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Beiging of adipocytes is characteristic of a higher number of mitochondria, the central hub of metabolism in the cell. However, studies show that beiging can improve metabolic health or cause metabolic disorders. Here we discuss a liver-fat crosstalk for iron flux associated with healthy beiging of adipocytes. Deletion of the transcription factor FoxO1 in adipocytes (adO1KO mice) induces a higher iron flux from the liver to white adipose tissue, concurrent with augmented mitochondrial biogenesis that increases iron demands. In addition, adO1KO mice adopt an alternate mechanism to sustain mitophagy, which enhances mitochondrial quality control, thereby improving mitochondrial respiratory capacity and metabolic health. However, the liver-fat crosstalk is not detectable in adipose Atg7 knockout (ad7KO) mice, which undergo beiging of adipocytes but have metabolic dysregulation. Autophagic clearance of mitochondria is blocked in ad7KO mice, which accumulates dysfunctional mitochondria and elevates mitochondrial content but lowers mitochondrial respiratory capacity. Mitochondrial biogenesis is comparable in the control and ad7KO mice, and the iron influx into adipocytes and iron efflux from the liver remain unchanged. Therefore, activation of the liver-fat crosstalk is critical for mitochondrial quality control that underlies healthy beiging of adipocytes.

Purpose Our study aimed to investigate the potential of radiomics with DCE-MRI for predicting Ki-67 expression in invasive ductal breast cancer. Method We conducted a retrospective study including 223 patients diagnosed with invasive ductal breast cancer. Radiomics features were extracted from DCE-MRI using 3D-Slicer software. Two Ki-67 expression cutoff values (20% and 29%) were examined. Patients were divided into training (70%) and test (30%) sets. The Elastic Net method selected relevant features, and five machine-learning models were established. Radiomics models were created from intratumoral, peritumoral, and combined regions. Performance was assessed using ROC curves, accuracy, sensitivity, and specificity. Result For a Ki-67 cutoff value of 20%, the combined model exhibited the highest performance, with area under the curve (AUC) values of 0.838 (95% confidence interval (CI): 0.774–0.897) for the training set and 0.863 (95% CI: 0.764–0.949) for the test set. The AUC values for the tumor model were 0.816 (95% CI: 0.745–0.880) and 0.830 (95% CI: 0.724–0.916), and for the peritumor model were 0.790 (95% CI: 0.711–0.857) and 0.808 (95% CI: 0.682–0.910). When the Ki-67 cutoff value was set at 29%, the combined model also demonstrated superior predictive ability in both training set (AUC: 0.796; 95% CI: 0.724–0.862) and the test set (AUC: 0.823; 95% CI: 0.723–0.911). The AUC values for the tumor model were 0.785 (95% CI: 0.708–0.861) and 0.784 (95% CI: 0.663–0.882), and for the peritumor model were 0.773 (95% CI: 0.690–0.844) and 0.729 (95% CI: 0.603–0.847). Conclusion Radiomics with DCE-MRI can predict Ki-67 expression in invasive ductal breast cancer. Integrating radiomics features from intratumoral and peritumoral regions yields a dependable prognostic model, facilitating pre-surgical detection and treatment decisions. This holds potential for commercial diagnostic tools.

One of the current mainstream treatments for multiple myeloma (MM) is chemotherapy. However, due to the high clonal heterogeneity and genomic complexity of MM, single-target drugs have limited efficacy and are prone to drug resistance. Therefore, there is an urgent need to develop multi-target drugs against MM. We screened drugs that simultaneously inhibit poly(ADP-ribose) polymerase 1 (PARP1) and 20S proteasome through computer-aided drug discovery (CADD) techniques, and explored the binding mode and dynamic stability of selected inhibitor to proteasome through Molecular biology (MD) simulation method. Thus, the dual-target inhibition effect of fluzoparib was proposed for the first time, and the ability of dual-target inhibition and tumor killing was explored at the enzyme, cell and animal level, respectively. This provides a theoretical and experimental basis for exploring multi-target inhibitory drugs for cancers.

Conventional type 1 dendritic cells (cDC1s) are superior in antigen cross-presentation and priming CD8+ T cell anti-tumor immunity and thus, are a target of high interest for cancer immunotherapy. Type I interferon (IFN) is a potent inducer of antigen cross-presentation, but, unfortunately, shows only modest results in the clinic given the short half-life and high toxicity of current type I IFN therapies, which limit IFN exposure in the tumor. CD8+ T cell immunity is dependent on IFN signaling in cDC1s and preclinical studies suggest targeting IFN directly to cDC1s may be sufficient to drive anti-tumor immunity. Here, we engineered an anti-XCR1 antibody (Ab) and IFN mutein (IFNmut) fusion protein (XCR1Ab-IFNmut) to determine whether systemic delivery could drive selective and sustained type I IFN signaling in cDC1s leading to anti-tumor activity and, in parallel, reduced systemic toxicity. We found that the XCR1Ab-IFNmut fusion specifically enhanced cDC1 activation in the tumor and spleen compared to an untargeted control IFN. However, multiple treatments with the XCR1Ab-IFNmut fusion resulted in robust anti-drug antibodies (ADA) and loss of drug exposure. Using other cDC1-targeting Ab-IFNmut fusions, we found that localizing IFN directly to cDC1s activates their ability to promote ADA responses, regardless of the cDC1 targeting antigen. The development of ADA remains a major hurdle in immunotherapy drug development and the cellular and molecular mechanisms governing the development of ADA responses in humans is not well understood. Our results reveal a role of cDC1s in ADA generation and highlight the potential ADA challenges with targeting immunostimulatory agents to this cellular compartment.

As the most abundant natural polymer material on the earth, cellulose is a promising sustainable sensing material due to its high mechanical strength, excellent biocompatibility, good degradation, and regeneration ability. Considering the inherent advantages of cellulose and the success of modern sensors, applying cellulose to sensors has always been the subject of considerable investigation, and significant progress has been made in recent decades. Herein, we reviewed the research progress of cellulose functional materials (CFMs) in recent years. According to the different sources of cellulose, the classification and preparation methods for the design and functionalization of cellulose were summarized with the emphasis on the relationship between their structure and properties. Besides, the applications of advanced sensors based on CFMs in recent years were also discussed. Finally, the potential challenges and prospects of the development of sensor based on CFMs were outlined.

The research field of Information Retrieval (IR) has evolved significantly, expanding beyond traditional search to meet diverse user information needs. Recently, Large Language Models (LLMs) have demonstrated exceptional capabilities in text understanding, generation, and knowledge inference, opening up exciting avenues for IR research. LLMs not only facilitate generative retrieval but also offer improved solutions for user understanding, model evaluation, and user-system interactions. More importantly, the synergistic relationship among IR models, LLMs, and humans forms a new technical paradigm that is more powerful for information seeking. IR models provide real-time and relevant information, LLMs contribute internal knowledge, and humans play a central role of demanders and evaluators to the reliability of information services. Nevertheless, significant challenges exist, including computational costs, credibility concerns, domain-specific limitations, and ethical considerations. To thoroughly discuss the transformative impact of LLMs on IR research, the Chinese IR community conducted a strategic workshop in April 2023, yielding valuable insights. This paper provides a summary of the workshop’s outcomes, including the rethinking of IR’s core values, the mutual enhancement of LLMs and IR, the proposal of a novel IR technical paradigm, and open challenges.

VEGF-VEGFR2 signaling pathway plays an important role in the course of psoriasis. Binding of VEGF to VEGFR2 induces receptor dimerization and autophosphorylation at multiple tyrosine sites, promoting the activation of the downstream ERK1/2 signaling pathway. Phosphorylated ERK1/2 is highly expressed in keratinocytes in psoriatic lesions, while VEGFR2 activation induces ERK1/2 phosphorylation and upregulates the expression of keratin K6, K16, and K17. At the same time, the activation of ERK1/2 can enhance inflammatory response and vascular proliferation. Therefore, blockade of VEGF-mediated vegF-VEGFR2 signaling pathway can regulate the expression of downstream genes in VEGF-VEGFR2 signaling pathway. VEGF and VEGFR2, the key molecules in VEGF-VEGFR2 signaling pathway, may serve as potential therapeutic targets for psoriasis. VEGF inhibitors can block vegF-VEGFR2 signaling pathway by inhibiting VEGF or VEGFR2, playing a therapeutic role in psoriasis. In this review, we review the recent advances in the involvement of VEGF-VEGFR2 pathway in psoriasis.

Adipose plasticity is critical for metabolic homeostasis. Adipocyte transdifferentiation plays an important role in adipose plasticity, but the molecular mechanism of transdifferentiation remains incompletely understood. Here we show that the transcription factor FoxO1 regulates adipose transdifferentiation by mediating Tgfβ1 signaling pathway. Tgfβ1 treatment induced whitening phenotype in beige adipocytes, reducing UCP1 and mitochondrial capacity and enlarging lipid droplets. Deletion of adipose FoxO1 (adO1KO) dampened Tgfβ1 signaling by downregulating Tgfbr2 and Smad3 and induced browning of adipose tissue in mice, increasing UCP1 and mitochondrial content and activating metabolic pathways. Silencing FoxO1 also abolished the whitening effect of Tgfβ1 on beige adipocytes. The adO1KO mice exhibited a significantly higher energy expenditure, lower fat mass, and smaller adipocytes than the control mice. The browning phenotype in adO1KO mice was associated with an increased iron content in adipose tissue, concurrent with upregulation of proteins that facilitate iron uptake (DMT1 and TfR1) and iron import into mitochondria (Mfrn1). Analysis of hepatic and serum iron along with hepatic iron-regulatory proteins (ferritin and ferroportin) in the adO1KO mice revealed an adipose tissue-liver crosstalk that meets the increased iron requirement for adipose browning. The FoxO1-Tgfβ1 signaling cascade also underlay adipose browning induced by β3-AR agonist CL316243. Our study provides the first evidence of a FoxO1-Tgfβ1 axis in the regulation of adipose browning-whitening transdifferentiation and iron influx, which sheds light on the compromised adipose plasticity in conditions of dysregulated FoxO1 and Tgfβ1 signaling.

The high toxicity of nerve agents makes the development of fluorescence sensors with suitable limit of detection challenging. Here, the authors propose a sensor design based on a conjugated microporous polymer film for the detection of diethyl chlorophosphate, a substitute of Sarin, with low detection limit of 2.5 ppt.

There are too few teachers and schools to meet the need for quality universal basic education. Therefore, alternative approaches to education provision need to be explored, such as open and distance learning methods and development and provision of curriculum-based Open Educational Resources (OER). However, distribution of printed materials is increasingly costly, and distribution of digital resources remains a challenge in areas with little or no connectivity. This case study explores the potential of using offline strategies to share digital OER. It suggests it is possible to provide access to digital learning resources even in the most remote areas by using appropriate technology, like the Commonwealth of Learning's Aptus device.

Abstract Sex difference in adiposity has long been recognized but the mechanism remains incompletely understood. Previous studies suggested that adiposity was regulated by autophagy in response to energy status change. Here, we show that the energy sensor Sirt1 mediates sex difference in adiposity by regulating autophagy and adipogenesis in partnership with estrogen receptor α (ERα). Autophagy and adipogenesis were suppressed by Sirt1 activation or overexpression, which was associated with reduced sex difference in adiposity. Mechanistically, Sirt1 deacetylated and activated AKT and STAT3, resulting in suppression of autophagy and adipogenesis via mTOR-ULK1 and p55 cascades. ERα induced Sirt1 expression and inhibited autophagy in adipocytes, while silencing Sirt1 reversed the effects of ERα on autophagy and promoted adipogenesis. Moreover, Sirt1 deacetylated ERα, which constituted a positive feedback loop in the regulation of autophagy and adiposity. Our results revealed a new mechanism of Sirt1 regulating autophagy in adipocytes and shed light on sex difference in adiposity.

Computed tomography (CT) reconstruction for limited-angle projection data is an ill-posed inverse problem, that often produces artifacts near the edges of an image. In this study, a hybrid minimization model based on a nonlocal low-rank approximation and a prior image in a wavelet tight framework is proposed to improve reconstructions from limited-angle projections. Low-frequency wavelet coefficients of the reconstructed image were estimated using a nonlocal low-rank approximation and the l2 norm minimization was applied to the difference between the high-frequency components of a prior image and the reconstructed image. In addition, the alternative direction method of multipliers (ADMM) was used for alternately minimization to solve two regularization terms which produce the most parameters. Experimental results demonstrated that the proposed algorithm offers several advantages over conventional iterative reconstruction techniques, including faster convergence, suppression of limited-angle artifacts, noise reduction, and the preservation of edges and other image details. This study represents the first time that nonlocal low-rank prior information has been applied to limited-angle CT.

In order to deal with the problem of multi-state frequency stability at DC receiving end, this paper studied the variation of inertia time constant and static characteristic coefficient of equivalent machine with or without pumped storage power generation by using the performance indexes of transient, dynamic and static frequency stability, namely reciprocal of instantaneous change rate, damping ratio and reciprocal of static deviation. The influence of pumped storage power generation on transient, dynamic and static frequency stability was analyzed. The performance indexes of each state were obtained and compared with those before. Finally, the model was built for simulation. Through theoretical analysis, it is concluded that pumped storage power generation improves the transient, dynamic and static frequency stability of the DC receiving end power grid. The correctness of theoretical analysis was verified by numerical simulation. The research results provid an important theoretical basis for the influence of pumped storage power generation on the multi-state frequency stability of DC receiving end power grid.

Sparse array arrangement has been widely used in vector-sensor arrays because of increased degree-of-freedoms for identifying more sources than sensors. For large-size sparse vector-sensor arrays, one-bit measurements can further reduce the receiver system complexity by using low-resolution ADCs. In this paper, we present a sparse cross-dipole array with one-bit measurements to estimate Direction of Arrivals (DOA) of electromagnetic sources. Based on the independence assumption of sources, we establish the relation between the covariance matrix of one-bit measurements and that of unquantized measurements by Bussgang Theorem. Then we develop a Spatial-Smooth MUSIC (SS-MUSIC) based method, One-Bit MUSIC (OB-MUSIC), to estimate the DOAs. By jointly utilizing the covariance matrices of two dipole arrays, we find that OB-MUSIC is robust against polarization states. We also derive the Cramer-Rao bound (CRB) of DOA estimation for the proposed scheme. Furthermore, we theoretically analyze the applicability of the independence assumption of sources, which is the fundamental of the proposed and other typical methods, and verify the assumption in typical communication applications. Numerical results show that, with the same number of sensors, one-bit sparse cross-dipole arrays have comparable performance with unquantized uniform linear arrays and thus provide a compromise between the DOA estimation performance and the system complexity.

Atherosclerosis is a chronic inflammatory disease of the blood vasculature. Endothelial dysfunction is an early event in the development of atherosclerosis and the endothelium plays an important role in the innate immune defense in the pathology of cardiovascular diseases. New therapies are being developed based on the involvement of the immune system in atherosclerosis. In this study, we demonstrate that a commonly used anti-rheumatic drug, tofacitinib, possesses vascular protective properties in cultured primary human aortic endothelial cells (HAECs). Tofacitinib ameliorates oxidized low-density lipoprotein (ox-LDL)-induced adhesion of THP-1 cells to HAECs, suppresses the expression of vascular adhesion molecules and production of cytokines, including vascular cell adhesion molecule 1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Moreover, tofacitinib inhibits elevation of endothelial lectin-like ox-LDL receptor-1 (LOX-1) and production of reactive oxygen species (ROS) triggered by ox-LDL. As a result, the presence of tofacitinib reduces ox-LDL-induced cytotoxicity and improves endothelial viability. Mechanistically, we demonstrate that tofacitinib suppresses ox-LDL-mediated activation of NF-κB inhibitor α (IκB-α), accumulation of nuclear p65 and activation of nuclear factor κB (NF-κB) promoter, indicating that tofacitinib inhibits NF-κB activation. Collectively, our data support that tofacitinib possesses a novel protective function in endothelial cells, implying that tofacitinib could have the therapeutic potential to modulate inflammation in cardiovascular diseases.

Objective: Given that cellular O-GlcNAcylation levels are thought to be real-time measures of cellular nutrient status and dysregulated O-GlcNAc signaling is associated with insulin resistance, we evaluated the role of O-GlcNAc transferase (OGT), the enzyme that mediates O-GlcNAcylation, in skeletal muscle. Methods: We assessed O-GlcNAcylation levels in skeletal muscle from obese, type 2 diabetic people, and we characterized muscle-specific OGT knockout (mKO) mice in metabolic cages and measured energy expenditure and substrate utilization pattern using indirect calorimetry. Whole body insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique and tissue-specific glucose uptake was subsequently evaluated. Tissues were used for histology, qPCR, Western blot, co-immunoprecipitation, and chromatin immunoprecipitation analyses. Results: We found elevated levels of O-GlcNAc-modified proteins in obese, type 2 diabetic people compared with well-matched obese and lean controls. Muscle-specific OGT knockout mice were lean, and whole body energy expenditure and insulin sensitivity were increased in these mice, consistent with enhanced glucose uptake and elevated glycolytic enzyme activities in skeletal muscle. Moreover, enhanced glucose uptake was also observed in white adipose tissue that was browner than that of WT mice. Interestingly, mKO mice had elevated mRNA levels of Il15 in skeletal muscle and increased circulating IL-15 levels. We found that OGT in muscle mediates transcriptional repression of Il15 by O-GlcNAcylating Enhancer of Zeste Homolog 2 (EZH2). Conclusions: Elevated muscle O-GlcNAc levels paralleled insulin resistance and type 2 diabetes in humans. Moreover, OGT-mediated signaling is necessary for proper skeletal muscle metabolism and whole-body energy homeostasis, and our data highlight O-GlcNAcylation as a potential target for ameliorating metabolic disorders. Keywords: O-GlcNAc signaling, Type 2 diabetes, N-acetyl-d-glucosamine, Tissue cross talk, Epigenetic regulation of Il15 transcription, Insulin sensitivity

Intelligent travel guide systems have grown increasingly popular in recent years. They also benefit a lot from the development of social media, resulting in a large amount of attractions uploaded by users. To tackle this, attractions should be real time classified by user-generated photos automatically to gain better user experience. However, in practice, the given label of photos and text ratings may be incomplete or missing. Moreover, recently, domain adaptation has been applied to deal with few labeled data. Thus, in this paper, we propose a novel framework for automatically attraction classification in leveraging web-harvesting data from search engine and the photos of attractions uploaded by users. Specifically, we assume that top-k web-harvesting images from search engines have correct labels. The classification problem is formulated as a regularized domain adaptation approach. Experiments conducted on the collected real-world data set demonstrated that the promising performance is gained over state-of-the art classification methods.

K-Ras works as a switch in many important intracellular signaling pathways and plays important roles in cell growth, proliferation, differentiation and carcinogenesis. For signal transduction from K-Ras to Raf1, the best-characterized effector of K-Ras, the general view is that Ras recruits Raf1 from the cytoplasm to the cell membrane. To elucidate this process, we constructed a series of fusion proteins (including Raf1 and K-Ras fused with either fluorescent proteins or fluorescent protein fragments) to compare subcellular localizations of these proteins. Bimolecular fluorescence complementation (BiFC) and a co-transfection system were used. In the BiFC system, the K-Ras/Raf1 complexes were mainly located in the cell membrane, while the Raf1 control was uniformly distributed in the cytoplasm. However, the complexes of Raf1 and K-RasC185S, a K-Ras mutant which loses membrane-localization, were also able to accumulate in the cell membrane. In contrast, an apparent cytosolic distribution pattern was observed in cells co-transfected with mcerulean-Raf1 and EGFP-K-RasC185S, suggesting that the membrane localization of K-Ras/Raf1 complexes is not entirely dependent on K-Ras, and that other factors, such as the irreversible conformation formed between K-Ras and Raf1 may play a role. This study sheds light on the interaction between K-Ras and Raf1 and provides a practical method to elucidate the mechanism underlying K-Ras and Raf1 binding to the cell membrane.

Insulin resistance and a progressive decline in functional β-cell mass are hallmarks of developing type 2 diabetes (T2D). Thus, searching for natural, low-cost compounds to target these two defects could be a promising strategy to prevent the pathogenesis of T2D. Here, we show that dietary intake of flavonol kaempferol (0.05% in the diet) significantly ameliorated hyperglycemia, hyperinsulinemia, and circulating lipid profile, which were associated with the improved peripheral insulin sensitivity in middle-aged obese mice fed a high-fat (HF) diet. Kaempferol treatment reversed HF diet impaired glucose transport-4 (Glut4) and AMP-dependent protein kinase (AMPK) expression in both muscle and adipose tissues from obese mice. In vitro, kaempferol increased lipolysis and prevented high fatty acid-impaired glucose uptake, glycogen synthesis, AMPK activity, and Glut4 expression in skeletal muscle cells. Using another mouse model of T2D generated by HF diet feeding and low doses of streptozotocin injection, we found that kaempferol treatment significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in obese diabetic mice, which are associated with the improved islet β-cell mass. These results demonstrate that kaempferol may be a naturally occurring anti-diabetic agent by improving peripheral insulin sensitivity and protecting against pancreatic β-cell dysfunction.