Tunable and mode-locked Tm,Ho:GdScO3 laser.

A novel, to the best of our knowledge, Tm,Ho:GdScO3 crystal grown using the Czochralski method was investigated for its polarized spectroscopic properties and laser performance in both tunable continuous-wave (CW) and mode-locked regimes. The crystal's multisite structure (Gd3+/Sc3+ site) and Tm3+/Ho3+ dopants contributed to spectral broadening, enabling a tunable laser operation from 1914 to 2125 nm (with a broad range of 215 nm). Additionally, a pulse duration of 72 fs was achieved for E || b polarization. These results demonstrate the potential of the Tm,Ho:GdScO3 perovskite crystal as a promising gain material for ultrafast lasers operating around 2 µm.

Microneedle Patch for Transdermal Sequential Delivery of KGF-2 and aFGF to Enhance Burn Wound Therapy.

Severe burn wounds usually destroy key cells' functions of the skin resulting in delayed re-epithelization and wound regeneration. Promoting key cells' activities is crucial for burn wound repair. It is well known that keratinocyte growth factor-2 (KGF-2) participates in the proliferation and morphogenesis of epithelial cells while acidic fibroblast growth factor (aFGF) is a key mediator for fibroblast and endothelial cell growth and differentiation. However, thick eschar and the harsh environment of a burn wound often decrease the delivery efficiency of fibroblast growth factor (FGF) to the wound site. Therefore, herein a novel microneedle patch for sequential transdermal delivery of KGF-2 and aFGF is fabricated to enhance burn wound therapy. aFGF is first loaded in the nanoparticle (NPaFGF) and then encapsulated NPaFGF with KGF-2 in the microneedle patch (KGF-2/NPaFGF@MN). The result shows that KGF-2/NPaFGF@MN can successfully get across the eschar and sequentially release KGF-2 and aFGF. Additional data demonstrated that KGF-2/NPaFGF@MN achieved a quicker wound closure rate with reduced necrotic tissues, faster re-epithelialization, enhanced collagen deposition, and increased neo-vascularization. Further evidence suggests that improved wound healing is regulated by significantly elevated expressions of hypoxia-inducible factor-1 alpha (HIF-1ɑ) and heat shock protein 90 (Hsp90) in burn wounds. All these data proved that KGF-2/NPaFGF@MN is an effective treatment for wound healing of burns.

Hybridizing carbonate and ether at molecular scales for high-energy and high-safety lithium metal batteries.

Commonly-used ether and carbonate electrolytes show distinct advantages in active lithium-metal anode and high-voltage cathode, respectively. While these complementary characteristics hold promise for energy-dense lithium metal batteries, such synergy cannot be realized solely through physical blending. Herein, a linear functionalized solvent, bis(2-methoxyethyl) carbonate (BMC), is conceived by intramolecularly hybridizing ethers and carbonates. The integration of the electron-donating ether group with the electron-withdrawing carbonate group can rationalizes the charge distribution, imparting BMC with notable oxidative/reductive stability and relatively weak solvation ability. Furthermore, BMC also offers advantages including the ability to slightly dissolve LiNO3, excellent thermostability and nonflammability. Consequently, the optimized BMC-based electrolyte, even with typical concentrations in the single solvent, demonstrates high-voltage tolerance (4.4 V) and impressive Li plating/stripping Coulombic efficiency (99.4%). Moreover, it fulfills practical lithium metal batteries with satisfactory cycling performance and exceptional tolerance towards thermal/mechanical abuse, showcasing its suitability for safe high-energy lithium metal batteries.

Sea Cucumber Plasmalogen Regulates the Lipid Profile in High-Fat Diet Mouse Liver via Lipophagy.

The sea cucumber plasmalogen PlsEtn has been shown to be associated with various chronic diseases related to lipid metabolism. However, the mechanism is unclear. Therefore, the present study used the sea cucumber plasmanylcholine PakCho as a structural contrast to PlsEtn and assessed its effect in 8 week high-fat diet (HFD)-fed mice. The lipidomic approach based on high-resolution mass spectrometry combined with molecular biology techniques was used to evaluate the mechanism of PlsEtn. The results showed that both PlsEtn and PakCho significantly inhibited an increase in mouse body weight and liver total triglyceride and total cholesterol levels caused by HFD. In addition, oil red O staining demonstrated that lipid droplets stored in the liver were degraded. Meanwhile, untargeted lipidomic experiments revealed that total lipids (increased by 42.8 mmol/mg prot; p < 0.05), triglycerides (increased by 38.9 mmol/mg prot; p < 0.01), sphingolipids (increased by 1.5 mmol/mg prot; p < 0.0001), and phospholipids (increased by 2.5 mmol/mg prot; p < 0.05) were all significantly elevated under HFD. PlsEtn resolved lipid metabolism disorders by alleviating the abnormal expression of lipid subclasses. In addition, five lipid molecular species, PE (18:1/20:4), PE (18:1/20:3), PE (18:1/18:3), TG (16:0/16:0/17:0), and TG (15:0/16:0/18:1), were identified as the biomarkers of HFD-induced lipid metabolism disorders. Finally, lipophagy-associated protein expression analysis showed that HFD abnormally activated lipophagy via ULK1 phosphorylation and PlsEtn alleviated lipophagy disorder through lysosomal function promotion. In addition, PlsEtn performed better than PakCho. Taken together, the current study results unraveled the mechanism of PlsEtn in alleviating lipid metabolism disorder and offered a new theoretical foundation for the high-value development of sea cucumber.

ITPRIPL1 binds CD3ε to impede T cell activation and enable tumor immune evasion.

Cancer immunotherapy has transformed treatment possibilities, but its effectiveness differs significantly among patients, indicating the presence of alternative pathways for immune evasion. Here, we show that ITPRIPL1 functions as an inhibitory ligand of CD3ε, and its expression inhibits T cells in the tumor microenvironment. The binding of ITPRIPL1 extracellular domain to CD3ε on T cells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial T cell activation. Treatment with a neutralizing antibody against ITPRIPL1 restrained tumor growth and promoted T cell infiltration in mouse models across various solid tumor types. The antibody targeting canine ITPRIPL1 exhibited notable therapeutic efficacy against naturally occurring tumors in pet clinics. These findings highlight the role of ITPRIPL1 (or CD3L1, CD3ε ligand 1) in impeding T cell activation during the critical "signal one" phase. This discovery positions ITPRIPL1 as a promising therapeutic target against multiple tumor types.

Sublayer-Sulfur-Vacancy-Induced Charge Redistribution of FeCuS Nanoflower Awakening Alkaline Hydrogen Evolution.

Advancing the progress of sustainable and green energy technologies requires the improvement of valid electrocatalysts for the hydrogen evolution reaction (HER). Reconfiguring charge distribution through heteroatom doping-induced vacancy serves as an effective approach to implement high performance for HER catalysts. Here, we successfully fabricated Fe-doped CuS (FeCuS) with the sublayer sulfur vacancy to judge its HER performance and dissect the activity origins. Density functional theory calculation further elucidates that the primary factor contributing to the heightened HER activity is that the sublayer sulfur vacancies awaken the charge redistribution. In addition to effectively decreasing the energy barrier associated with the Volmer step, it modulates the adsorption/desorption capacity of H*. As a result, its intrinsic activity for the HER has significantly increased. Concretely, the obtained FeCuS displays an excellent catalytic performance, whose Tafel slope is only 59 mV dec-1 and the overpotential (at 10 mA cm-2) is as low as 71 mV in an alkaline environment, surpassing the majority of previously documented catalysts in scientific literature. This work shows that the construction of sublayer sulfur vacancies by Fe doping can achieve the charge redistribution and precise tuning of electronic structure; thereby, the inert CuS can be transformed into highly efficient electrocatalysts.

[Hydrochemical Characteristics, Controlling Factors and Water Quality Evaluation of Shallow Groundwater in Tan-Lu Fault Zone （Anhui Section）].

To study the hydrochemical characteristics, controlling factors, and groundwater quality of the Tan-Lu fault zone (Anhui section), 86 groundwater samples were taken from the areas surrounding the Tan-Lu fault zone (Anhui section), which included the Jianghuai Wavy Plain, the Yanjiang Hill Plain, and the Dabie Mountains in western Anhui. Descriptive statistics, Piper diagram, Gibbs diagram, ion ratio analysis, saturation index, chloride-alkalinity index, and entropy weight water quality index (EWQI) were used to comprehensively study the hydrochemical characteristics and controlling factors of groundwater and to evaluate its quality. The results showed that the shallow groundwater in the Tan-Lu fault zone (Anhui section) was weakly alkaline, with dominant anions and cations of HCO3-, Ca2+ and Na+, respectively, and the hydrochemical types were mainly HCO3-Ca·Mg and HCO3-Na·Ca. The solute source of groundwater was mainly controlled by water-rock interactions, and the weathering of silicate and carbonate rocks jointly contributed to the formation of the chemical components of groundwater. Strong cation exchange adsorption was an important factor causing Na+ enrichment. The overall quality of groundwater in the study area was good but was polluted to a certain extent by human activities. Most of the groundwater in the Jianghuai Wavy Plain and Yanjiang Hill Plain was not suitable for direct drinking. The results of this research have important implications for the sustainable development and utilization of shallow groundwater resources and environmental protection in the Tan-Lu fault zone (Anhui section).

Sea cucumber plasmalogen enhance lipophagy to alleviate abnormal lipid accumulation induced by high-fat diet.

Sea cucumber phospholipids, including the plasmalogen (PlsEtn) and plasmanylcholine (PakCho), have been shown to play a regulatory role in lipid metabolism disorders, but their mechanism of action remains unclear. Therefore, high-fat diet (HFD) and palmitic acid were used to establish lipid accumulation models in mice and HepG2 cells, respectively. Results showed that PlsEtn can reduce lipid deposition both in vivo and in vitro. HFD stimulation abnormally activated lipophagy through the phosphorylation of the AMPK/ULK1 pathway. The lipophagy flux monitor revealed abnormalities in the fusion stage of lipophagy. Of note, only PlsEtn stimulated the dynamic remodeling of the autophagosome membrane, which was indicated by the significantly decreased LC3 II/I ratio and p62 level. In all experiments, the effect of PlsEtn was significantly higher than that of PakCho. These findings elucidated the mechanism of PlsEtn in alleviating lipid accumulation, showed that it might be a lipophagy enhancer, and provided new insights into the high-value utilization of sea cucumber as an agricultural resource.

DFSNet: A 3D Point Cloud Segmentation Network toward Trees Detection in an Orchard Scene.

In order to guide orchard management robots to realize some tasks in orchard production such as autonomic navigation and precision spraying, this research proposed a deep-learning network called dynamic fusion segmentation network (DFSNet). The network contains a local feature aggregation (LFA) layer and a dynamic fusion segmentation architecture. The LFA layer uses the positional encoders for initial transforming embedding, and progressively aggregates local patterns via the multi-stage hierarchy. The fusion segmentation module (Fus-Seg) can format point tags by learning a multi-embedding space, and the generated tags can further mine the point cloud features. At the experimental stage, significant segmentation results of the DFSNet were demonstrated on the dataset of orchard fields, achieving an accuracy rate of 89.43% and an mIoU rate of 74.05%. DFSNet outperforms other semantic segmentation networks, such as PointNet, PointNet++, D-PointNet++, DGCNN, and Point-NN, with improved accuracies over them by 11.73%, 3.76%, 2.36%, and 2.74%, respectively, and improved mIoUs over the these networks by 28.19%, 9.89%, 6.33%, 9.89, and 24.69%, respectively, on the all-scale dataset (simple-scale dataset + complex-scale dataset). The proposed DFSNet can capture more information from orchard scene point clouds and provide more accurate point cloud segmentation results, which are beneficial to the management of orchards.

Development of an attenuated potato virus Y mutant carrying multiple mutations in helper-component protease for cross-protection.

Tobacco (Nicotiana tabacum) is one of the major cash crops in China. Potato virus Y (PVY), a representative member of the genus Potyvirus, greatly reduces the quality and yield of tobacco leaves by inducing veinal necrosis. Mild strain-mediated cross-protection is an attractive method of controlling diseases caused by PVY. Currently, there is a lack of effective and stable attenuated PVY mutants. Potyviral helper component-protease (HC-Pro) is a likely target for the development of mild strains. Our previous studies showed that the residues lysine at positions 124 and 182 (K124 and K182) in HC-Pro were involved in PVY virulence, and the conserved KITC motif in HC-Pro was involved in aphid transmission. In this study, to improve the stability of PVY mild strains, K at position 50 (K50) in KITC motif, K124, and K182 were separately substituted with glutamic acid (E), leucine (L), and arginine (R), resulting in a triple-mutant PVY-HCELR. The mutant PVY-HCELR had attenuated virulence and did not induce leaf veinal necrosis symptoms in tobacco plants and could not be transmitted by Myzus persicae. Furthermore, PVY-HCELR mutant was genetically stable after six serial passages, and only caused mild mosaic symptoms in tobacco plants even at 90 days post inoculation. The tobacco plants cross-protected by PVY-HCELR mutant showed high resistance to the wild-type PVY. This study showed that PVY-HCELR mutant was a promising mild mutant for cross-protection to control PVY.

The UBE2F-CRL5ASB11-DIRAS2 axis is an oncogene and tumor suppressor cascade in pancreatic cancer cells.

UBE2F, a neddylation E2, neddylates CUL5 to activate cullin-RING ligase-5, upon coupling with neddylation E3 RBX2/SAG. Whether and how UBE2F controls pancreatic tumorigenesis is previously unknown. Here, we showed that UBE2F is essential for the growth of human pancreatic cancer cells with KRAS mutation. In the mouse KrasG12D pancreatic ductal adenocarcinoma (PDAC) model, Ube2f deletion suppresses cerulein-induced pancreatitis, and progression of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Mechanistically, Ube2f deletion inactivates the Mapk-c-Myc signals via blocking ubiquitylation of Diras2, a substrate of CRL5Asb11 E3 ligase. Biologically, DIRAS2 suppresses growth and survival of human pancreatic cancer cells harboring mutant KRAS, and Diras2 deletion largely rescues the phenotypes induced by Ube2f deletion. Collectively, Ube2f or Diras2 plays a tumor-promoting or tumor-suppressive role in the mouse KrasG12D PDAC model, respectively. The UBE2F-CRL5ASB11 axis could serve as a valid target for pancreatic cancer, whereas the levels of UBE2F or DIRAS2 may serve as prognostic biomarkers for PDAC patients.

Global research trends and hotspots in patellofemoral pain syndrome from 2000 to 2023: a bibliometric and visualization study.

Background: Patellofemoral pain syndrome (PFPS) is a prevalent condition in sports medicine, and as sports competitions become more popular, the incidence of sports injuries is on the rise. Despite the increasing research on PFPS, there remains a lack of bibliometric analyses on this topic. The aim of this study was to identify the research hotspots and trends in the field of PFPS by reviewing 23 years of literature in this field. Methods: By analyzing the literature on PFPS research from 2000 to 2023 in the core dataset of the Web of Science database and utilizing bibliometric tools like CiteSpace 6.1, VOSviewer 1.6.18, R-bibliometrix 4.6.1, Pajek 5.16, and Scimago Graphica 1.0.26, our aim was to gain insights into the current status and key areas of PFPS research. The study examined various aspects including the number of publications, countries, institutions, journals, authors, collaborative networks, keywords, and more. Through the visualization of relevant data, we also attempted to forecast future trends in the field. Results: There were 2,444 publications were included in this visualization study, published in 322 journals by 1,247 authors from 818 institutions in 67 countries. The Journal of Orthopaedic and Sports Physical Therapy had the highest number of publications, with the USA leading in article count. La Trobe University contributed the most articles, while Rathleff MS and Barton CJ emerged as the most prolific authors. Hip and knee strength and core strength, lower extremity kinematics and biomechanics, females (runners), muscle activation, risk factors, gait retraining, clinical practice guidelines, and rehabilitation were research hotspot keywords. Conclusion: Current research suggests that there is still significant potential for the development of PFPS research. Key areas of focus include the clinical effectiveness of combined hip and knee strengthening to address PFPS, characterization of lower limb kinematics and biomechanics, gait retraining, risk factors, and clinical practice guidelines. Future research could explore the effectiveness of innovative exercise therapies such as blood flow restricting training, gait retraining, and neuromuscular control training for PFPS improvement. Further investigation into gait retraining for runners, particularly females, and clinical efficacy study of a novel PRP formulation for the treatment of PFPS.

Real-time tunable notched waveguide based on voltage controllable ferroelectric resonator.

In the present study, we have devised and conducted an investigation into a real-time tunable notched waveguide, employing a voltage-controllable plasmonic resonator. This plasmonic resonator is meticulously engineered from a ferroelectric substrate featuring a compound multilayer structure, thereby conferring it with the remarkable capability of flexible permittivity control. Furthermore, we have implemented two non-intersecting Archimedean spiral electrodes on the surface of the ferroelectric substrate, dedicated to applying the bias field onto the controllable plasmonic ferroelectric resonator (CPFR). Notably, our system affords the capability to finely tune both the magnetic and electric modes, achieving precise adjustments of 8.7% and 11%, respectively. The performance is complemented by minimal insertion loss, rapid response times, and a broad range of potential applications, positioning it as a candidate for a diverse array of notched waveguide scenarios.

Accurate prediction of myopic progression and high myopia by machine learning.

Background: Myopia is a leading cause of visual impairment in Asia and worldwide. However, accurately predicting the progression of myopia and the high risk of myopia remains a challenge. This study aims to develop a predictive model for the development of myopia. Methods: We first retrospectively gathered 612 530 medical records from five independent cohorts, encompassing 227 543 patients ranging from infants to young adults. Subsequently, we developed a multivariate linear regression algorithm model to predict the progression of myopia and the risk of high myopia. Result: The model to predict the progression of myopia achieved an R2 value of 0.964 vs a mean absolute error (MAE) of 0.119D [95% confidence interval (CI): 0.119, 1.146] in the internal validation set. It demonstrated strong generalizability, maintaining consistent performance across external validation sets: R2 = 0.950 vs MAE = 0.119D (95% CI: 0.119, 1.136) in validation study 1, R2 = 0.950 vs MAE = 0.121D (95% CI: 0.121, 1.144) in validation study 2, and R2 = 0.806 vs MAE = -0.066D (95% CI: -0.066, 0.569) in the Shanghai Children Myopia Study. In the Beijing Children Eye Study, the model achieved an R2 of 0.749 vs a MAE of 0.178D (95% CI: 0.178, 1.557). The model to predict the risk of high myopia achieved an area under the curve (AUC) of 0.99 in the internal validation set and consistently high area under the curve values of 0.99, 0.99, 0.96 and 0.99 in the respective external validation sets. Conclusion: Our study demonstrates accurate prediction of myopia progression and risk of high myopia providing valuable insights for tailoring strategies to personalize and optimize the clinical management of myopia in children.

Association between cognitive function and skeletal muscle in patients undergoing maintenance hemodialysis.

Background: Patients on hemodialysis have a higher burden of cognitive impairment than individuals of the same age in the general population. Studies have found a link between cognition and skeletal muscle function. However, few studies have investigated these associations and the underlying mechanisms in patients on hemodialysis. Methods: A total of 166 patients on hemodialysis were enrolled in this longitudinal study. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) scores. Skeletal muscle indicators were evaluated using Inbody S10. Plasma brain-derived neurotrophic factor (BDNF) concentrations were measured by enzyme-linked immunosorbent assay. The primary outcome was a change in the MoCA scores. A mediation analysis was performed to examine the indirect effect of skeletal muscle on cognitive decline through BDNF. Results: Among the 166 patients, the average age was 49.9 ± 11.2 years. Of these patients with a median follow-up of 1,136 days, 133 participated in the study. We defined MoCA scores decreased by ≥2 points at 3 years from the baseline measurement as cognitive decline (CD). Compared to the cognitively unchanged group, patients with CD had significantly lower fat-free mass, soft lean mass, skeletal muscle mass, and skeletal muscle index (all P<0.05). After adjusting for potential confounders, skeletal muscle indicators were protective predictors of CD. A significant increase in plasma BDNF levels was observed in the CD group. Mediation analysis suggested that BDNF played a mediating role of 20-35% between cognitive impairment and skeletal muscle. Conclusion: Skeletal muscle is a protective predictor of CD in patients undergoing dialysis. BDNF mediates the relationship between cognitive impairment and skeletal muscle function.

Proteinase­3­antineutrophil cytoplasmic antibody­associated vasculitis secondary to subacute infective endocarditis: A case report.

A 58-year-old male patient was admitted to Peking University First Hospital (Beijing, China) due to recurrent hematuria, proteinuria and kidney dysfunction. The patient was positive for proteinase-3 (PR3)-antineutrophil cytoplasmic antibody (ANCA). Pathology of the kidney showed focal proliferative necrotizing glomerulonephritis with crescent formation and immune complex-mediated glomerulonephritis. The patient was diagnosed with PR3-ANCA-associated vasculitis (AAV), received intensive immunosuppressive therapy and experienced two relapses within 1 year. After admission, aortic valve vegetation was observed via echocardiography. The patient subsequently received antibiotic treatment and valve replacement, and achieved complete remission of kidney and cardiac function. The present case emphasized the importance of identifying secondary reasons for ANCA formation, especially infective endocarditis in patients with PR3-AAV.

Electrospun Aligned Nanofiber Yarns Constructed Biomimetic M-Type Interface Integrated into Precise Co-Culture System as Muscle-Tendon Junction-on-a-Chip for Drug Development.

The incorporation of engineered muscle-tendon junction (MTJ) with organ-on-a-chip technology provides promising in vitro models for the understanding of cell-cell interaction at the interface between muscle and tendon tissues. However, developing engineered MTJ tissue with biomimetic anatomical interface structure remains challenging, and the precise co-culture of engineered interface tissue is further regarded as a remarkable obstacle. Herein, an interwoven waving approach is presented to develop engineered MTJ tissue with a biomimetic "M-type" interface structure, and further integrated into a precise co-culture microfluidic device for functional MTJ-on-a-chip fabrication. These multiscale MTJ scaffolds based on electrospun nanofiber yarns enabled 3D cellular alignment and differentiation, and the "M-type" structure led to cellular organization and interaction at the interface zone. Crucially, a compartmentalized co-culture system is integrated into an MTJ-on-a-chip device for the precise co-culture of muscle and tendon zones using their medium at the same time. Such an MTJ-on-a-chip device is further served for drug-associated MTJ toxic or protective efficacy investigations. These results highlight that these interwoven nanofibrous scaffolds with biomimetic "M-type" interface are beneficial for engineered MTJ tissue development, and MTJ-on-a-chip with precise co-culture system indicated their promising potential as in vitro musculoskeletal models for drug development and biological mechanism studies.

Morphologic and mechanical adaptive variations in Saiga tatarica calcaneus: A model for interpreting the bone functional adaptation of wild artiodactyl in captivity.

Background and Aim: Captivity alters the locomotor behavior of wild artiodactyls and affects the mechanical loading of the calcaneus; however, the resulting adaptive changes in calcaneus morphology have not been sufficiently studied to date. This study aimed to investigate the morphological and mechanical adaptive variations in the calcaneus of Saiga tatarica to understand further the functional adaptation of the calcaneus in wild artiodactyl to captivity. Materials and Methods: Paired calcanei from autopsy samples of six captive wild artiodactyls (S. tatarica) and six domesticated artiodactyls (Ovis aries) were divided into skeletally immature and mature groups using X-ray evaluation of growth plate closure. High-resolution microcomputed tomography revealed a calcaneal diaphyseal cross-section. The mechanical and nanomorphological characteristics of the trabecular bone were determined by atomic force microscopy. Results: The percent cortical bone area (%CA), cortical thickness ratio (CTR), and Young's modulus (E) differed between species in the immature groups but not in the mature groups. S. tatarica had significantly higher growth rates for %CA, CTR, and E in the mid-shaft than O. aries (p < 0.05). Conclusion: The calcaneus morphology of S. tatarica converges with that of domesticated O. aries during ontogeny. These results indicate that the calcaneus of wild artiodactyls can undergo potentially transitional changes during the short-term adaptation to captivity. The above parameters can be preliminarily identified as morphological signs of functional bone adaptation in artiodactyls.

The identification of a novel shared therapeutic target and drug across all insulin-sensitive tissues under insulin resistance.

Background: To identify key and shared insulin resistance (IR) molecular signatures across all insulin-sensitive tissues (ISTs), and their potential targeted drugs. Methods: Three datasets from Gene Expression Omnibus (GEO) were acquired, in which the ISTs (fat, muscle, and liver) were from the same individual with obese mice. Integrated bioinformatics analysis was performed to obtain the differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) was carried out to determine the "most significant trait-related genes" (MSTRGs). Enrichment analysis and PPI network were performed to find common features and novel hub genes in ISTs. The shared genes of DEGs and genes between DEGs and MSTRGs across four ISTs were identified as key IR therapeutic target. The Attie Lab diabetes database and obese rats were used to verify candidate genes. A medical drug-gene interaction network was conducted by using the Comparative Toxicogenomics Database (CTD) to find potential targeted drugs. The candidate drug was validated in Hepa1-6 cells. Results: Lipid metabolic process, mitochondrion, and oxidoreductase activity as common features were enriched from ISTs under an obese context. Thirteen shared genes (Ubd, Lbp, Hp, Arntl, Cfd, Npas2, Thrsp., Tpx2, Pkp1, Sftpd, Mthfd2, Tnfaip2, and Vnn3) of DEGs across ISTs were obtained and confirmed. Among them, Ubd was the only shared gene between DEGs and MSTRGs across four ISTs. The expression of Ubd was significantly upregulated across four ISTs in obese rats, especially in the liver. The IR Hepa1-6 cell models treated with dexamethasone (Dex), palmitic acid (PA), and 2-deoxy-D-ribose (dRib) had elevated expression of Ubd. Knockdown of Ubd increased the level of p-Akt. A lowing Ubd expression drug, promethazine (PMZ) from CTD analysis rescued the decreased p-Akt level in IR Hepa1-6 cells. Conclusion: This study revealed Ubd, a novel and shared IR molecular signature across four ISTs, as an effective biomarker and provided new insight into the mechanisms of IR. PMZ was a candidate drug for IR which increased p-Akt level and thus improved IR by targeting Ubd and downregulation of Ubd expression. Both Ubd and PMZ merit further clinical translational investigation to improve IR.

An Interpretable Population Graph Network to Identify Rapid Progression of Alzheimer's Disease Using UK Biobank.

Alzheimer's disease (AD) manifests with varying progression rates across individuals, necessitating the understanding of their intricate patterns of cognition decline that could contribute to effective strategies for risk monitoring. In this study, we propose an innovative interpretable population graph network framework for identifying rapid progressors of AD by utilizing patient information from electronic health-related records in the UK Biobank. To achieve this, we first created a patient similarity graph, in which each AD patient is represented as a node; and an edge is established by patient clinical characteristics distance. We used graph neural networks (GNNs) to predict rapid progressors of AD and created a GNN Explainer with SHAP analysis for interpretability. The proposed model demonstrates superior predictive performance over the existing benchmark approaches. We also revealed several clinical features significantly associated with the prediction, which can be used to aid in effective interventions for the progression of AD patients.