Search

Objectives: This study was aimed at analyzing the burden and trend of Alzheimer's disease and other dementias attributed to smoking (SADD) in the Belt and Road Initiative (BRI) countries during 1990–2019. Methods: Data from The 2019 Global Burden of Disease Study was used to extract information on the burden of SADD in terms of the numbers and age-standardized rate of mortality (ASMR) and disability-adjusted life years (ASDALR) in the BRI countries for 1990–2019. The average annual percent change (AAPC) was used to analyze the temporal trends of ASDALR from 1990 to 2019 and in the final decade by Joinpoint regression analysis. Results: The DALYs of SADD were the highest in China, India, and the Russian Federation in 1990 and in Lebanon, Montenegro and Bosnia, and Herzegovina in 2019. From 1990 to 2019, the ASDALR in China had increased from 55.50/105 to 66.18/105, but decreased from 2010 to 2019, while that of India had declined from 32.84/105 to 29.35/105, but increased from 2010 to 2019. The ASDALR showed the fastest increase in the Russian Federation, with AAPC of 1.97% (95% confidence interval [CI]: 1.77%, 2.16%), and the fastest decline in Sri Lanka, with AAPC of −2.69% (95% CI: 2.79%, −2.59%). ASMR and ASDALR from SADD showed a substantial decline during 1990–2019 both globally and in the different socio-demographic index (SDI) regions (all P

Background: Hypothalamic neuroinflammation is associated with disorders of lipid metabolism. Considering the anti-neuroinflammation effects of sodium-glucose cotransporter 2(SGLT2) inhibitors, a central administration of Dapagliflozin is postulated to provide hypothalamic protection and change lipid metabolism in kidney against diabetic kidney disease (DKD). Methods: Blood samples of DKD patients were collected. Male Sprague-Dawley (SD) rats with 30 mg/kg streptozotocin and a high-fat diet, db/db mice and palmitic acid (PA)-stimulated BV2 microglia were used for study models. 0.28 mg/3ul dapagliflozin was injected into the lateral ventricle in db/db mice. Genes and protein expression levels were determined by qPCR, western blotting, immunofluorescence, and immunohistochemistry staining. Secreted IL-1β and IL-6 were quantified by ELISA. Oil red O staining, lipidomic, and non-targeted metabolomics were performed to evaluate abnormal lipid metabolism in kidney. Results: The decrease of serum MCPIP1 was an independent risk factor for renal progression in DKD patients (OR=1.22, 95 %CI: 1.02–1.45, P = 0.033). Higher microglia marker IBA1 and lower MCPIP1 in the hypothalamus, as well as lipid droplet deposition increasing in the kidney were observed in DKD rats. Central dapagliflozin could reduce the blood sugar, hypothalamic inflammatory cytokines, lipid droplet deposition in renal tubular. Lipidomics and metabolomics results showed that dapagliflozin changed 37 lipids and 19 metabolites considered on promoting lipolysis. These lipid metabolism changes were attributed to dapagliflozin by upregulating MCPIP1, and inhibiting cytokines in the microglia induced by PA. Conclusions: Central administrated Dapagliflozin elicits an anti-inflammatory effect by upregulating MCPIP1 levels in microglia and changes lipid metabolism in kidney of DKD.

Furandicarboxylic acid is considered one of the most representative biomass matrix platforms and has been widely used to synthesize various novel biomaterials. In this study, a series of copolymerized poly (aryl ether ketone) resins with excellent properties have been prepared by combining the nonlinear structure of furan ketone with the weakly polarized cyclohexane structure. And the relationship between the structure and properties of the resins has been systematically studied. The results showed that the synthesized resins had excellent thermal properties, and the 5% thermal decomposition temperature could reach up to 478 °C. In addition, the resin exhibits good solubility and can be dissolved in the most common solvents. Its water absorption is deficient, at only 0.71%. At 10 GHz, the lowest dielectric constant of the resin is 3.05. Most importantly, using bio-based monomers in this study provides an environmentally friendly strategy for material design and synthesis, providing a green way to develop high-performance low-dielectric materials.

This paper presents an experimental investigation on the damage characteristics and microstructures of hybrid fiber reinforced concrete (HFRC) subjected to the freeze-thaw（F-T）cycles and compound- salt attack. The effect of steel fiber content and steel-polypropylene fiber hybridization on the apparent morphology, mass loss, relative dynamic elastic modulus (RDEM), mechanical strengths in terms of compressive and flexural strengths were studied. The damage mechanism was explored based on an analysis of pore structures of specimens. The results showed that the F-T cycle has adverse effect on the physical and mechanical properties of specimens. The addition of fibers alleviates the damage degree of concrete, and the fiber hybridization shows more pronounced effect. Results from the porosity analysis indicate the pore sizes of 1.2HFRC are mainly distributed within 40 nm and those of OC are within 60 nm. The volume of larger pore size of 1.2HFRC increases less than the others after salt F-T cycles. Finally, based on Weibull distribution function, evolution equations for the salt-frozen damage of HFRC are developed by a combination of strength attenuation and RDEM degradation. The research results provide theoretical basis and reference for the practical application and building maintenance of fiber reinforced concrete.

Background/purpose: Cement-retained restorations have the advantages of passive fit, less complexity of clinical and laboratory methods, cost, esthetics, and dimensional stability over screw-retained restorations, especially in multiple abutment implant-supported prostheses. A common and difficult technical problem with cement-retained implant prostheses is abutment screw loosening. Three-dimensional (3D) printing is a technology that has been rapidly developed and has become widely accepted in dentistry. The aim of this study was to establish a novel method of using 3D implant planning guide to locate the abutment screw in cement-retained implant prosthesis. Materials and methods: Six standard gypsum complete denture models were used to locate the abutment screw. An implant analog (4.5 mm in diameter and 12 mm in length) was placed in the drilling hole (5 mm in diameter and 14 mm in depth). After scanning with a 3D scanner, the 3D printing software was used to design the abutment screw location guide, which was printed by a resin-based 3D printer. Results: A total of 30 abutment screws were located and removed using the guide. The locating guide's actual diameter was 2.4 mm. The drilling point was accurate and precise, and no excessive loss of the abutment was noticed. Conclusion: The guide would help the dentist in locating the abutment screw access channel, resulting in a more precise and accurate drilling point. The guide for locating the abutment screw enhances the accuracy of screw channel access and reduces damage to the crown and abutment.

Summary: Three-dimensional structure and dynamics are essential for protein function. Advancements in hydrogen-deuterium exchange (HDX) techniques enable probing protein dynamic information in physiologically relevant conditions. HDX-coupled mass spectrometry (HDX-MS) has been broadly applied in pharmaceutical industries. However, it is challenging to obtain dynamics information at the single amino acid resolution and time consuming to perform the experiments and process the data. Here, we demonstrate the first deep learning model, artificial intelligence-based HDX (AI-HDX), that predicts intrinsic protein dynamics based on the protein sequence. It uncovers the protein structural dynamics by combining deep learning, experimental HDX, sequence alignment, and protein structure prediction. AI-HDX can be broadly applied to drug discovery, protein engineering, and biomedical studies. As a demonstration, we elucidated receptor-binding domain structural dynamics as a potential mechanism of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody efficacy and immune escape. AI-HDX fundamentally differs from the current AI tools for protein analysis and may transform protein design for various applications.

Summary: Tumor-associated macrophages (TAMs) are a major cellular component in the tumor microenvironment (TME). However, the relationship between the phenotype and metabolic pattern of TAMs remains poorly understood. We performed single-cell transcriptome profiling on hepatic TAMs from mice bearing liver metastatic tumors. We find that TAMs manifest high heterogeneity at the levels of transcription, development, metabolism, and function. Integrative analyses and validation experiments indicate that increased purine metabolism is a feature of TAMs with pro-tumor and terminal differentiation phenotypes. Like mouse TAMs, human TAMs are highly heterogeneous. Human TAMs with increased purine metabolism exhibit a pro-tumor phenotype and correlate with poor therapeutic efficacy to immune checkpoint blockade. Altogether, our work demonstrates that TAMs are developmentally, metabolically, and functionally heterogeneous and purine metabolism may be a key metabolic feature of a pro-tumor macrophage population.

The dynamic architecture of the human brain has been consistently observed. However, there is still limited modeling work to elucidate how neuronal circuits are hierarchically and flexibly organized in functional systems. Here we proposed a reachable probability approach based on non-homogeneous Markov chains, to characterize all possible connectivity flows and the hierarchical structure of brain functional systems at the dynamic level. We proved at the theoretical level the convergence of the functional brain network system, and demonstrated that this approach is able to detect network steady states across connectivity structure, particularly in areas of the default mode network. We further explored the dynamically hierarchical functional organization centered at the primary sensory cortices. We observed smaller optimal reachable steps to their local functional regions, and differentiated patterns in larger optimal reachable steps for primary perceptual modalities. The reachable paths with the largest and second largest transition probabilities between primary sensory seeds via multisensory integration regions were also tracked to explore the flexibility and plasticity of the multisensory integration. The present work provides a novel approach to depict both the stable and flexible hierarchical connectivity organization of the human brain.

Cyclization reaction of poly(acrylonitrile-co-2-acrylamido-2-methylpropane sulfonic acid) [P(AN-co-AMPS)] copolymer during thermal oxidative stabilization (TOS) process was investigated by FTIR and two dimensional (2D) correlation analysis technique. The results showed the mechanism of cyclization reaction at different temperatures were varying. At 200 °C, the cyclization reactions generated by autocatalytic cyclization mechanism. While at higher temperatures, the cyclization reactions took place through ionic cyclization mechanism and free radical cyclization mechanism. The AMPS comonomer could reduce the heat release of cyclization reactions and improve the stability at 200 and 230 °C. At higher temperatures, the cyclization reactions were facilitated rapidly. However, the oxidation and degradation reactions were also intense, which will cause the molecular chain to break and defects in the final carbon fibers (CFs). This research has theoretical guiding significance for the optimization of heat treatment conditions for PAN copolymers used as CFs.

The recent establishment of mammalian haploid embryonic stem cells (ESCs) provides new possibilities for genetic screening and for understanding genome evolution and function. However, the dynamics of mitosis in haploid ESCs is still unclear. Here, we report that the duration of mitosis in haploid ESCs, especially the metaphase, is significantly longer than that in diploid ESCs. Delaying mitosis by chemicals increased self-diploidization of haploid ESCs, while shortening mitosis stabilized haploid ESCs. Taken together, our study suggests that the delayed mitosis of haploid ESCs is associated with self-diploidization.

Astrocytes, due to the proximity to neuronal lineage and capability to proliferate, are ideal starting cells to regenerate neurons. Human fetal astrocytes have been successfully converted into neuronal cells by small molecules, which offered a broader range of further applications than transcription factor-mediated neuronal reprogramming. Here we report that human adult astrocytes could also be converted into neuronal cells by a different set of small molecules. These induced cells exhibited typical neuronal morphologies, expressed neuronal markers, and displayed neuronal electrophysiological properties. Genome-wide RNA-sequencing analysis showed that the global gene expression profile of induced neuronal cells resembled that of human embryonic stem cell-differentiated neurons. When transplanted into post-natal mouse brains, these induced neuronal cells could survive and become electrophysiologically mature. Altogether, our study provides a strategy to directly generate transgene-free neuronal cells from human adult astrocytes by small molecules.

Summary: Background: Atrial cardiomyopathy (ACM) is responsible for atrial fibrillation (AF) and thromboembolic events. Diabetes mellitus (DM) is an important risk factor for ACM. However, the potential mechanism between ACM and DM remains elusive. Methods: Atrial tissue samples were obtained from patients diagnosed with AF or sinus rhythm (SR) to assess alterations in NR4A3 expression, and then two distinct animal models were generated by subjecting Nr4a3−/− mice and WT mice to a high-fat diet (HFD) and Streptozotocin (STZ), while db/db mice were administered AAV9-Nr4a3 or AAV9-ctrl. Subsequently, in vivo and in vitro experiments were conducted to assess the impact of NR4A3 on diabetes-induced atrial remodeling through electrophysiological, biological, and histological analyses. RNA sequencing (RNA-seq) and metabolomics analysis were employed to unravel the downstream mechanisms. Findings: The expression of NR4A3 was significantly decreased in atrial tissues of both AF patients and diabetic mice compared to their respective control groups. NR4A3 deficiency exacerbated atrial hypertrophy and atrial fibrosis, and increased susceptibility to pacing-induced AF. Conversely, overexpression of NR4A3 alleviated atrial structural remodeling and reduced AF induction rate. Mechanistically, we confirmed that NR4A3 improves mitochondrial energy metabolism and reduces oxidative stress injury by preserving the transcriptional expression of Sdha, thereby exerting a protective influence on atrial remodeling induced by diabetes. Interpretation: Our data confirm that NR4A3 plays a protective role in atrial remodeling caused by diabetes, so it may be a new target for treating ACM. Funding: This study was supported by the major research program of National Natural Science Foundation of China (NSFC) No: 82370316 (to Q-S. W.), No. 81974041 (to Y-P. W.), and No. 82270447 (to Y-P. W.) and Fundation of Shanghai Hospital Development Center (No. SHDC2022CRD044 to Q-S. W.).

Silicosis is a devastating interstitial lung disease arising from long-term exposure to inhalable silica. Regrettably, no therapy currently can effectively reverse the silica-induced fibrotic lesion. Emerging evidence has indicated that the dysregulation of microRNAs is involved in silica-induced pulmonary fibrosis. The aim of this study is to explore the expression pattern and underlying mechanisms of miR-770–5p in silica-induced pulmonary fibrosis. Consistent with our previous miRNA microarray analysis, the results of qRT-PCR showed that miR-770–5p expression was downregulated in silica-induced pulmonary fibrosis in humans and animal models. Administration of miR-770–5p agomir significantly reduced the fibrotic lesions in the lungs of mice exposed to silica dust. MiR-770–5p also exhibited a dramatic reduction in TGF-β1-activated human pulmonary fibroblasts (MRC-5). Transfection of miR-770–5p mimics significantly decreased the viability, migration ability, and S/G0 phase distribution, as well as the expression of fibronectin, collagen I, and α-SMA in TGF-β1-treated MRC-5 cells. Transforming growth factor-β receptor 1 (TGFBR1) was confirmed as a direct target of regulation by miR-770–5p. The expression of TGFBR1 was significantly increased in pulmonary fibrosis. Knockdown of TGFBR1 blocked the transduction of the TGF-β1 signaling pathway and attenuated the activation of MRC-5 cells, while overexpression of TGFBR1 effectively restored the activation of MRC-5 cells inhibited by miR-770–5p. Together, our results demonstrated that miR-770–5p exerted an anti-fibrotic effect in silica-induced pulmonary fibrosis by targeting TGFBR1. Targeting miR-770–5p might provide a new therapeutic strategy to prevent the abnormal activation of pulmonary fibroblasts in silicosis.

It is little known about the lncRNA-PVT1 effect on occupational pulmonary fibrosis, although researches show it plays an essential role in cancer. Studies reveal that lung fibroblast activation is one of the key events in silica-induced fibrosis. Here, we found that lncRNA-PVT1 promoted the proliferation, activation, and migration of lung fibroblasts. The isolation of cytoplasmic and nuclear RNA assay and fluorescence in situ hybridization experiment showed that lncRNA-PVT1 was abundantly expressed in the cytoplasm. Luciferase reporter gene assay and RNA pull-down experiment indicated that the cytoplasmic-localized lncRNA-PVT1 could competitively bind miR-497-5p. MiR-497-5p was further observed to attenuate silica-induced pulmonary fibrosis by targeting Smad3 and Bcl2. Moreover, the transcription factor FOXM1 acted as a profibrotic factor by elevating lncRNA-PVT1 transcription in lung fibroblasts. Inhibition of FOXM1 expression with thiostrepton alleviated silica-induced pulmonary fibrosis in vivo. Collectively, we revealed that FOXM1-facilitated lncRNA-PVT1 activates lung fibroblasts via miR-497-5p during silica-induced pulmonary fibrosis, which may provide potential therapeutic targets for pulmonary fibrosis.