Multiple sclerosis and COVID-19: a northern China survey.

BACKGROUND: There is insufficient data on severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) infection in Chinese patients with multiple sclerosis (pwMS). This study aims to explore the manifestation of pwMS during the Coronavirus disease 2019 (COVID-19) pandemic and the effect of SARS-CoV-2 infection on the prognosis of MS in northern China. METHODS: In this cross-sectional study, an online self-administered questionnaire and telephone interviews were conducted among pwMS of northern China. Clinical correlation of SARS-CoV-2 infection since the onset of the COVID-19 pandemic in northern China was analyzed. RESULTS: 164 patients with an average age of 38.9 ± 12.2 years were included, of which 57.3% had a disease course ≤ 5 years. 33.5% of the patients were COVID-19 vaccinated. 87.2% received disease-modifying therapy (DMT), and the average immunotherapy duration was 1.9 ± 1.6 years. 83.5% were SARS-CoV-2 infected, 14.6% reported worsening of their original condition after infection, and 5.1% had a relapse of MS. Shorter disease course was independently related to infection risk (P = 0.046), whereas increasing age was related to aggravated behavioral symptoms (P = 0.008). However, gender, vaccination, and DMT were not associated with susceptibility or poor prognosis. CONCLUSION: A shorter disease course is independently associated with an increased risk of SARS-CoV-2 infection, and age is associated with worsening disability. It seems to be safe and necessary to use DMT during the pandemic, however, the use of B cell-depletion agents should be approached with caution.

Differential contributions of G protein- or arrestin subtype-mediated signalling underlie urocortin 3-induced somatostatin secretion in pancreatic δ cells.

BACKGROUND AND PURPOSE: Pancreatic islets are modulated by cross-talk among different cell types and paracrine signalling plays important roles in maintaining glucose homeostasis. Urocortin 3 (UCN3) secreted by pancreatic ß cells activates the CRF2 receptor (CRF2R) and downstream pathways mediated by different G protein or arrestin subtypes in δ cells to cause somatostatin (SST) secretion, and constitutes an important feedback circuit for glucose homeostasis. EXPERIMENTAL APPROACH: Here, we used Arrb1-/-, Arrb2-/-, Gsfl/fl and Gqfl/fl knockout mice, the G11-shRNA-GFPfl/fl lentivirus, as well as functional assays and pharmacological characterization to study how the coupling of Gs, G11 and ß-arrestin1 to CRF2R contributed to UCN3-induced SST secretion in pancreatic δ cells. KEY RESULTS: Our study showed that CRF2R coupled to a panel of G protein and arrestin subtypes in response to UCN3 engagement. While RyR3 phosphorylation by PKA at the S156, S2706 and S4697 sites may underlie the Gs-mediated UCN3- CRF2R axis for SST secretion, the interaction of SYT1 with ß-arrestin1 is also essential for efficient SST secretion downstream of CRF2R. The specific expression of the transcription factor Stat6 may contribute to G11 expression in pancreatic δ cells. Furthermore, we found that different UCN3 concentrations may have distinct effects on glucose homeostasis, and these effects may depend on different CRF2R downstream effectors. CONCLUSIONS AND IMPLICATIONS: Collectively, our results provide a landscape view of signalling mediated by different G protein or arrestin subtypes downstream of paracrine UCN3- CRF2R signalling in pancreatic ß-δ-cell circuits, which may facilitate the understanding of fine-tuned glucose homeostasis networks.

Association between metabolic syndrome severity score and cardiovascular disease: results from a longitudinal cohort study on Chinese adults.

Objective: This study aimed to quantify the severity of metabolic syndrome(MetS) and investigate its association with cardiovascular disease(CVD) risk on Chinese adults. Methods: 13,500 participants from the Zhejiang Adult Chronic Disease Study were followed up between 2010 and 2021. A continuous MetS severity score derived from the five components of MetS was used to quantify MetS severity, and the association between MetS severity and the risk of incident CVD was assessed using Cox proportional hazard and restricted cubic spline regression. Results: Both the presence and severity of MetS were strongly associated with CVD risk. MetS was related to an increased risk of CVD (hazard ratio(HR):1.700, 95% confidence interval(CI): 1.380-2.094). Compared with the hazard ratio for CVD in the lowest quartile of the MetS severity score, that in the second, third, and highest quartiles were 1.812 (1.329-2.470), 1.746 (1.265-2.410), and 2.817 (2.015-3.938), respectively. A linear and positive dose-response relationship was observed between the MetS severity and CVD risk (P for non-linearity = 0.437). Similar results were found in various sensitivity analyses. Conclusion: The MetS severity score was significantly associated with CVD risk. Assessing MetS severity and further ensuring intervention measures according to the different severities of MetS may be more useful in preventing CVD.

Enhancing healthy aging with small molecules: A mitochondrial perspective.

The pursuit of enhanced health during aging has prompted the exploration of various strategies focused on reducing the decline associated with the aging process. A key area of this exploration is the management of mitochondrial dysfunction, a notable characteristic of aging. This review sheds light on the crucial role that small molecules play in augmenting healthy aging, particularly through influencing mitochondrial functions. Mitochondrial oxidative damage, a significant aspect of aging, can potentially be lessened through interventions such as coenzyme Q10, alpha-lipoic acid, and a variety of antioxidants. Additionally, this review discusses approaches for enhancing mitochondrial proteostasis, emphasizing the importance of mitochondrial unfolded protein response inducers like doxycycline, and agents that affect mitophagy, such as urolithin A, spermidine, trehalose, and taurine, which are vital for sustaining protein quality control. Of equal importance are methods for modulating mitochondrial energy production, which involve nicotinamide adenine dinucleotide boosters, adenosine 5'-monophosphate-activated protein kinase activators, and compounds like metformin and mitochondria-targeted tamoxifen that enhance metabolic function. Furthermore, the review delves into emerging strategies that encourage mitochondrial biogenesis. Together, these interventions present a promising avenue for addressing age-related mitochondrial degradation, thereby setting the stage for the development of innovative treatment approaches to meet this extensive challenge.

Monodispersed and Monofunctionalized DNA-Caged Au Nano-Clusters with Enhanced Optical Properties for STED Imaging.

The performance of Stimulated Emission Depletion (STED) microscopy depends critically on the fluorescent probe. Ultrasmall Au nanoclusters (Au NCs) exhibit large Stokes shift, and good stimulated emission response, which are potentially useful for STED imaging. However, Au NCs are polydispersed in size, sensitive to the surrounding environment, and difficult to control surface functional group stoichiometry, which results in reduced density and high heterogeneity in the labeling of biological structures. Here, this limitation is overcome by developing a method to encapsulate ultrasmall Au NCs with DNA cages, which yielded monodispersed, and monofunctionalized Au NCs that are long-term stable. Moreover, the DNA-caging also greatly improved the fluorescence quantum yield and photostability of Au NCs. In STED imaging, the DNA-caged Au NCs yielded ≈40 nm spatial resolution and are able to resolve microtubule line shapes with good labeling density and homogeneity. In contrast, without caging, the Au NCs-DNA conjugates only achieved ≈55 nm resolution and yielded spotted, poorly resolved microtubule structures, due to the presence of aggregates. Overall, a method is developed to achieve precise surface functionalization and greatly improve the monodispersity, stability, as well as optical properties of Au NCs, providing a promising class of fluorescent probes for STED imaging.

Optimization of the Zhou Tian Formula extraction technology based on AHP-CRITIC method and analysis of transfer efficiency of key components based on HPLC fingerprinting.

INTRODUCTION: Zhou Tian Formula (ZTF) is an antidepressant traditional Chinese medicine utilized widely in clinical settings for the treatment of patients with depression. However, shortcomings persist in its extraction technology and quality control. OBJECTIVE: This study aimed to propose a methodology for ZTF extraction technology based on the analytic hierarchy process (AHP)-criteria importance through intercriteria correlation (CRITIC) method and to establish a quality control framework for the efficient transfer of index components. METHOD: Firstly, we analyzed the chemical components of ZTF and determined the optimal extraction technology. Secondly, we calculated the transfer efficiency of the index components during the conversion of water decoction to extract powder and subsequently to granules. Thirdly, we established HPLC fingerprints for 15 batches of ZTF water decoction, extract powder, and granules. We employed SIMCA software to analyze the chemicals responsible for variations in quality among different batches of ZTF granules. RESULTS: We determined the optimal extraction process. The average transfer efficiency of ferulic acid, puerarin, mirificin, isoferulic acid, and calycosin during the conversion of water decoction to extract powder and subsequently to granules exceeded 41%. The HPLC fingerprints of ZTF exhibited a similarity exceeding 0.890. Variable importance in projection values indicated that calycosin, ferulic acid, and puerarin were the primary contributors to quality variations. CONCLUSIONS: The AHP-CRITIC method, coupled with an orthogonal array design, could be used for exploring extraction technology. In addition, the rules governing the transfer of index components from water decoction to extract powder, and subsequently to granules, could be applied for the evaluation and quality assessment of ZTF.

Potato virus Y viral protein 6K1 inhibits the interaction between defense proteins during virus infection.

14-3-3 proteins play vital roles in plant defense against various pathogen invasions. To date, how 14-3-3 affects virus infections in plants remains largely unclear. In this study, we found that Nicotiana benthamiana 14-3-3h interacts with TRANSLATIONALLY CONTROLLED TUMOR PROTEIN (TCTP), a susceptibility factor of potato virus Y (PVY). Silencing of Nb14-3-3h facilitates PVY accumulation, whereas overexpression of Nb14-3-3h inhibits PVY replication. The antiviral activities of 3 Nb14-3-3h dimerization defective mutants are significantly decreased, indicating that dimerization of Nb14-3-3h is indispensable for restricting PVY infection. Our results also showed that the mutant Nb14-3-3hE16A, which is capable of dimerizing but not interacting with NbTCTP, has reduced anti-PVY activity; the mutant NbTCTPI65A, which is unable to interact with Nb14-3-3h, facilitates PVY replication compared with the wild-type NbTCTP, indicating that dimeric Nb14-3-3h restricts PVY infection by interacting with NbTCTP and preventing its proviral function. As a counter-defense, PVY 6K1 interferes with the interaction between Nb14-3-3h and NbTCTP by competitively binding to Nb14-3-3h and rescues NbTCTP to promote PVY infection. Our results provide insights into the arms race between plants and potyviruses.

Case Report: Telitacicept in severe myasthenia gravis: a case study with multiple autoantibodies.

Multi-antibody-positive myasthenia gravis (MG) presentations are relatively rare, often found in older patients, and generally predict a poor prognosis. We report a case of a female patient with generalized MG, testing positive for Titin antibodies (Titin-Ab), ryanodine receptor antibodies (RyR-Ab), and acetylcholine receptor antibodies (AChR-Ab), and resistant to acetylcholinesterase inhibitors. Following unsuccessful traditional therapies, she received Telitacicept, leading to significant improvements. This case underscores Telitacicept's potential efficacy for similar patients and offers insights into the clinical characteristics of multi-antibody MG.

Corrigendum: miR-766-3p targeting BCL9L suppressed tumorigenesis, epithelial-mesenchymal transition, and metastasis through the ß-catenin signaling pathway in osteosarcoma cells.

[This corrects the article DOI: 10.3389/fcell.2020.594135.].

The pharmacology and therapeutic role of cannabidiol in diabetes.

In recent years, cannabidiol (CBD), a non-psychotropic cannabinoid, has garnered substantial interest in drug development due to its broad pharmacological activity and multi-target effects. Diabetes is a chronic metabolic disease that can damage multiple organs in the body, leading to the development of complications such as abnormal kidney function, vision loss, neuropathy, and cardiovascular disease. CBD has demonstrated significant therapeutic potential in treating diabetes mellitus and its complications owing to its various pharmacological effects. This work summarizes the role of CBD in diabetes and its impact on complications such as cardiovascular dysfunction, nephropathy, retinopathy, and neuropathy. Strategies for discovering molecular targets for CBD in the treatment of diabetes and its complications are also proposed. Moreover, ways to optimize the structure of CBD based on known targets to generate new CBD analogues are explored.

Distributionally Robust Memory Evolution With Generalized Divergence for Continual Learning.

Continual learning (CL) aims to learn a non-stationary data distribution and not forget previous knowledge. The effectiveness of existing approaches that rely on memory replay can decrease over time as the model tends to overfit the stored examples. As a result, the model's ability to generalize well is significantly constrained. Additionally, these methods often overlook the inherent uncertainty in the memory data distribution, which differs significantly from the distribution of all previous data examples. To overcome these issues, we propose a principled memory evolution framework that dynamically adjusts the memory data distribution. This evolution is achieved by employing distributionally robust optimization (DRO) to make the memory buffer increasingly difficult to memorize. We consider two types of constraints in DRO: f-divergence and Wasserstein ball constraints. For f-divergence constraint, we derive a family of methods to evolve the memory buffer data in the continuous probability measure space with Wasserstein gradient flow (WGF). For Wasserstein ball constraint, we directly solve it in the euclidean space. Extensive experiments on existing benchmarks demonstrate the effectiveness of the proposed methods for alleviating forgetting. As a by-product of the proposed framework, our method is more robust to adversarial examples than compared CL methods.

Hyperbranched Polymer Dots with Strong Absorption and High Fluorescence Quantum Yield for In Vivo NIR-II Imaging.

In order to improve the fluorescence quantum yield (QY) of NIR-II-emitting nanoparticles, D-A-D fluorophores are typically linked to intramolecular rotatable units to reduce aggregation-induced quenching. However, incorporating such units often leads to a twisted molecular backbone, which affects the coupling within the D-A-D unit and, as a result, lowers the absorption. Here, we overcome this limitation by cross-linking the NIR-II fluorophores to form a 2D polymer network, which simultaneously achieves a high QY by well-controlled fluorophore separation and strong absorption by restricting intramolecular distortion. Using the strategy, we developed polymer dots with the highest NIR-II single-particle brightness among reported D-A-D-based nanoparticles and applied them for imaging of hindlimb vasculatures and tumors as well as fluorescence-guided tumor resection. The high brightness of the polymer dots offered exceptional image quality and excellent surgical results, showing a promising performance for these applications.

Effects of pressure and temperature on topological electronic materials X2Y3 (X = As, Sb, Bi; Y = Se, Te) using first-principles.

We systematically study the thermal and topological properties of X2Y3 (X = As, Sb, Bi; Y = Se, Te) and the effects of pressure and temperature on their electronic properties using first-principles. We find that the external pressure-induced electronic topological transition occurs at about 5 GPa for Bi2Se3, and the type of band gap tends to become indirect with the increase of pressure. We also investigate the lattice expansion with temperature in quasi-harmonic approximation and further explore the effect of temperature on the volume, band gap, and volumetric thermal expansion coefficient of the studied selenides and tellurides. Finally, we calculate the evolution of the Wannier charge center of X2Y3 to determine their topological invariants, and theoretically suggest that Bi2Se3 changes from a topological to an ordinary insulator when the pressure decreases to -8 GPa; As2Se3 is found to be an ordinary insulator, while all other four compounds are always strong topological insulators at any pressure or temperature.

The RNA-binding protein LRPPRC promotes resistance to CDK4/6 inhibition in lung cancer.

Kinase inhibitors against Cyclin Dependent Kinase 4 and 6 (CDK4/6i) are promising cancer therapeutic drugs. However, their effects are limited by primary or acquired resistance in virtually all tumor types. Here, we demonstrate that Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) controls CDK4/6i response in lung cancer by forming a feedback loop with CDK6. LRPPRC binds to CDK6-mRNA, increasing the stability and expression of CDK6. CDK6 and its downstream E2F Transcription Factor 1 (E2F1), bind to the LRPPRC promoter and elevate LRPPRC transcription. The activation of the LRPPRC-CDK6 loop facilitates cell cycle G1/S transition, oxidative phosphorylation, and cancer stem cell generation. Gossypol acetate (GAA), a gynecological medicine that has been repurposed as a degrader of LRPPRC, enhances the CDK4/6i sensitivity in vitro and in vivo. Our study reveals a mechanism responsible for CDK4/6i resistance and provides an enlightening approach to investigating the combinations of CDK4/6 and LRPPRC inhibitors in cancer therapy.

Mitochondrial Protease Targeting Chimeras for Mitochondrial Matrix Protein Degradation.

Targeted protein degradation (TPD) is an emerging technique for protein regulation. Currently, all TPD developed in eukaryotic cells relies on either ubiquitin-proteasome or lysosomal systems, thus are powerless against target proteins in membrane organelles lacking proteasomes and lysosomes, such as mitochondria. Here, we developed a mitochondrial protease targeting chimera (MtPTAC) to address this issue. MtPTAC is a bifunctional small molecule that can bind to mitochondrial caseinolytic protease P (ClpP) at one end and target protein at the other. Mechanistically, MtPTAC activates the hydrolase activity of ClpP while simultaneously bringing target proteins into proximity with ClpP. Taking mitochondrial RNA polymerase (POLRMT) as a model protein, we have demonstrated the powerful proteolytic ability and antitumor application prospects of MtPTAC, both in vivo and in vitro. This is the first modularly designed TPD that can specifically hydrolyze target proteins inside mitochondria.

Deciphering the photolysis products and biological concerns of triclosan under UVC and UVA.

Triclosan (TCS) is omnipresent in the environment and has drawn increasing attention due to its potential adverse effects on human health. Direct photolysis of TCS readily occurs, especially in the surface layers of waters that receive abundant ultraviolet radiation during the daytime. However, biological concerns and the identification of toxic products during TCS photolysis have been explored limitedly. Therefore, in the present work, the structural characterization of the photolysis products by UVC and UVA were performed based on the mass spectra and fragmental ions. The results displayed that TCS was more readily eliminated by UVC than UVA, and the product species were completely different when TCS was degraded by UVC and UVA, respectively. Two products, m/z 235 and m/z 252, were produced via reductive dechlorination and nucleophilic substitution with UVC, while three dioxin-like isomer products were generated by dechlorination, cyclization and hydroxylation. Furthermore, the results of biological concerns suggested that the elimination of TCS did not represent the disappearance of biological risks. Specifically, more hazardous and photolysis products were formed during TCS photolysis with ultraviolets. For instance, the dioxin-like isomer products were highly microtoxic and genotoxic, and mildly antiestrogenic. The positive findings highlighted the biological concerns of TCS photolysis by ultraviolet radiation in the aquatic environment.

The association of body mass index and its interaction with family history of dyslipidemia towards dyslipidemia in patients with type 2 diabetes: a cross-sectional study in Zhejiang Province, China.

Objectives: This study aimed to investigate the association between body mass index (BMI) and dyslipidemia and to explore the interaction between BMI and family history of dyslipidemia towards dyslipidemia in patients with type 2 diabetes. Methods: This cross-sectional study was conducted between March and November 2018 in Zhejiang Province, China. A total of 1,756 patients with type 2 diabetes were included, physical examination data, fasting blood samples and face-to-face questionnaire survey data were collected. Restricted cubic spline analysis was used to evaluate the association between BMI and the risk of dyslipidemia. Unconditional multivariable logistic regression was used to estimate the interaction between BMI and family history of dyslipidemia towards dyslipidemia. Results: The prevalence of dyslipidemia was 53.7% in the study population. The risk of dyslipidemia elevated with increased BMI value (p for non-linearity <0.05). After adjusting for covariates, individuals with high BMI (≥24 kg/m2) and a family history of dyslipidemia had a 4.50-fold (95% CI: 2.99-6.78) increased risk of dyslipidemia compared to the normal reference group, which was higher than the risk associated with high BMI alone (OR = 1.83, 95% CI: 1.47-2.28) or family history of dyslipidemia alone (OR = 1.79 95% CI: 1.14-2.83). Significant additive interaction between high BMI and a family history of dyslipidemia was detected, with RERI, AP, and SI values of 1.88 (95% CI: 0.17-4.10), 0.42 (95% CI: 0.02-0.62), and 2.16 (95% CI: 1.07-4.37), respectively. However, stratified by status of diabetes control, this additive interaction was only find significant among patients with controlled diabetes. Conclusion: Both high BMI and a family history of dyslipidemia were related with high risk of dyslipidemia. Moreover, there were synergistic interaction between these two factors. Patients with type 2 diabetes who had a family history of dyslipidemia were more susceptible to the negative impact of being overweight or obesity on dyslipidemia.

RuCu Nanosheets with Ultrahigh Nanozyme Activity for Chemodynamic Therapy.

Nanoenzymes have been widely explored for chemodynamic therapy (CDT) in cancer treatment. However, poor catalytic efficiency of nanoenzymes, especially in the tumor microenvironment with insufficient H2 O2 and mild acidity, limits the effect of CDT. Herein, a new ultrathin RuCu nanosheet (NS) based nanoenzyme which has a large specific surface area and abundant channels and defects is developed. The RuCu NSs show superb catalytic efficiency for the oxidation of peroxidase substrate H2 O2 at a wide range of pH and their catalytic efficiency (kcat /Km = 177.2 m-1  s-1 ) is about 14.9 times higher than that of the single-atom catalyst FeN3 P. Besides being an efficient nanozyme as peroxidase, the RuCu NSs possess other two enzyme activities, not only disproportionating superoxide anion to produce H2 O2 but also consuming glutathione to keep a high concentration of H2 O2 in the tumor microenvironment for Fenton reaction. With these advantages, the RuCu NSs exhibit good performance to kill cancer cells and inhibit tumor growth in mice, demonstrating a promising potential as new CDT reagent.

How a Ferroelectric Layer Can Tune a Two-Dimensional Electron Gas at the Interface of LaInO3 and BaSnO3: A First-Principles Study.

The emerging interest in two-dimensional electron gases (2DEGs), formed at interfaces between two insulating oxide perovskites, poses a crucial fundamental question in view of future electronic devices. In the framework of density-functional theory, we investigate the possibility to control the characteristics of the 2DEG formed at the LaInO3/BaSnO3 interface by including a ferroelectric layer. To do so, we consider BaTiO3 as a prototype example and examine how the orientation of the ferroelectric polarization impacts density and confinement of the 2DEG. We find that aligning the ferroelectric polarization toward (outward) the LaInO3/BaSnO3 interface leads to an accumulation (depletion) of the interfacial 2DEG. Varying its magnitude, we find a linear effect on the 2DEG charge density that is confined within the BaSnO3 side. Analysis of the optimized geometries reveals that inclusion of the ferroelectric layer makes structural distortions at the LaInO3/BaSnO3 junction less pronounced, which, in turn, enhances the 2DEG density. Thicker ferroelectric layers allow for reaching higher polarization magnitude. We discuss the mechanisms behind all these findings and rationalize how the characteristics of both 2DEGs and 2D hole gases can be controlled in the considered heterostructures. Overall, our results can be generalized to other combinations of ferroelectric, polar, and nonpolar materials.

A LSTM-RNN based intelligent control approach for temperature and humidity environment of urban utility tunnels.

Temperature and relative humidity are important indicators of utility tunnel indoor atmosphere hazards and operational risks, which can be effectively mitigated by accurate forecasting and corrective control measures. To this end, this paper proposed a multi-layer long short-term memory (LSTM) recurrent neural network (RNN) architecture to forecast the changing trend of temperature and relative humidity inside utility tunnels with distant past monitoring data. Based on the forecasting architecture, an intelligent control approach was designed, including early warning and ventilation control measures. Case study results showed that the proposed architecture fit the training dataset well and the prediction accuracy on testing datasets of temperature and relative humidity exceeded 98% and 99%, respectively. Meanwhile, the proposed LSTM-RNN architecture can also be used to simulate and evaluate the ventilation effects on the temperature and relative humidity environment of urban utility tunnels. Findings of this paper provide a reference for the safe, efficient and energy-saving indoor environment control of urban utility tunnels.