Targeting the HSP47-collagen axis inhibits brain metastasis by reversing M2 microglial polarization and restoring anti-tumor immunity.

Brain metastases (BrMs) are the leading cause of death in patients with solid cancers. BrMs exhibit a highly immunosuppressive milieu and poor response to immunotherapies; however, the underlying mechanism remains largely unclear. Here, we show that upregulation of HSP47 in tumor cells drives metastatic colonization and outgrowth in the brain by creating an immunosuppressive microenvironment. HSP47-mediated collagen deposition in the metastatic niche promotes microglial polarization to the M2 phenotype via the α2ß1 integrin/nuclear factor κB pathway, which upregulates the anti-inflammatory cytokines and represses CD8+ T cell anti-tumor responses. Depletion of microglia reverses HSP47-induced inactivation of CD8+ T cells and abolishes BrM. Col003, an inhibitor disrupting HSP47-collagen association restores an anti-tumor immunity and enhances the efficacy of anti-PD-L1 immunotherapy in BrM-bearing mice. Our study supports that HSP47 is a critical determinant of M2 microglial polarization and immunosuppression and that blocking the HSP47-collagen axis represents a promising therapeutic strategy against brain metastatic tumors.

Methyl-ß-cyclodextrin asymmetrically extracts phospholipid from bilayers, granting tunable control over differential stress in lipid vesicles.

Lipid asymmetry - that is, a nonuniform lipid distribution between the leaflets of a bilayer - is a ubiquitous feature of biomembranes and is implicated in several cellular phenomena. Differential tension - that is, unequal lateral monolayer tensions comparing the leaflets of a bilayer- is closely associated with lipid asymmetry underlying these varied roles. Because differential tension is not directly measurable in combination with the fact that common methods to adjust this quantity grant only semi-quantitative control over it, a detailed understanding of lipid asymmetry and differential tension are impeded. To overcome these challenges, we leveraged reversible complexation of phospholipid by methyl-ß-cyclodextrin (mbCD) to tune the direction and magnitude of lipid asymmetry in synthetic vesicles. Lipid asymmetry generated in our study induced (i) vesicle shape changes and (ii) gel-liquid phase coexistence in 1-component vesicles. By applying mass-action considerations to interpret our findings, we discuss how this approach provides access to phospholipid thermodynamic potentials in bilayers containing lipid asymmetry (which are coupled to the differential tension of a bilayer). Because lipid asymmetry yielded by our approach is (i) tunable and (ii) maintained over minute to hour timescales, we anticipate that this approach will be a valuable addition to the experimental toolbox for systematic investigation into the biophysical role(s) of lipid asymmetry (and differential tension).

Novel therapeutic strategies for rare mutations in non-small cell lung cancer.

Lung cancer is still the leading cause of cancer-related mortality. Over the past two decades, the management of non-small cell lung cancer (NSCLC) has undergone a significant revolution. Since the first identification of activating mutations in the epidermal growth factor receptor (EGFR) gene in 2004, several genetic aberrations, such as anaplastic lymphoma kinase rearrangements (ALK), neurotrophic tropomyosin receptor kinase (NTRK) and hepatocyte growth factor receptor (MET), have been found. With the development of gene sequencing technology, the development of targeted drugs for rare mutations, such as multikinase inhibitors, has provided new strategies for treating lung cancer patients with rare mutations. Patients who harbor this type of oncologic driver might acquire a greater survival benefit from the use of targeted therapy than from the use of chemotherapy and immunotherapy. To date, more new agents and regimens can achieve satisfactory results in patients with NSCLC. In this review, we focus on recent advances and highlight the new approval of molecular targeted therapy for NSCLC patients with rare oncologic drivers.

[Research progress of ultrasound in diagnosis and treatment of shoulder joint diseases].

Objective: To review the research progress of ultrasound in the diagnosis and treatment of shoulder diseases, in order to provide a theoretical basis for the further development of ultrasound in shoulder surgery. Methods: The recent literature on the application of ultrasound in the shoulder joint was extensively reviewed. The application of ultrasound in the diagnosis and treatment of shoulder joint diseases, and the advantages and disadvantages of ultrasound were analysed, and the development trend of ultrasound technology in the shoulder joint area was prospected. Results: At present, the diagnosis of shoulder joint diseases mainly relies on MRI, however, with the development of ultrasound technology, ultrasound with the characteristics of convenient, reliable, and real-time dynamic evaluation is more and more recognized in the diagnosis process of shoulder joint diseases, combined with three-dimensional ultrasound, ultrasound intervention, and elastography can improve the accuracy, sensitivity, and specificity of the diagnosis, and is suitable for the diagnosis and treatment of various shoulder joint diseases, which is expected to carry out early prevention of shoulder joint diseases in the future and achieve more refined and minimally invasive treatment. Conclusion: Ultrasound technology has wide application prospect in shoulder joint diseases, but it is still in the developing stage, and the subjective dependence needs to be solved further.

Spatial distribution, mass flux, and ecological risk of antibiotics in Taiwan and Luzon Straits: A case in the West Pacific Region.

Emerging pollutants are hazardous to the ecological environment and human health, and these issues have attracted increasing attention from scholars. In the current study, the Taiwan Strait is long and narrow, highly influenced by terrestrial domains, and frequently disturbed by human activities. Conversely, the Luzon Strait is an open sea far from the shore, and the impact of human activities on it is minimal. The description of antibiotics in two different types of seas revealed that contaminants were most commonly detected in both straits. In particular, the coasts of the Minjiang River, Jinjiang River, and Jiulong River were found to be pollution hotspots in the Taiwan Strait. The calculation of risk quotients revealed that antibiotics were more sensitive to algae. Furthermore, estimation of the risk quotients of the mixtures found that antibiotics in the environment do not pose a high risk to aquatic organisms at different trophic levels.

Arabidopsis ERD15 regulated by BBX24 plays a positive role in UV-B signaling.

Ultraviolet-B (UV-B, 280-315 nm) is a minor component of solar radiation, but it has a major regulatory impact on plant growth and development. Solar UV-B regulates numerous aspects of plant metabolism, morphology and physiology through altering the expression of hundreds of genes. EARLY RESPONSIVE TO DEHYDRATION 15 (ERD15) is a drought-induced rapid response gene, formerly known as a negative regulator of the abscisic acid (ABA) signaling pathway. It is unclear whether ERD15 is involved in UV-B-induced photomorphogenesis. Previously, we reported that the BBX24 transcriptional factor negatively regulated UV-B signaling. In the present study, we identified that ERD15 is involved in UV-B photomorphogenesis as a positive regulator at phenotypic, physiological and molecular levels. Our results indicated that ERD15 expression is suppressed by UV-B, inhibited the elongation of Arabidopsis hypocotyls in a UV-B-dependent manner, promoted the expression of related UV-B signaling genes and increased the total antioxidant capacity of Arabidopsis under UV-B. Genetic hybridization results show that ERD15 acts downstream of BBX24, and BBX24 protein mediated the expression of ERD15 by binding to its promoter. Thus, ERD15 is a novel positive regulator of the UV-B signaling pathway, which is downstream of BBX24 and regulated by BBX24 protein to participate in UV-B photomorphogenesis.

Comprehensive review regarding the association of E2Fs with the prognosis and immune infiltrates in human head and neck squamous cell carcinoma.

E2F transcription factors (E2Fs) are a group of genes that encode a family of transcription factors. They have been identified as being involved in the tumor progression of various cancer types. However, little is known about the expression level, genetic variation, molecular mechanism, and prognostic value and immune infiltration of different E2Fs in HNSCC.In this study, we utilized multiple databases to investigate the mRNA expression level, genetic alteration, and biological function of E2Fs in HNSCC patients. Then, the relationship between E2Fs expression and its association with the occurrence, progress, prognosis, and immune cell infiltration in patients with HNSCC was evaluated. We found that all eight E2Fs were higher expressed in HNSCC tissues than in normal tissues, and the expression levels of E2F1/2/3/4/5/6/8 were also associated with the stage and grade of HNSCC. The abnormal expression of E2F1/2/4/8 in HNSCC patients is related to the clinical outcome. The expression of E2Fs was statistically correlated with the immune cell infiltration in HNSCC and the infiltration of B cells and CD8+ T cells were positively associated with better OS in HNSCC patients. Furthermore, we verified the E2F2 at the tissue level in the validation experiment. Our study may provide novel insights into the choice of immunotherapy targets and potential prognostic biomarkers in HNSCC patients.

Altered White-Matter Functional Network in Children with Idiopathic Generalized Epilepsy.

RATIONALE AND OBJECTIVES: The white matter (WM) functional network changes offers insights into the potential pathological mechanisms of certain diseases, the alterations of WM functional network in idiopathic generalized epilepsy (IGE) remain unclear. We aimed to explore the topological characteristics changes of WM functional network in childhood IGE using resting-state functional Magnetic resonance imaging (MRI) and T1-weighted images. METHODS: A total of 84 children (42 IGE and 42 matched healthy controls) were included in this study. Functional and structural MRI data were acquired to construct a WM functional network. Group differences in the global and regional topological characteristics were assessed by graph theory and the correlations with clinical and neuropsychological scores were analyzed. A support vector machine algorithm model was employed to classify individuals with IGE using WM functional connectivity as features, and the model's accuracy was evaluated using leave-one-out cross-validation. RESULTS: In IGE group, at the network level, the WM functional network exhibited increased assortativity; at the nodal level, 17 nodes presented nodal disturbances in WM functional network, and nodal disturbances of 11 nodes were correlated with cognitive performance scores, disease duration and age of onset. The classification model achieved the 72.6% accuracy, 0.746 area under the curve, 69.1% sensitivity, 76.2% specificity. CONCLUSION: Our study demonstrated that the WM functional network topological properties changes in childhood IGE, which were associated with cognitive function, and WM functional network may help clinical classification for childhood IGE. These findings provide novel information for understanding the pathogenesis of IGE and suggest that the WM function network might be qualified as potential biomarkers.

Trends of mean systolic and diastolic blood pressure among adults in Shenzhen, China, 1997-2018: findings from three rounds of the population-based survey.

OBJECTIVE: To quantify the trends in systolic and diastolic blood pressure (BP) among adults in Shenzhen from 1997 to 2018. DESIGN: Cross-sectional study. SETTINGS: The data were collected from all districts in Shenzhen, China in the years of 1997, 2009 and 2018 by multistage cluster sampling procedure. PARTICIPANTS: Participants were residents aged 18-69 years in Shenzhen, China. A total of 26 621 people were included: 8266 people in 1997, 8599 people in 2009 and 9756 people in 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: All participants were surveyed about their sociodemographic and lifestyle information. BP was measured by trained physicians using a mercury sphygmomanometer. Hypertension was defined as systolic BP of at least 140 mm Hg and diastolic BP of at least 90 mm Hg, self-reported use of antihypertensive medications or both. Hypertension control was defined as systolic BP values of less than 140 mm Hg and diastolic BP values of less than 90 mm Hg. RESULT: Age-adjusted mean systolic BP increased from 117±16 mm Hg to 123±15 mm Hg (p<0.001) in males, and from 113±18 mm Hg to 115±16 mm Hg (p<0.001) in females from 1997 to 2018. Diastolic BP among males increased from 75 mm Hg (SD=11) to 79 mm Hg (SD=11) and increased from 71 mm Hg (SD=10) to 73 mm Hg (SD=10) among females between 1997 and 2018 (p<0.001). Rate of hypertension rose rapidly from 17.71% (95% CI: 16.60% to 18.90%) in 2009 to 24.01% (95% CI: 22.84% to 25.22%) in 2018 among males (p<0.001), whereas the prevalence among females remained stable at around 13.5% (p=0.98). Both awareness and treatment rates of hypertension among males and females showed a decreased trend between 2009 and 2018, while no significant changes were observed for control rates. CONCLUSIONS: The mean systolic BP and diastolic BP among adults in Shenzhen increased from 1997 to 2018, and no improvements in hypertension awareness, treatment and control rates were found.

A superior mulberry-like nanoparticle NiB binary catalyst for borohydride oxidation.

A NiB binary catalyst with a unique mulberry-like nanoparticle morphology has been prepared by one-step electrodeposition. The NiB-0.2 catalyst exhibits excellent catalytic activity, selectivity, and stability for the borohydride oxidation reaction. Moreover, a direct borohydride fuel cell using the NiB-0.2 catalyst anode can deliver a peak power density of 453 mW cm-2 and open-circuit voltage of 1.96 V at 343 K. The improved performances are due to the introduction of B. This study may inspire the development of efficient noble-metal-free anode catalysts for DBFCs.

GIGANTEA Unveiled: Exploring Its Diverse Roles and Mechanisms.

GIGANTEA (GI) is a conserved nuclear protein crucial for orchestrating the clock-associated feedback loop in the circadian system by integrating light input, modulating gating mechanisms, and regulating circadian clock resetting. It serves as a core component which transmits blue light signals for circadian rhythm resetting and overseeing floral initiation. Beyond circadian functions, GI influences various aspects of plant development (chlorophyll accumulation, hypocotyl elongation, stomatal opening, and anthocyanin metabolism). GI has also been implicated to play a pivotal role in response to stresses such as freezing, thermomorphogenic stresses, salinity, drought, and osmotic stresses. Positioned at the hub of complex genetic networks, GI interacts with hormonal signaling pathways like abscisic acid (ABA), gibberellin (GA), salicylic acid (SA), and brassinosteroids (BRs) at multiple regulatory levels. This intricate interplay enables GI to balance stress responses, promoting growth and flowering, and optimize plant productivity. This review delves into the multifaceted roles of GI, supported by genetic and molecular evidence, and recent insights into the dynamic interplay between flowering and stress responses, which enhance plants' adaptability to environmental challenges.

BAF45D-binding to HOX genes was differentially targeted in H9-derived spinal cord neural stem cells.

Chromatin accessibility has been used to define how cells adopt region-specific neural fates. BAF45D is one of the subunits of a specialised chromatin remodelling BAF complex. It has been reported that BAF45D is expressed in spinal cord neural stem cells (NSCs) and regulates their fate specification. Within the developing vertebrate spinal cord, HOX genes exhibit spatially restricted expression patterns. However, the chromatin accessibility of BAF45D binding HOX genes in spinal cord NSCs is unclear. In the present study, we found that in H9-derived spinal cord NSCs, BAF45D targets TBX6, a gene that regulates spinal cord neural mesodermal progenitors. Furthermore, BAF45D binding to the NES gene is much more enriched in H9-derived spinal cord NSCs chromatin compared to ESCs chromatin. In addition, BAF45D binding to anterior and trunk/central HOX genes, but not to lumbosacral HOX genes, was much more enriched in NSCs chromatin compared to ESCs chromatin. These results may shed new light on the role of BAF45D in regulating region-specific spinal cord NSCs by targeting HOX genes.

Insight into modulators of sphingosine-1-phosphate receptor and implications for cardiovascular therapeutics.

Cardiovascular disease is the leading cause of death worldwide, and it's of great importance to understand its underlying mechanisms and find new treatments. Sphingosine 1-phosphate (S1P) is an active lipid that exerts its effects through S1P receptors on the cell surface or intracellular signal, and regulates many cellular processes such as cell growth, cell proliferation, cell migration, cell survival, and so on. S1PR modulators are a class of modulators that can interact with S1PR subtypes to activate receptors or block their activity, exerting either agonist or functional antagonist effects. Many studies have shown that S1P plays a protective role in the cardiovascular system and regulates cardiac physiological functions mainly through interaction with cell surface S1P receptors (S1PRs). Therefore, S1PR modulators may play a therapeutic role in cardiovascular diseases. Here, we review five S1PRs and their functions and the progress of S1PR modulators. In addition, we focus on the effects of S1PR modulators on atherosclerosis, myocardial infarction, myocardial ischaemia/reperfusion injury, diabetic cardiovascular diseases, and myocarditis, which may provide valuable insights into potential therapeutic strategies for cardiovascular disease.

Discovery of PRDM16-Mediated TRPA1 Induction as the Mechanism for Low Tubulo-Interstitial Fibrosis in Diabetic Kidney Disease.

The pathogenesis of Diabetic kidney disease(DKD) involves pathological changes in both tubulo-interstitium and the glomerulus. Surprisingly, tubulo-interstitial fibrosis (TIF), does not develop significantly until the late stage of DKD. Here, it is demonstrated that PR domain-containing 16 (PRDM16) is a key to the low level of TIF in DKD. In the experiments, PRDM16 is upregulated in high glucose-treated renal tubular cells, DKD mouse kidneys, and renal biopsy of human DKD patients via activation of NF-κB signal pathway. High glucose-induced expression of fibrotic proteins in renal tubular cells is suppressed by PRDM16. Mechanistically, PRDM16 bound to the promotor region of Transient receptor potential ankyrin 1 (TRPA1) to transactivate its expression and then suppressed MAPK (P38, ERK1/2) activation and downstream expression of TGF-ß1. Knockout of PRDM16 from kidney proximal tubules in mice blocked TRPA1 expression and enhanced MAPK activation, TGF-ß1 production, TIF development, and DKD progression, whereas knock-in of PRDM16 has opposite effects. In addition, overexpression of PRDM16 or its induction by formononetin ameliorated renal dysfunction and fibrosis in db/db diabetic mice. Finally, the above finding are detected in renal biopsies of DKD patients. Together, these results unveil PRDM16/TRPA1 as the mechanism responsible for the low level of TIF in the early stage of DKD by suppressing and TGF-ß1 expression.

Identification of formononetin as the active compound of CR-SR in hepatocellular carcinoma treatment: An integrated approach combining network pharmacology and weighted gene co-expression networks.

Hepatocellular carcinoma (HCC) is a life-threatening disease for which there is no cure. Traditional Chinese medicine is a treasure trove of Medicinals that has been used for thousands of years. In China, the traditional herb pair, Curcumae Rhizoma and Sparganii Rhizoma (CR-SR) represent a classic herbal combination used for the treatment of HCC. However, the drug targets and pharmacological mechanism of action of CR-SR in the treatment of HCC are unclear. To address this, we screened the active components and drug targets of CR-SR from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and a high-throughput experiment- and reference-guided database of traditional Chinese medicines (HERB database). Combined with the weighted co-expression network analysis of dataset GSE76427, we constructed an active component-target-disease regulatory network. It was found that CR-SR's active components for HCC treatment included trans-gondoic acid, beta-sitosterol, stigmasterol, hederagenin, and formononetin. These compounds specifically targeted the genes Estrogen Receptor 1 (ESR1), Cyclin A2 (CCNA2), Checkpoint Kinase 1 (CHEK1), and Nuclear Receptor Coactivator 2 (NCOA2). ESR1, CCNA2, and CHEK1 genes showed significant differences in survival prognosis, expression levels, and statistical significance during the pathological stage. Moreover, their high affinity for formononetin was determined through molecular docking analysis. Cell assays and high-throughput sequencing were performed to reveal that the inhibitory effect of formononetin on HepG2 cell proliferation was related to hepatocyte metabolism and cell cycle regulation-related pathways. This study provides insights into potential HCC treatments.

Virus-like Iron-Gold Heterogeneous Nanoparticles for Drug Target Screening.

Drug-target recognition has great impacts on revealing mechanisms of pharmacological activities, especially drug resistance and off-target effects. In recent years, chemoproteomics has been widely used for drug target screening and discovery due to its high-throughput, high accuracy, and sensitivity. However, there still remain challenges on how to efficiently and unambiguously track target proteins from complex biological matrices. Herein, we report a drug target screening method based on virus-like iron-gold heterogeneous nanoparticles (Au@Fe3O4 NPs). The unique structure of Au@Fe3O4 NPs not only maintains the magnetism of Fe3O4 NPs to facilitate protein enrichment and purification, but also increases drug modification by introducing more active sites on the surface of Au NPs. After coincubating the drug modified NPs with the cell lysate, the high loading of drug on the surface of Au@Fe3O4 NPs was beneficial for capturing target proteins with low abundance. This well-designed heterogeneous nanomaterial provides a novel strategy for improving the efficiency and accuracy of affinity-based proteomics.

Metagenomic analysis reveals distinct changes in the gut microbiome of obese Chinese children.

BACKGROUND: The prevalence of obese children in China is increasing, which poses a great challenge to public health. Gut microbes play an important role in human gut health, and changes in gut status are closely related to obesity. However, how gut microbes contribute to obesity in children remains unclear. In our study, we performed shotgun metagenomic sequencing of feces from 23 obese children, 8 overweight children and 22 control children in Chengdu, Sichuan, China. RESULTS: We observed a distinct difference in the gut microbiome of obese children and that of controls. Compared with the controls, bacterial pathogen Campylobacter rectus was significantly more abundant in obese children. In addition, functional annotation of microbial genes revealed that there might be gut inflammation in obese children. The guts of overweight children might belong to the transition state between obese and control children due to a gradient in relative abundance of differentially abundant species. Finally, we compared the gut metagenomes of obese Chinese children and obese Mexican children and found that Trichuris trichiura was significantly more abundant in the guts of obese Mexican children. CONCLUSIONS: Our results contribute to understanding the changes in the species and function of intestinal microbes in obese Chinese children.

Theoretical Insights into the Generation Mechanism of the Tyr122 Radical Catalyzed by Intermediate X in Class Ia Ribonucleotide Reductase.

Ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to deoxyribonucleotides in all organisms. There is an ∼35 Å long-range electron-hole transfer pathway during the catalytic process of class Ia RNR, which can be described as Tyr122ß â†” [Trp48ß]? ↔ Tyr356ß â†” Tyr731α ↔ Tyr730α ↔ Cys439α. The formation of the Y122• radical initiates this long-range radical transfer process. However, the generation mechanism of Y122• is not yet clear due to confusion over the intermediate X structures. Based on the two reported X structures, we examined the possible mechanisms of Y122• generation by density functional theory (DFT) calculations. Our examinations revealed that the generation of the Y122• radical from the two different core structures of X was via a similar two-step reaction, with the first step of proton transfer for the formation of the proton receptor of Y122 and the second step of a proton-coupled long-range electron transfer reaction with the proton transfer from the Y122 hydroxyl group to the terminal hydroxide ligand of Fe1III and simultaneously electron transfer from the side chain of Y122 to Fe2IV. These findings provide an insight into the formation mechanism of Y122• catalyzed by the double-iron center of the ß subunit of class Ia RNR.

FBXO7 Confers Mesenchymal Properties and Chemoresistance in Glioblastoma by Controlling Rbfox2-Mediated Alternative Splicing.

Mesenchymal glioblastoma (GBM) is highly resistant to radio-and chemotherapy and correlates with worse survival outcomes in GBM patients; however, the underlying mechanism determining the mesenchymal phenotype remains largely unclear. Herein, it is revealed that FBXO7, a substrate-recognition component of the SCF complex implicated in the pathogenesis of Parkinson's disease, confers mesenchymal properties and chemoresistance in GBM by controlling Rbfox2-mediated alternative splicing. Specifically, FBXO7 ubiquitinates Rbfox2 Lys249 through K63-linked ubiquitin chains upon arginine dimethylation at Arg341 and Arg441 by PRMT5, leading to Rbfox2 stabilization. FBXO7 controls Rbfox2-mediated splicing of mesenchymal genes, including FoxM1, Mta1, and Postn. FBXO7-induced exon Va inclusion of FoxM1 promotes FoxM1 phosphorylation by MEK1 and nuclear translocation, thereby upregulates CD44, CD9, and ID1 levels, resulting in GBM stem cell self-renewal and mesenchymal transformation. Moreover, FBXO7 is stabilized by temozolomide, and FBXO7 depletion sensitizes tumor xenografts in mice to chemotherapy. The findings demonstrate that the FBXO7-Rbfox2 axis-mediated splicing contributes to mesenchymal transformation and tumorigenesis, and targeting FBXO7 represents a potential strategy for GBM treatment.