Association of circulating inflammatory proteins with type 2 diabetes mellitus and its complications: a bidirectional Mendelian randomization study.

Background: Increasing evidence indicates that immune response underlies the pathology of type 2 diabetes (T2D). Nevertheless, the specific inflammatory regulators involved in this pathogenesis remain unclear. Methods: We systematically explored circulating inflammatory proteins that are causally associated with T2D via a bidirectional Mendelian randomization (MR) study and further investigated them in prevalent complications of T2D. Genetic instruments for 91 circulating inflammatory proteins were derived from a genome-wide association study (GWAS) that enrolled 14,824 predominantly European participants. Regarding the summary-level GWASs of type 2 diabetes, we adopted the largest meta-analysis of European population (74,124 cases vs. 824,006 controls) and a prospective nested case-cohort study in Europe (9,978 cases vs. 12,348 controls). Summary statistics for five complications of T2D were acquired from the FinnGen R9 repository. The inverse variance-weighted method was applied as the primary method for causal inference. MR-Egger, weighted median and maximum likelihood methods were employed as supplementary analyses. Results from the two T2D studies were combined in a meta-analysis. Sensitivity analyses and phenotype-wide association studies (PheWAS) were performed to detect heterogeneity and potential horizontal pleiotropy in the study. Results: Genetic evidence indicated that elevated levels of TGF-α (OR = 1.16, 95% CI = 1.15-1.17) and CX3CL1 (OR = 1.30, 95% CI = 1.04-1.63) promoted the occurrence of T2D, and increased concentrations of FGF-21 (OR = 0.87, 95% CI = 0.81-0.93) and hGDNF (OR = 0.96, 95% CI = 0.95-0.98) mitigated the risk of developing T2D, while type 2 diabetes did not exert a significant influence on said proteins. Elevated levels of TGF-α were associated with an increased risk of ketoacidosis, neurological complications, and ocular complications in patients with T2D, and increased concentrations of FGF-21 were potentially correlated with a diminished risk of T2D with neurological complications. Higher levels of hGDNF were associated with an increased risk of T2D with peripheral vascular complications, while CX3CL1 did not demonstrate a significant association with T2D complications. Sensitivity analyses and PheWAS further ensure the robustness of our findings. Conclusion: This study determined four circulating inflammatory proteins that affected the occurrence of T2D, providing opportunities for the early prevention and innovative therapy of type 2 diabetes and its complications.

Interaction between lactic acid bacteria and Polygonatum sibiricum saponins and its application to microencapsulated co-delivery.

This study aimed to investigate the interaction between L.casei and L.bulgaricus with Polygonatum sibiricum saponins (PSS) and to explore the co-microencapsulation to reduce their loss rate during storage and consumption. 1% PSS was added to the culture broth, and it was found that the growth and metabolism of the strains were accelerated, especially in the compound probiotic group, indicating that PSS has potential for prebiotics. LC-MS observed significant differences in the composition and content of saponins in PSS. The metabolomics results suggest that the addition of PSS resulted in significant changes in the metabolites of probiotics. In addition, it was found that the combination of probiotics and PSS may have stronger hypoglycemic ability (ɑ-glucosidase, HepG2). Finally, a co-microencapsulated delivery system was constructed using zein and isomaltooligosaccharide. This system can achieve more excellent resistance of probiotics and PSS in gastrointestinal fluids, effectively transporting both to the small intestine.

Identification and validation of aging-related gene signatures and their immune landscape in diabetic nephropathy.

Background: Aging and immune infiltration have essential role in the physiopathological mechanisms of diabetic nephropathy (DN), but their relationship has not been systematically elucidated. We identified aging-related characteristic genes in DN and explored their immune landscape. Methods: Four datasets from the Gene Expression Omnibus (GEO) database were screened for exploration and validation. Functional and pathway analysis was performed using Gene Set Enrichment Analysis (GSEA). Characteristic genes were obtained using a combination of Random Forest (RF) and Support Vector Machine Recursive Feature Elimination (SVM-RFE) algorithm. We evaluated and validated the diagnostic performance of the characteristic genes using receiver operating characteristic (ROC) curve, and the expression pattern of the characteristic genes was evaluated and validated. Single-Sample Gene Set Enrichment Analysis (ssGSEA) was adopted to assess immune cell infiltration in samples. Based on the TarBase database and the JASPAR repository, potential microRNAs and transcription factors were predicted to further elucidate the molecular regulatory mechanisms of the characteristic genes. Results: A total of 14 differentially expressed genes related to aging were obtained, of which 10 were up-regulated and 4 were down-regulated. Models were constructed by the RF and SVM-RFE algorithms, contracted to three signature genes: EGF-containing fibulin-like extracellular matrix (EFEMP1), Growth hormone receptor (GHR), and Vascular endothelial growth factor A (VEGFA). The three genes showed good efficacy in three tested cohorts and consistent expression patterns in the glomerular test cohorts. Most immune cells were more infiltrated in the DN samples compared to the controls, and there was a negative correlation between the characteristic genes and most immune cell infiltration. 24 microRNAs were involved in the transcriptional regulation of multiple genes simultaneously, and Endothelial transcription factor GATA-2 (GATA2) had a potential regulatory effect on both GHR and VEGFA. Conclusion: We identified a novel aging-related signature allowing assessment of diagnosis for DN patients, and further can be used to predict immune infiltration sensitivity.

Preparation of synbiotic milk powder and its effect on calcium absorption and the bone microstructure in calcium deficient mice.

Calcium deficiency can lead to osteoporosis. Adequate calcium intake can improve calcium deficiency and prevent osteoporosis. Milk powder is the best source of dietary calcium supplements. Probiotics and prebiotics are considered to be beneficial substances for promoting calcium absorption. In this study, synbiotic milk powder (SMP) was prepared by combining the three, and its calcium supplementation effect and osteogenic activity were evaluated in calcium deficient mice. Through prebiotic screening experiments in vitro, after adding 1.2% iso-malto-oligosaccharide, the number of viable bacteria and the calcium enrichment of Lactobacillus plantarum JJBYG12 increased by 8.15% and 94.53% compared with those of the control group. Long-term calcium deficiency led to a significant reduction in calcium absorption and bone calcium content in mice, accompanied by structural deterioration of bone trabeculae. SMP significantly improved apparent calcium absorption, increased serum calcium and phosphorus levels, and decreased ALP activity and CTX-1 levels. In the meantime, the bone mineral density increased significantly, and the number of bone trabeculae and the proliferation and differentiation of osteoblasts also increased. SMP has good dietary calcium supplementation capacity and bone remodeling ability without significant side effects on major organs. These findings provide insights into using SMP as a dietary calcium source to improve bone health.

Polygonatum sibiricum saponin Exerts Beneficial Hypoglycemic Effects in Type 2 Diabetes Mice by Improving Hepatic Insulin Resistance and Glycogen Synthesis-Related Proteins.

Type 2 diabetes mellitus (T2DM) is a systemic metabolic disorder characterized by insulin deficiency and insulin resistance. Recently, it has become a significant threat to public health. Polygonatum sibiricum saponin (PSS) has potential hypoglycemic effects, but its specific mechanism needs further study. In this study, PSS significantly decreased the level of blood glucose, water intake, and the organ index in diabetic mice. Meanwhile, PSS effectively reduced the content of total triglyceride (TG), total cholesterol (TCHO), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in the blood, and increased the content of high-density lipoprotein cholesterol (HDL-C). This suggests that PSS could reduce the content of blood lipids and initially improve the damage of hepatocytes. We found that PSS alleviated hepatic insulin resistance, repaired islet beta cells, and enabled insulin to play its biological role normally. It also improved oral glucose tolerance and abated serum lipopolysaccharide (LPS) and glycosylated hemoglobin (HbA1c) levels in T2DM mice. Furthermore, studies have found that PSS increased the content of phosphorylated protein kinase B (AKT), thereby promoting the effect of glucose transporter 4 (GLUT-4), and activating glycogen synthase kinase 3beta (GSK-3ß) and glycogen synthase (GS) proteins to promote hepatic glycogen synthesis. Finally, we found that PSS could promote the growth of beneficial bacteria such as Bifidobacterium and Lactobacillus, reduce the growth of harmful bacteria such as Enterococcus and Enterobacter, and preliminarily improve the composition of important bacteria in the intestine. These studies indicate that PSS has an excellent hypoglycemic effect, which provides a potential new treatment for T2DM and guidance for more in-depth research.

MHSA-EC: An Indoor Localization Algorithm Fusing the Multi-Head Self-Attention Mechanism and Effective CSI.

Channel state information (CSI) provides a fine-grained description of the signal propagation process, which has attracted extensive attention in the field of indoor positioning. The CSI signals collected by different fingerprint points have a high degree of discrimination due to the influence of multi-path effects. This multi-path effect is reflected in the correlation between subcarriers and antennas. However, in mining such correlations, previous methods are difficult to aggregate non-adjacent features, resulting in insufficient multi-path information extraction. In addition, the existence of the multi-path effect makes the relationship between the original CSI signal and the distance not obvious, and it is easy to cause mismatching of long-distance points. Therefore, this paper proposes an indoor localization algorithm that combines the multi-head self-attention mechanism and effective CSI (MHSA-EC). This algorithm is used to solve the problem where it is difficult for traditional algorithms to effectively aggregate long-distance CSI features and mismatches of long-distance points. This paper verifies the stability and accuracy of MHSA-EC positioning through a large number of experiments. The average positioning error of MHSA-EC is 0.71 m in the comprehensive office and 0.64 m in the laboratory.

Grafting of Gd-DTPA onto MOF-808 to enhance MRI performance for guiding photothermal therapy.

Gd(III) chelates are important T1-weighted contrast agents used in clinical magnetic resonance imaging (MRI), but their low longitudinal relaxivity (r1) results in limited imaging efficiency. In this study, we utilize a geometric confinement strategy to restrict a Gd chelate (Gd-DTPA) within the channels of a porous metal-organic framework material (MOF-808) for increasing its r1 relaxivity. Moreover, the Gd-DTPA-grafted MOF-808 nanoparticles were further surface modified with polyaniline (PANI) to construct an MRI-guided photothermal therapy platform. The resulting Gd-DTPA-MOF-808@PANI shows a high r1 relaxivity of 30.1 mM-1 s-1 (0.5 T), which is 5.4 times higher than that of the commercial contrast agent Magnevist. In vivo experiments revealed that Gd-DTPA-MOF-808@PANI has good T1-weighted contrast performance and can effectively guide photothermal ablation of tumors upon 808 nm laser irradiation. This work may shed some light on the design and preparation of high relaxation rate Gd-based contrast agents for theranostic application via utilization of versatile MOF materials.

C-GCN: A Flexible CSI Phase Feature Extraction Network for Error Suppression in Indoor Positioning.

Channel state information (CSI) provides a fine-grained description of the signal propagation process, which has attracted extensive attention in the field of indoor positioning. However, considering the influence of environment and hardware, the phase of CSI is distorted in most cases. It is difficult to extract effective location features in multiple scenes only through the determined artificial experience model. Graph neural network has performed well in many fields in recent years, but there is still a lot of room to explore in the field of indoor positioning. In this paper, a phase feature extraction network based on multi-dimensional correlation is proposed, named Cooperation-Graph Convolution Network (C-GCN). The purpose of C-GCN is to extract new features of multiple correlation and to mine the relationship between antenna and subcarrier as much as possible. C-GCN is composed of convolution layer and graph convolution layer. In the graph convolution layer, C-GCN regards each subcarrier of each antenna as a node in the graph network, constructs the connection by the correlation between the antenna and the subcarrier, and aggregates the node vectors by graph convolution. In the convolution layer, there is a natural corresponding structure between data packets, C-GCN extracts the fluctuation with convolution in Euclidean space. C-GCN combines these two layers, and applies end-to-end supervised training to obtain effective features. Extensive experiments are conducted in typical indoor environments to verify the superior performance of C-GCN in restraining error tailing. The average positioning error of C-GCN is 1.29 m in comprehensive office and 1.71 m in garage. Combined with the amplitude feature, the average positioning error is 0.99 m in comprehensive office and 1.14 m in garage.

Tumor Microenvironment-Responsive Reagent DFS@HKUST-1 for Photoacoustic Imaging-Guided Multimethod Therapy.

Although multimethod therapy has shown great promise for effective cancer treatment, it is still a great challenge to develop simple and effective strategies to construct multifunctional therapeutic reagents. According to the characteristics of the tumor microenvironment, such as a mild acidic environment and overexpression of H2O2, an intelligent therapeutic reagent with photoacoustic (PA) imaging-guided photothermal therapy, chemodynamic therapy, and in situ chemotherapy was constructed by simply loading disulfiram (DSF) in a Cu-based porous metal-organic framework (HKUST-1). The resultant material DFS@HKUST-1 shows near-infrared adsorption around 600-900 nm and effective photoacoustic imaging properties and photothermal conversion efficiency upon 808 nm irradiation. Besides, after DFS@HKUST-1 is enriched in the tumor, the acidic environment of the tumor will slowly trigger the decomposition of HKUST-1, leading to the release of Cu2+ ions to react with DSF and endogenous H2O2 to generate the Cu/DSF complex (CuET) and cytotoxic •OH for chemotherapy and chemodynamic therapy, respectively. Therefore, DFS@HKUST-1 can serve as a promising tumor microenvironment response therapeutic reagent for photoacoustic imaging-guided multimethod therapy.

Self-Assembly of Giant Mo240 Hollow Opening Dodecahedra.

The synthesis of hollow opening polyhedral cages has always been an attractive but challenging goal, especially with regard to inorganic polyhedral cages. Herein, we present a novel, 240-nuclearity giant polymolybdate cage prepared via hydrothermal synthesis. This cage is composed of 20 tripod-shaped [Mo6O22(SO3)]n-/[Mo6O21(SO4)]n- building blocks with three connected vertices and 30 cubane-type [Mo4O16]n- edge building blocks, featuring a rare, nearly regular pentagonal dodecahedron with a large inner cavity (diameter up to 1.8 nm) and 12 opening pentagonal windows. This is the highest nuclearity hollow opening dodecahedral cage reported to date. Importantly, this cage exhibits good stability in solution, as revealed by scanning transmission electron microscopy (STEM), TEM, UV-vis, and Raman spectra. In addition, the bulk sample of this compound exhibits an ultrahigh proton conductivity of 1.03 × 10-1 S cm-1 at 80 °C and 98% relative humidity, which is the highest among polyoxometalate-based crystalline proton conductors.

Multiphysics simulation of ion concentration polarization induced by a surface-patterned nanoporous membrane in single channel devices.

Microfluidic devices utilize ion concentration polarization (ICP) phenomena for a variety of applications, but a comprehensive understanding of the generation of ICP is still necessary. Recently, the emergence of a novel single channel ICP (SC-ICP) device has stimulated further research on the mechanism of ICP generation, so that we developed a 2-D model of an SC-ICP device that integrates a nanoporous membrane on the bottom surface of the channel, allowing bulk flow over the membrane. We solved a set of coupled governing equations with appropriate boundary conditions to explore ICP numerically. As a result, we not only showed that the simulation results held a strong qualitative agreement with experimental results, but also found the distribution of ion concentrations in the SC-ICP device that has never been reported in previous studies. We confirmed again that the electrophoretic mobility (EPM) of counterions in the membrane is the most dominant factor determining the generation and strength of ICP, whereas the charge density of the membrane was dominant to the ICP strength only when a high EPM value was assumed. From the viewpoint of practical applications, an SC-ICP device with a long membrane under low buffer strength showed enhanced performance in the preconcentration of charged molecules. Therefore, we believe that the simulation results could not only provide sharp insight into ICP phenomena but also predict and optimize the performance of SC-ICP devices in various microfluidic applications.

Multiphysics simulation of ion concentration polarization induced by nanoporous membranes in dual channel devices.

Many microfluidic devices have been utilizing ion concentration polarization (ICP) phenomena by using a permselective, nanoporous membrane with electric fields for a variety of preconcentration applications. However, numerical analyses on the ICP phenomena have not drawn sufficient attention, although they are an intriguing and interdisciplinary research area. In this work, we propose a 2-D model and present numerical simulation results on the ICP, which were obtained by solving three coupled governing equations: Nernst-Planck, Navier-Stokes, and Poisson. With improved boundary conditions and assumptions, we demonstrated that the simulation results not only are consistent with other experimental results but also make it possible to thoroughly understand the ICP phenomena. In addition, we demonstrated that the preconcentration of analytes can be simulated and quantified in terms of concentration enhancement factors (CEFs) that were related to many factors, such as ionic concentration distribution, electric fields, and flow fields including vortex flows across the membrane. Furthermore, we demonstrated that a high electrophoretic mobility (EPM) of counterions in the membrane plays the most important role in producing accurate simulation results while the effect of the charge density of the membrane is relatively insignificant. Hence, it is believed that the model and simulation results would provide good guidelines to better develop microfluidic preconcentration devices based on the ICP phenomena.

Ion concentration polarization in a single and open microchannel induced by a surface-patterned perm-selective film.

We describe a novel and simple mechanism for inducing ion concentration polarization (ICP) using a surface-patterned perm-selective nanoporous film like Nafion in single, open microchannels. Such a surface-patterned Nafion film can rapidly transport only cations from the anodic side to the cathodic side through the nanopore clusters so that it is possible to generate an ICP phenomenon near the Nafion film. In this work, we characterize transport phenomena and distributions of ion concentration under various electric fields near the Nafion film and show that single-channel based ICP (SC-ICP) is affected by Nafion film thicknesses, strengths of applied electric fields, and ionic strengths of buffer solutions. We also emphasize that SC-ICP devices have several advantages over previous dual-channel ICP (DC-ICP) devices: easy and simple fabrication processes, inherently leak-tight, simple experimental setup requiring only one pair of electrodes, stable and robust ICP induced rapidly, and low electrical resistances helping to avoid Joule heating, and membrane perm-selectivity breakdown but allowing as high bulk flow as an open, plain microchannel. As an example of applications, we demonstrate that SC-ICP devices not only have high potential in pre-concentrating proteins in massively parallel microchannels but also enable the concentration and lysis of bacterial cells simultaneously and continuously on a chip; therefore, proteins within the cells are extracted, separated from the concentrated cells and then pre-concentrated at a different location that is closer to the Nafion film. Hence, we believe that the SC-ICP devices have higher possibilities of being easily integrated with traditional microfluidic systems for analytical and biotechnological applications.