused by a multitude of microorganisms, including viruses and bacteria. Early detection of respiratory infections through rapid pathogen screening is vital in averting infectious respiratory disease epidemics. This study utilized a multiplex real-time PCR system to develop a three-tube reverse transcription-PCR (RT-PCR) assay, enabling simultaneously detect nine respiratory pathogens, including: influenza A and B, adenovirus, respiratory syncytial virus (RSV), Streptococcus pneumoniae, Legionella pneumophila, Haemophilus influenzae, Chlamydia pneumoniae, and Mycoplasma pneumoniae. This technique utilizes a one-step assay, with specifically designed TaqMan primer-probe sets combined in the same tube. This assay provided rapid and simplified detection of the nine prevalent pathogens, as well as increased sensitivity and reduced cross-contamination. This assay was evaluated using 25 related viral/bacterial strains as positive references, the other 25 irrelevant strains as negative controls, and clinical specimens from 179 patients. All positive strains were detected with no amplification of the non-target microorganism mixtures and the assay's detection limits ranged between 250-500 copies/ml (1.25-2.5 copies/reaction). A total of 167 (93.3%) samples tested positive for at least one of the pathogens identified; 109 of these samples were from patients confirmed to have RSV infections. The diagnostic accuracy of our assay was further confirmed by matching results from classical direct immunofluorescence assay and nucleotide sequencing. These data demonstrate the innovative multiplex real-time PCR assay as a promising alternative to the current approaches used for early screening of acute respiratory infections.

Recurrent neural network based high-precision position compensation control of magnetic levitation system.

For improving the dynamic quality and steady-state performance, the hybrid controller based on recurrent neural network (RNN) is designed to implement the position control of the magnetic levitation ball system in this study. This hybrid controller consists of a baseline controller, an RNN identifier, and an RNN controller. In the hybrid controller, the baseline controller based on the control law of proportional-integral-derivative is firstly employed to provide the online learning sample and maintain the system stability at the early control phase. Then, the RNN identifier is trained online to learn the accurate inverse model of the controlled object. Next, the RNN controller shared the same structures and parameters with the RNN identifier is applied to add the precise compensation control quantity in real-time. Finally, the effectiveness and advancement of the proposed hybrid control strategy are comprehensively validated by the simulation and experimental tests of tracking step, square, sinusoidal, and trapezoidal signals. The results indicate that the RNN-based hybrid controller can obtain higher precision and faster adjustment than the comparison controllers and has strong anti-interference ability and robustness.

[Activation of JNK induces apoptosis to autophagy conversion and enhances the survival of oxygen-glycogen deprived rat neurons].

Objective To investigate the efficacy and mechanism of c-Jun N-terminal kinase (JNK) in boosting survival of oxygen glucose deprivation (OGD) rat neurons. Methods The cortex neurons from fetal rats were primarily cultured to prepare a model of OGD neurons in vitro, and the characteristic endpoints were filtered to intervene with JNK inducer anisomycin (AN), respectively. The cells were randomly divided into control group, solvent control group (a same volume of solvent DMSO was added into the culture medium of the OGD neuron), AN group (OGD neurons were treated with JNK inducer AN for 5 hours at the end of OGD). After that, Western blotting and immunofluorescence cytometry were respectively performed to detect the protein expressions in OGD neurons, including beclin 1, microtubule-associated protein 1 light chain 3 (LC3), B cell lymphoma 2 (Bcl2), caspase-3, P62, ubiquitin, cathepsin B and lysosomal associated membrane protein 1 (LAMP1). The cell activity was evaluated by CCK-8 assay, and the axon length was measured by IPP software. Results Activation of JNK significantly promoted the expressions of beclin 1, LC3, and Bcl2, and markedly reduced the content of beclin 1-Bcl2 complex and attenuated the expressions of P62 and ubiquitin. Meanwhile, the expressions of cathepsin B and LAMP1 were not obviously altered. In this way, the survival rate of OGD neurons was improved. Conclusion Activation of JNK exerts a neuroprotective effect by facilitating dissociation of beclin 1-Bcl2 and inducing a switch from apoptosis to autophagy in OGD neurons.

m6A demethylase FTO regulates the apoptosis and inflammation of cardiomyocytes via YAP1 in ischemia-reperfusion injury.

Reperfusion therapy after acute myocardial infarction can induce myocardial ischemia-reperfusion injury (IRI). Novel evidence has illustrated that N6-methyladenosine (m6A) modification modulates the myocardial IRI progression. Here, our study focuses on the role of m6A methyltransferase fat mass and obesity-associated protein (FTO) in myocardial ischemia/reoxygenation injury and explores potential regulatory mechanisms. Results discovered that FTO down-expressed in myocardial IRI mice and hypoxia/reoxygenation (H/R)-induced cardiomyocytes. Functionally, FTO overexpression attenuated the H/R-induced apoptosis and inflammation of cardiomyocytes. Mechanistically, methylated RNA immunoprecipitation quantitative polymerase chain reaction (MeRIP-qPCR) assay and RIP assay revealed that Yap1 mRNA acted as the target of FTO in cardiomyocytes. Moreover, FTO uninstalled the methylation of Yap1 mRNA, and enforced the stability of Yap1 mRNA. Taken together, our study reveals the role of FTO in H/R-induced myocardial cell injury via m6A-dependent manner, which may provide a new approach to improve myocardial IRI.

Neural network compensation control of magnetic levitation ball position based on fuzzy inference.

Aiming at the problem of poor transient performance of the control system caused by the control uncertainty of the undertrained neural network, a neural network compensation control method based on fuzzy inference is proposed in this paper. The method includes three control substructures: fuzzy inference block, neural network control block and basic control block. The fuzzy inference block adaptively adjusts the neural network compensation control quantity according to the control error and the error rate of change, and adds a dynamic adjustment factor to ensure the control quality at the initial stage of network learning or at the moment of signal transition. The neural network control block is composed of an identifier and a controller with the same network structure. After the identifier learns the dynamic inverse model of the controlled object online, its training parameters are dynamically copied to the controller for real-time compensation control. The basic control block uses a traditional PID controller to provide online learning samples for the neural network control block. The simulation and experimental results of the position control of the magnetic levitation ball show that the proposed method significantly reduces the overshoot and settling time of the control system without sacrificing the steady-state accuracy of neural network compensation control, and has good transient and steady-state performance and strong robustness simultaneously.

New wine in old bottles: current progress on P5 ATPases.

P5 ATPases are evolutionarily conserved P-type transporters. Despite their important roles in the endoplasmic reticulum (ER) and in lysosomes, the substrate specificities and transporting mechanisms of P5 ATPases have remained mysterious. Recently, several studies have provided genetic, biochemical, and structural evidence to help elucidate the physiological functions and substrates of P5 ATPases. Here, we summarize this progress and discuss the potential transport mechanisms of the P5 ATPases-in particular, P5A ATPase-for further study.

Serum Uric Acid and Cardiovascular or All-Cause Mortality in Peritoneal Dialysis Patients: A Systematic Review and Meta-Analysis.

Background: Studies have shown inconsistent associations between serum uric acid (SUA) levels and mortality in peritoneal dialysis (PD) patients. We conducted this meta-analysis to determine whether SUA levels were associated with cardiovascular or all-cause mortality in PD patients. Methods: PubMed, Embase, Web of Science, the Cochrane Library, CNKI, VIP, Wanfang Database, and trial registry databases were systematically searched up to April 11, 2021. Cohort studies of SUA levels and cardiovascular or all-cause mortality in PD patients were obtained. Random effect models were used to calculate the pooled adjusted hazard ratio (HR) and corresponding 95% confidence interval (CI). Sensitivity analyses were conducted to assess the robustness of the pooled results. Subgroup analyses and meta-regression analyses were performed to explore the sources of heterogeneity. Funnel plots, Begg's tests, and Egger's tests were conducted to evaluate potential publication bias. The GRADE approach was used to rate the certainty of evidence. This study was registered with PROSPERO, CRD42021268739. Results: Seven studies covering 18,113 PD patients were included. Compared with the middle SUA levels, high SUA levels increased the risk of all-cause mortality (HR = 1.74, 95%CI: 1.26-2.40, I 2 = 34.8%, τ2 = 0.03), low SUA levels were not statistically significant with the risk of all-cause or cardiovascular mortality (HR = 1.04, 95%CI: 0.84-1.29, I 2 = 43.8%, τ2 = 0.03; HR = 0.89, 95%CI: 0.65-1.23, I 2 = 36.3%, τ2 = 0.04; respectively). Compared with the low SUA levels, high SUA levels were not statistically associated with an increased risk of all-cause or cardiovascular mortality (HR = 1.19, 95%CI: 0.59-2.40, I 2 = 88.2%, τ2 = 0.44; HR = 1.22, 95%CI: 0.39-3.85, I 2 = 89.3%, τ2 = 0.92; respectively). Conclusion: Compared with middle SUA levels, high SUA levels are associated with an increased risk of all-cause mortality in PD patients. SUA levels may not be associated with cardiovascular mortality. More high-level studies, especially randomized controlled trials, are needed to determine the association between SUA levels and cardiovascular or all-cause mortality in PD patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021268739, identifier: CRD42021268739.

Melibiose Confers a Neuroprotection against Cerebral Ischemia/Reperfusion Injury by Ameliorating Autophagy Flux via Facilitation of TFEB Nuclear Translocation in Neurons.

Autophagic/lysosomal dysfunction is a critical pathogenesis of neuronal injury after ischemic stroke. Trehalose has been validated to restore the impaired autophagy flux by boosting transcription factor EB (TFEB) nuclear translocation, but orally administrated trehalose can be greatly digested by intestinal trehalase before entering into brain. Melibiose (MEL), an analogue of trehalose, may thoroughly exert its pharmacological effects through oral administration due to absence of intestinal melibiase. The present study was to investigate whether melibiose could also confer a neuroprotection by the similar pharmacological mechanism as trehalose did after ischemic stroke. The rats were pretreated with melibiose for 7 days before middle cerebral artery occlusion (MCAO) surgery. Twenty-four hours following MCAO/reperfusion, the cytoplasmic and nuclear TFEB, and the proteins in autophagic/lysosomal pathway at the penumbra were detected by western blot and immunofluorescence, respectively. Meanwhile, the neurological deficit, neuron survival, and infarct volume were assessed to evaluate the therapeutic outcomes. The results showed that the neurological injury was significantly mitigated in MCAO+MEL group, compared with that in MCAO group. Meanwhile, nuclear TFEB expression in neurons at the penumbra was significantly promoted by melibiose. Moreover, melibiose treatment markedly enhanced autophagy flux, as reflected by the reinforced lysosomal capacity and reduced autophagic substrates. Furthermore, the melibiose-elicited neuroprotection was prominently counteracted by lysosomal inhibitor Bafilomycin A1 (Baf-A1). Contrarily, reinforcement of lysosomal capacity with EN6 further improved the neurological performance upon melibiose treatment. Our data suggests that melibiose-augmented neuroprotection may be achieved by ameliorating autophagy flux via facilitation of TFEB nuclear translocation in neurons after ischemic stroke.

Batch Similarity Based Triplet Loss Assembled into Light-Weighted Convolutional Neural Networks for Medical Image Classification.

In many medical image classification tasks, there is insufficient image data for deep convolutional neural networks (CNNs) to overcome the over-fitting problem. The light-weighted CNNs are easy to train but they usually have relatively poor classification performance. To improve the classification ability of light-weighted CNN models, we have proposed a novel batch similarity-based triplet loss to guide the CNNs to learn the weights. The proposed loss utilizes the similarity among multiple samples in the input batches to evaluate the distribution of training data. Reducing the proposed loss can increase the similarity among images of the same category and reduce the similarity among images of different categories. Besides this, it can be easily assembled into regular CNNs. To appreciate the performance of the proposed loss, some experiments have been done on chest X-ray images and skin rash images to compare it with several losses based on such popular light-weighted CNN models as EfficientNet, MobileNet, ShuffleNet and PeleeNet. The results demonstrate the applicability and effectiveness of our method in terms of classification accuracy, sensitivity and specificity.

Associations between the serum levels of PFOS/PFOA and IgG N-glycosylation in adult or children.

BACKGROUND: Perfluorooctanoic acid (PFOA) and perfluorooctanoic sulfonate (PFOS) have been shown to be associated with disease development. Immunoglobulin G (IgG) N-glycosylation plays a vital role in human immune system and inflammatory activities. Altered IgG glycosylation was one of the molecular markers of various disorders. However, whether the chemicals affect IgG glycosylation has not been investigated. METHODS: Serum samples of 190 individuals including 95 adults and 95 children were selected based on the sex, age and PFOA/PFOS concentration. IgG N-glycome profile was obtained from glycan release, derivatization, and MALDI-MS analysis. One-factor ANOVA test was performed to analyze the association between different levels of PFOS/PFOA and IgG glycosylation changes. Evaluation of the diagnostic performance of significantly changed IgG glycosylation was performed by receiver operating characteristic curve. PFOS/PFOA concentrations were studied in relation to IgG glycosylation by 3D-nonlinear regression analysis. RESULTS: 10 of the 28 individual IgG glycans were significantly altered between different levels of PFOS/PFOA in adult serum. Among children with high serum levels of PFOS or PFOA, a total of 12 IgG N-glycans were markedly different from those with lower serum PFOS/PFOA. The glycan derived traits for adults with higher serum PFOS or PFOA were marked by significant alterations in IgG digalactosylation, agalactosylation, fucosylation, fucosylated sialylation, and disialylation. Similarly, pronounced changes in agalactosylation, digalactosylation, mono-sialylation and total sialylation, as well as neutral and sialo bisection, were associated with elevated serum PFOS or PFOA in children. Several glycans gained moderately accurate scores of area under the curve for diagnosis of PFOS or PFOA pollution. Nonlinear surface fitting showed the independent or coordinate effect of PFOS or PFOA on the expression of IgG glycosylation. CONCLUSIONS: High levels of PFOS or PFOA in human serum were strongly associated with altered IgG glycosylation and therefore are a potential risk factor for the development of diseases.