Low-dose metformin targets the lysosomal AMPK pathway through PEN2.

Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects1-4. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action4,5; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation6. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase7, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase8, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.

AMG232 inhibits angiogenesis in glioma through the p53-RBM4-VEGFR2 pathway.

AMG232 effectively inhibits cancers with wild-type p53 (also known as TP53) by reactivating p53, but whether it inhibits glioma angiogenesis remains unclear. This study confirms that AMG232 inhibits the proliferation of glioma endothelial cells (GECs) in a dose-dependent manner and inhibits the angiogenesis of GECs. p53 and RNA-binding motif protein 4 (RBM4) were expressed at low levels in GECs, while MDM2 and vascular endothelial growth factor receptor 2 (VEGFR2, also known as KDR) were highly expressed. In vitro and in vivo experiments confirmed that AMG232 upregulated p53 and RBM4, and downregulated MDM2 and VEGFR2 by blocking the MDM2-p53 interaction. Both p53 silencing and RBM4 silencing significantly upregulated the expression of VEGFR2, promoted the proliferation, migration and tube formation of GECs, and reversed the effects of AMG232 on downregulating VEGFR2 and inhibiting the angiogenesis of GECs. AMG232 increased RBM4 expression by upregulating p53, and p53 bound to RBM4 and promoted its transcription. RBM4 bound to and shortened the half-life of VEGFR2, promoting its degradation. Finally, AMG232 produced a significant decrease in new vessels and hemoglobin content in vivo. This study proves that AMG232 inhibits glioma angiogenesis by blocking the MDM2-p53 interaction, in which the p53-RBM4-VEGFR2 pathway plays an important role.

GraphPath: a graph attention model for molecular stratification with interpretability based on the pathway-pathway interaction network.

MOTIVATION: Studying the molecular heterogeneity of cancer is essential for achieving personalized therapy. At the same time, understanding the biological processes that drive cancer development can lead to the identification of valuable therapeutic targets. Therefore, achieving accurate and interpretable clinical predictions requires paramount attention to thoroughly characterizing patients at both the molecular and biological pathway levels. RESULTS: Here, we present GraphPath, a biological knowledge-driven graph neural network with multi-head self-attention mechanism that implements the pathway-pathway interaction network. We train GraphPath to classify the cancer status of patients with prostate cancer based on their multi-omics profiling. Experiment results show that our method outperforms P-NET and other baseline methods. Besides, two external cohorts are used to validate that the model can be generalized to unseen samples with adequate predictive performance. We reduce the dimensionality of latent pathway embeddings and visualize corresponding classes to further demonstrate the optimal performance of the model. Additionally, since GraphPath's predictions are interpretable, we identify target cancer-associated pathways that significantly contribute to the model's predictions. Such a robust and interpretable model has the potential to greatly enhance our understanding of cancer's biological mechanisms and accelerate the development of targeted therapies. AVAILABILITY AND IMPLEMENTATION: https://github.com/amazingma/GraphPath.

An integrated multi-omics analysis of identifies distinct molecular characteristics in pulmonary infections of Pseudomonas aeruginosa.

Pseudomonas aeruginosa (P. aeruginosa) can cause severe acute infections, including pneumonia and sepsis, and cause chronic infections, commonly in patients with structural respiratory diseases. However, the molecular and pathophysiological mechanisms of P. aeruginosa respiratory infection are largely unknown. Here, we performed assays for transposase-accessible chromatin using sequencing (ATAC-seq), transcriptomics, and quantitative mass spectrometry-based proteomics and ubiquitin-proteomics in P. aeruginosa-infected lung tissues for multi-omics analysis, while ATAC-seq and transcriptomics were also examined in P. aeruginosa-infected mouse macrophages. To identify the pivotal factors that are involved in host immune defense, we integrated chromatin accessibility and gene expression to investigate molecular changes in P. aeruginosa-infected lung tissues combined with proteomics and ubiquitin-proteomics. Our multi-omics investigation discovered a significant concordance for innate immunological and inflammatory responses following P. aeruginosa infection between hosts and alveolar macrophages. Furthermore, we discovered that multi-omics changes in pioneer factors Stat1 and Stat3 play a crucial role in the immunological regulation of P. aeruginosa infection and that their downstream molecules (e.g., Fas) may be implicated in both immunosuppressive and inflammation-promoting processes. Taken together, these findings indicate that transcription factors and their downstream signaling molecules play a critical role in the mobilization and rebalancing of the host immune response against P. aeruginosa infection and may serve as potential targets for bacterial infections and inflammatory diseases, providing insights and resources for omics analyses.

Inhibition of Fap Promotes Cardiac Repair by Stabilizing BNP.

BACKGROUND: Myocardial infarction (MI) elicits cardiac fibroblast activation and extracellular matrix (ECM) deposition to maintain the structural integrity of the heart. Recent studies demonstrate that Fap (fibroblast activation protein)-a prolyl-specific serine protease-is an important marker of activated cardiac fibroblasts after MI. METHODS: Left ventricle and plasma samples from patients and healthy donors were used to analyze the expression level of FAP and its prognostic value. Echocardiography and histological analysis of heart sections were used to analyze cardiac functions, scar formation, ECM deposition and angiogenesis after MI. RNA-Sequencing, biochemical analysis, cardiac fibroblasts (CFs) and endothelial cells co-culture were used to reveal the molecular and cellular mechanisms by which Fap regulates angiogenesis. RESULTS: We found that Fap is upregulated in patient cardiac fibroblasts after cardiac injuries, while plasma Fap is downregulated and functions as a prognostic marker for cardiac repair. Genetic or pharmacological inhibition of Fap in mice significantly improved cardiac function after MI. Histological and transcriptomic analyses showed that Fap inhibition leads to increased angiogenesis in the peri-infarct zone, which promotes ECM deposition and alignment by cardiac fibroblasts and prevents their overactivation, thereby limiting scar expansion. Mechanistically, we found that BNP (brain natriuretic peptide) is a novel substrate of Fap that mediates postischemic angiogenesis. Fap degrades BNP to inhibit vascular endothelial cell migration and tube formation. Pharmacological inhibition of Fap in Nppb (encoding pre-proBNP) or Npr1 (encoding the BNP receptor)-deficient mice showed no cardioprotective effects, suggesting that BNP is a physiological substrate of Fap. CONCLUSIONS: This study identifies Fap as a negative regulator of cardiac repair and a potential drug target to treat MI. Inhibition of Fap stabilizes BNP to promote angiogenesis and cardiac repair.

Trade-Off between Rough and Smooth Electrode Surfaces toward Stable Zn Stripping/Plating in Aqueous Electrolytes.

The effects of surface roughness on the performance of the Zn metal anode in aqueous electrolytes are investigated by experiments and computational simulations. Smooth surfaces can homogenize the nucleation and growth of Zn, which helps to form a flat Zn anode under high current density. In spite of these advantages, the whole surface of the smooth electrode serves as the reactive contact area for parasitic reactions, generating severe hydrogen evolution, corrosion, and byproduct formation, which seriously hinder the long-term cycle stability of the Zn anode. To trade off this double-sided effect, we identify a medium degree of surface roughness that could stabilize the Zn anode for 1000 h cycling at 1.0 mAh cm-2. The electrode also enabled stable cycling for 800 h at a high current density of 5.0 mAh cm-2. This naked Zn metal anode with optimized surface roughness holds great promise for direct use in aqueous zinc ion batteries.

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy.

BACKGROUND: A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear. METHODS: We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed Jmjd4 in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy. RESULTS: We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of Jmjd4 led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with Jmjd4 deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by Jmjd4 deficiency, and heart failure induced by pressure overload, as well. CONCLUSIONS: Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well.

A Tunable Hydrophilic-Hydrophobic, Stimulus Responsive, and Robust Iridescent Structural Color Bionic Film with Chiral Photonic Crystal Nanointerface.

Bio-inspired in nature, using nanomaterials to fabricate the vivid bionic structural color and intelligent stimulus responsive interface as smart skin or optical devices are widely concerned and remain a huge challenge. Here, the bionic flexible film is designed and fabricated with chiral nanointerface and tunable hydrophilic-hydrophobic by the ultrasonic energy perturbation strategy and crosslinking of the cellulose nanocrystals (CNC). An intelligent nanointerface with adjustable hydrophilic and hydrophobic properties is constructed by the supramolecular assembly using a smart ionic liquid molecule. The bionic flexible film possessed the variable hydrophilic-hydrophobic, stimulus responsive, and robust iridescent structural color. The reflective wavelength and the helical pitch of the film can be easily modulated through the ultrasonic energy perturbation strategy. The bionic flexible film by covalent cross-linking has excellent robustness, good elasticity and flexibility. The tunable brilliant structural color of the chiral nanointerface is attributed to the surface charge change of the CNC photonic crystal, which is disturbed by ultrasonic energy perturbation. The bionic flexible film with tunable structure color has intelligent hydrophilic and hydrophobic stimulus response properties. The chiral bionic materials have potential applications in smart skin, optical devices, bionic materials, robots, anti-counterfeiting, colorful displays, and stealth materials.

A Functionalized Scaffold Facilitates Neurites Extension for Spinal Cord Injury Therapy.

Scaffolds have garnered considerable attention for enhancing neural repairment for spinal cord injury (SCI) treatment. Both microstructural features and biochemical modifications play pivotal roles in influencing the interaction of cells with the scaffold, thereby affecting tissue regeneration. Here, a scaffold is designed with spiral structure and gradient peptide modification (GS) specifically for SCI treatment. The spiral structure provides crucial support and space, while the gradient peptide isoleucine-lysine-valine-alanine-valine (IKVAV) modification imparts directional guidance for neuronal and axonal extension. GS scaffold shows a significant nerve extension induction effect through its interlayer gap and gradient peptide density to dorsal root ganglia in vitro, while in vivo studies reveal its substantial promotion for functional recovery and neural repair. Additionally, the GS scaffold displays impressive drug-loading capacity, mesenchymal stem cell-derived exosomes can be efficiently loaded into the GS scaffold and delivered to the injury site, thereby synergistically promoting SCI repair. Overall, the GS scaffold can serve as a versatile platform and present a promising multifunctional approach for SCI treatment.

Upregulation of collagen type X alpha 1 promotes the progress of triple-negative breast cancer via Wnt/ß-catenin signaling.

Triple-negative breast cancer (TNBC) is a malignant tumor with high degree of malignancy and lack of effective target treatment. The research aims to explore the role and mechanism of X collagen alpha-1 chain protein (COL10A1 gene) in TNBC. UALCAN and Kaplan-Meier were used to detect the expression of COL10A1 and its role in the prognosis of breast cancer patients. The cells with stably expressing high levels of COL10A1 were obtained by recombinant lentivirus infection. The expression of COL10A1 in cells was temporarily downregulated by siRNA interference fragments. Real-time quantitative polymerase chain reaction and western blot analysis were utilized to detect the changes of COL10A1 mRNA and protein expression. The biological functions of the cells were evaluated by colony formation, cell counting kit-8, cell invasion and wound healing experiments. In addition, the effect of COL10A1 on angiogenesis was investigated by tube formation assay. Xenograft tumor model was used to confirm the effect of COL10A1 on tumorigenicity in vivo and multiplex fluorescent immunohistochemistry to detect multiple proteins simultaneously. The possible molecular mechanism of the function of COL10A1 was speculated through the detection of proteins in functionally related pathways. COL10A1 is highly expressed and is significantly associated with worse overall survival (OS) and recurrence-free survival (RFS) in TNBC. Overexpression of COL10A1 increased the clone formation rate and cell migration capacity of TNBC cells. In the COL10A1 overexpression group, the clone formation rates of MD-MB-231 and BT-549 cells (21.5 ± 0.62, 27.83 ± 3.72)% were significantly higher than those in the control group(15.23 ± 2.79, 19.4 ± 1.47)%, and the relative migration ratio (47.40 ± 3.09, 41.26 ± 4.33)% were higher than those in the control group (34.48 ± 2.03, 21.80 ± 1.03)%. When the expression of COL10A1 was downregulated, the ability of clone formation and wound-healing migration capacity in TNBC cells was weakened. Upregulated COL10A1 in TNBC cells generated more junctions and longer total segments between vascular endothelial cells, and promoted angiogenesis of the cells, and thus enhanced the tumorigenesis. In TNBC, it was found that COL10A1 might affect epithelial-mesenchymal transition (EMT) of the cells through Wnt/ß-catenin signaling pathway by the detection of the related pathway proteins. COL10A1 is highly expressed in TNBC, and its high expression leads to poor OS and RFS. COL10A1 may enhance TNBC cell proliferation, migration and tumor-related angiogenesis, and promote tumorigenesis in vivo via Wnt/ß-catenin signaling.

Multi-color transparent display based on perovskite quantum dots fabricated by laser-induced plasma etching.

Display technology is being revolutionized by cutting-edge transparent displays that can provide visual information on the screen while allowing the surrounding environment to be visible. In this report, a new method is proposed for patterning displays based on perovskite quantum dots (PQDs) on glass surfaces. A glass substrate with a polyvinylidene fluoride (PVDF) constraint layer is patterned using laser-induced plasma etching, and then a PQDs film is spin-coated on the etched sample. The PQDs pattern on the glass substrate is obtained after peeling off the PVDF constraint layer. The thickness of the film is obtained by carrying out simulations. The plasma output from different metal targets is recorded and analyzed to select the most suitable parameters and materials for improvement of the patterning accuracy. The transparent pattern display of PQDs is realized with an accuracy of 10-20 µm and a burial depth of about 1 µm. This method allows PQDs to be encapsulated under the substrate surface, which decreases the susceptibility of environmental impact. Additionally, encapsulation prevents the quantum dots from leaking out and causing environmental pollution. The proposed method has potential in the design of transparent displays and anti-counterfeiting applications.

STAT3-induced lncRNA GNAS-AS1 accelerates keloid formation by mediating the miR-196a-5p/CXCL12/STAT3 axis in a feedback loop.

Keloids are pathological scar tissue resulting from skin trauma or spontaneous formation, often accompanied by itching and pain. Although GNAS antisense RNA 1 (GNAS-AS1) shows abnormal upregulation in keloids, the underlying molecular mechanism is unclear. The levels of genes and proteins in clinical tissues from patients with keloids and human keloid fibroblasts (HKFs) were measured using quantitative reverse transcription PCR, western blot and enzyme-linked immunosorbent assay. The features of HKFs, including proliferation and migration, were evaluated using cell counting kit 8 and a wound healing assay. The colocalization of GNAS-AS1 and miR-196a-5p in HKFs was measured using fluorescence in situ hybridization. The relationships among GNAS-AS1, miR-196a-5p and C-X-C motif chemokine ligand 12 (CXCL12) in samples from patients with keloids were analysed by Pearson correlation analysis. Gene interactions were validated by chromatin immunoprecipitation and luciferase reporter assays. GNAS-AS1 and CXCL12 expression were upregulated and miR-196a-5p expression was downregulated in clinical tissues from patients with keloids. GNAS-AS1 knockdown inhibited proliferation, migration, and extracellular matrix (ECM) accumulation of HKFs, all of which were reversed by miR-196a-5p downregulation. Signal transducer and activator of transcription 3 (STAT3) induced GNAS-AS1 transcription through GNAS-AS1 promoter interaction, and niclosamide, a STAT3 inhibitor, decreased GNAS-AS1 expression. GNAS-AS1 positively regulated CXCL12 by sponging miR-196-5p. Furthermore, CXCL12 knockdown restrained STAT3 phosphorylation in HKFs. Our findings revealed a feedback loop of STAT3/GNAS-AS1/miR-196a-5p/CXCL12/STAT3 that promoted HKF proliferation, migration and ECM accumulation and affected keloid progression.

Tumor Receptor-Mediated Morphological Transformation and In Situ Polymerization of Diacetylene-Containing Lipidated Peptide Amphiphile on Cell Membranes for Tumor Suppression.

In situ polymerization on cell membranes can decrease cell mobility, which may inhibit tumor growth and invasion. However, the initiation of radical polymerization traditionally requires exogenous catalysts or free radical initiators, which might cause side effects in normal tissues. Herein, we synthesized a Y-type diacetylene-containing lipidated peptide amphiphile (TCDA-KFFFFK(GRGDS)-YIGSR, Y-DLPA) targeting integrins and laminin receptors on murine mammary carcinoma 4T1 cells, which underwent nanoparticle-to-nanofiber morphological transformation and in situ polymerization on cell membranes. Specifically, the polymerized Y-DLPA induced 4T1 cell apoptosis and disturbed the substance exchange and metabolism. In vitro assays demonstrated that the polymerized Y-DLPA nanofibers decreased the migration capacity of 4T1 cells, potentially suppressing tumor invasion and metastasis. When administered locally to 4T1 tumor-bearing mice, the Y-DLPA nanoparticles formed a biomimetic extracellular matrix that effectively suppressed tumor growth. This study provides an in situ polymerization strategy that can serve as an effective drug-free biomaterial with low side effects for antitumor therapy.

Baseline gut microbiome as a predictive biomarker of response to probiotic adjuvant treatment in gout management.

Gout is characterized by dysregulation of uric acid (UA) metabolism, and the gut microbiota may serve as a regulatory target. This two-month randomized, double-blind, placebo-controlled trial aimed to investigate the additional benefits of coadministering Probio-X alongside febuxostat. A total of 160 patients with gout were randomly assigned to either the probiotic group (n = 120; Probio-X [1 ×1011 CFU/day] with febuxostat) or the placebo group (n = 40; placebo material with febuxostat). Coadministration of Probio-X significantly decreased serum UA levels and the rate of acute gout attacks (P < 0.05). Based on achieving a target sUA level (360 µmol/L) after the intervention, the probiotic group was further subdivided into probiotic-responsive (ProA; n = 54) and probiotic-unresponsive (ProB; n = 66) subgroups. Post-intervention clinical indicators, metagenomic, and metabolomic changes in the ProB and placebo groups were similar, but differed from those in the ProA group, which exhibited significantly lower levels of acute gout attack, gout impact score, serum indicators (UA, XOD, hypoxanthine, and IL-1ß), and fecal gene abundances of UA-producing pathways (KEGG orthologs of K13479 and K01487; gut metabolic modules for formate conversion and lactose and galactose degradation). Additionally, the ProA group showed significantly higher levels (P < 0.05) of gut SCFAs-producing bacteria and UA-related metabolites (xanthine, hypoxanthine, bile acids) after the intervention. Finally, we established a gout metagenomic classifier to predict probiotic responsiveness based on subjects' baseline gut microbiota composition. Our results indicate that probiotic-driven therapeutic responses are highly individual, with the probiotic-responsive cohort benefitting significantly from probiotic coadministration.

Evaluation of tumor microvasculature with 3D ultrasound localization microscopy based on 2D matrix array.

OBJECTIVE: Evaluation of tumor microvascular morphology is of great significance in tumor diagnosis, therapeutic effect prediction, and surgical planning. Recently, two-dimensional ultrasound localization microscopy (2DULM) has demonstrated its superiority in the field of microvascular imaging. However, it suffers from planar dependence and is unintuitive. We propose a novel three-dimensional ultrasound localization microscopy (3DULM) to avoid these limitations. METHODS: We investigated 3DULM based on a 2D array for tumor microvascular imaging. After intravenous injection of contrast agents, all elements of the 2D array transmit and receive signals to ensure a high and stable frame rate. Microbubble signal extraction, filtering, positioning, tracking, and other processing were used to obtain a 3D vascular map, flow velocity, and flow direction. To verify the effectiveness of 3DULM, it was validated on double helix tubes and rabbit VX2 tumors. Cisplatin was used to verify the ability of 3DULM to detect microvascular changes during tumor treatment. RESULTS: In vitro, the sizes measured by 3DULM at 3 mm and 13 mm were 178 µ m and 182 µ m , respectively. In the rabbit tumors, we acquired 9000 volumes to reveal vessels about 30 µ m in diameter, which surpasses the diffraction limit of ultrasound in traditional ultrasound imaging, and the results matched with micro-angiography. In addition, there were significant changes in vascular density and curvature between the treatment and control groups. CONCLUSIONS: The effectiveness of 3DULM was verified in vitro and in vivo. Hence, 3DULM may have potential applications in tumor diagnosis, tumor treatment evaluation, surgical protocol guidance, and cardiovascular disease. CLINICAL RELEVANCE STATEMENT: 3D ultrasound localization microscopy is highly sensitive to microvascular changes; thus, it has clinical potential for tumor diagnosis and treatment evaluation. KEY POINTS: • 3D ultrasound localization microscopy is demonstrated on double helix tubes and rabbit VX2 tumors. • 3D ultrasound localization microscopy can reveal vessels about 30 µ m in diameter-far smaller than traditional ultrasound. • This form of imaging has potential applications in tumor diagnosis, tumor treatment evaluation, surgical protocol guidance, and cardiovascular disease.

Construction of Stable 2D Cationic Breathing Ni-MOF for Cr(VI) Trapping and Electrochemical Sensing.

Pollution of surface water by heavy metal hexavalent chromium ions poses a serious threat to human health; herein, a two-dimensional (2D) cationic breathing Ni-MOF with free nitrate ions between the layers was designed and synthesized according to the characteristics of hexavalent chromium ions, {[Ni(L)2](NO3)2·5H2O}n (L = 1,3,5-tris[4-(imidazol-1-yl)phenyl]benzene). The flexible layer spacing of the 2D breathing Ni-MOF allows the exchange of NO3- by CrO42- without destroying the original structure. Electrostatic and hydrogen bonding interactions between CrO42- and Ni-MOF facilitate its exchange with NO3-. Moreover, CrO42- exhibits a higher binding energy with Ni-MOF compared to NO3-, and the hydrophobic channels of Ni-MOF favor CrO42- trapping due to its lower hydration energy. Consequently, Ni-MOF demonstrates both effective sorption and electrochemical sensing of Cr(VI), achieving a sensitivity of 2.091 µA µM-1 and a detection limit of 0.07 µM.

Genome-wide identification and expression analysis of C-type lectins in discus fish (Symphysodon aequifasciatus) during parental care.

Discus fish (Symphysodon aequifasciatus) exhibit a unique parental care behavior: adult discus produces secretion through their skin, on which the larvae live after birth. The immune components in the skin mucus of parental discus would change during different parental care. C-type lectins (CTLs) could identify and eliminate pathogenic microorganisms and play important roles in innate immunity. Studies on CTLs of discus fish especially during parental care, however, are scarce. Here, we identified 186 CTL genes that distributed in 27 linkage groups based on discus genome. Phylogenetic analysis showed that S. aequifasciatus CTL (SaCTL) members were grouped into 14 subfamilies. A total of 80 gene replication events occurred, of which 15 pairs were subjected to segmental duplication and 65 pairs underwent tandem duplication. Ka/Ks ranged from 0.11 (SaCTL25/SaCTL158) to 0.68 (SaCTL36/SaCTL69), all undergoing purifying selection. RNA-seq analysis revealed that SaCTL members, including duplicated genes, in the skin of parental discus show distinct expression patterns in different care stages and between male and female parents. The SaCTL11 was differentially expressed in most care stages and reached the maximum after eggs spawned, but the expression of its paired SaCTL14 was low in each stage. The SaCTL39 increased first and then decreased, reaching a peak in eggs spawned, while paired SaCTL48 first decreased and then increased, reaching a peak in hatched eggs. The SaCTL50 was differentially expressed only in female fish during care, but not in male fish. These results provide new insights into the evolution and potential functional differentiation of CTLs in discus fish during parental care.

Bottom-Up Construction of Rhombic Lamellar CoNi-MOFs for the Electrochemical Sensing of H2S.

Lamellar metal-organic frameworks (MOFs) have attracted significant attention in the field of electrochemical sensing due to their abundant open active sites and specific electron conductivity. Herein, by employing a bottom-up synthesis strategy, rhombic lamellar heterometallic CoNi-MOFs with varying thicknesses are constructed. This is achieved by using 4-methylpyridine as a capping agent based on the (4,6)-linked Co2(azpy)2(bptc) (azpy = 4,4'-azopyridine, bptc = 3,3',5,5'-biphenyltetracarboxylic acid) structure with a fsc topology and by introducing Ni species simultaneously. To mitigate sulfur deposition on electrodes, the triple pulse amperometry (TPA) method is employed. Among the synthesized lamellar CoNi-MOFs, lamellar CoNi-MOF-3 with the minimum thickness exhibits an optimal electrochemical sensing performance toward hydrogen sulfide, with a sensitivity of 119.3 µA·mM-1·cm-2 in the linear range of 2-2000 µM. This study pioneers a new approach to the controlled construction and electrochemical activity modification of lamellar MOF materials.

HNRNPA2B1 stabilizes NFATC3 levels to potentiate its combined actions with FOSL1 to mediate vasculogenic mimicry in GBM cells.

BACKGROUND: Vasculogenic mimicry (VM) is an enigmatic physiological feature that influences blood supply within glioblastoma (GBM) tumors for their sustained growth. Previous studies identify NFATC3, FOSL1 and HNRNPA2B1 as significant mediators of VEGFR2, a key player in vasculogenesis, and their molecular relationships may be crucial for VM in GBM. AIMS: The aim of this study was to understand how NFATC3, FOSL1 and HNRNPA2B1 collectively influence VM in GBM. METHODS: We have investigated the underlying gene regulatory mechanisms for VM in GBM cell lines U251 and U373 in vitro and in vivo. In vitro cell-based assays were performed to explore the role of NFATC3, FOSL1 and HNRNPA2B1 in GBM cell proliferation, VM and migration, in the context of RNA interference (RNAi)-mediated knockdown alongside corresponding controls. Western blotting and qRT-PCR assays were used to examine VEGFR2 expression levels. CO-IP was employed to detect protein-protein interactions, ChIP was used to detect DNA-protein complexes, and RIP was used to detect RNA-protein complexes. Histochemical staining was used to detect VM tube formation in vivo. RESULTS: Focusing on NFATC3, FOSL1 and HNRNPA2B1, we found each was significantly upregulated in GBM and positively correlated with VM-like cellular behaviors in U251 and U373 cell lines. Knockdown of NFATC3, FOSL1 or HNRNPA2B1 each resulted in decreased levels of VEGFR2, a key growth factor gene that drives VM, as well as the inhibition of proliferation, cell migration and extracorporeal VM activity. Chromatin immunoprecipitation (ChIP) studies and luciferase reporter gene assays revealed that NFATC3 binds to the promoter region of VEGFR2 to enhance VEGFR2 gene expression. Notably, FOSL1 interacts with NFATC3 as a co-factor to potentiate the DNA-binding capacity of NFATC3, resulting in enhanced VM-like cellular behaviors. Also, level of NFATC3 protein in cells was enhanced through HNRNPA2B1 binding of NFATC3 mRNA. Furthermore, RNAi-mediated silencing of NFATC3, FOSL1 and HNRNPA2B1 in GBM cells reduced their capacity for tumor formation and VM-like behaviors in vivo. CONCLUSION: Taken together, our findings identify NFATC3 as an important mediator of GBM tumor growth through its molecular and epistatic interactions with HNRNPA2B1 and FOSL1 to influence VEGFR2 expression and VM-like cellular behaviors.

Neurovascular decoupling measured with quantitative susceptibility mapping is associated with cognitive decline in patients with type 2 diabetes.

Disturbance of neurovascular coupling (NVC) is suggested to be one potential mechanism in type 2 diabetes mellitus (T2DM) associated mild cognitive impairment (MCI). However, NVC evidence derived from functional magnetic resonance imaging ignores the relationship of neuronal activity with vascular injury. Twenty-seven T2DM patients without MCI and thirty healthy controls were prospectively enrolled. Brain regions with changed susceptibility detected by quantitative susceptibility mapping (QSM) were used as seeds for functional connectivity (FC) analysis. NVC coefficients were estimated using combined degree centrality (DC) with susceptibility or cerebral blood flow (CBF). Partial correlations between neuroimaging indicators and cognitive decline were investigated. In T2DM group, higher susceptibility values in right hippocampal gyrus (R.PHG) were found and were negatively correlated with Naming Ability of Montreal Cognitive Assessment. FC increased remarkably between R.PHG and right middle temporal gyrus (R.MTG), right calcarine gyrus (R.CAL). Both NVC coefficients (DC-QSM and DC-CBF) reduced in R.PHG and increased in R.MTG and R.CAL. Both NVC coefficients in R.PHG and R.MTG increased with the improvement of cognitive ability, especially for executive function. These demonstrated that QSM and DC-QSM coefficients can be promising biomarkers for early evaluation of cognitive decline in T2DM patients and help to better understand the mechanism of NVC.