Helicobacter pylori upregulates PAD4 expression via stabilising HIF-1α to exacerbate rheumatoid arthritis.

OBJECTIVE: Helicobacter pylori infection has been reported to aggravate rheumatoid arthritis (RA), but the relevant mechanism remains unclear. This study aimed to investigate the underlying pathogenic mechanism of H. pylori infection in the progression of RA. METHODS: The Disease Activity Score (DAS-28) and serum anticitrullinated protein antibody (ACPA) levels were compared between H. pylori-negative and H. pylori-positive patients with RA. MH7A cells were stimulated with polyclonal ACPA purified from the peripheral blood of patients with RA. The citrullination levels were assessed by western blot in GES-1 cells and sera. ChIP, luciferase reporter assays, mass spectrometry and ELISA were applied to explore the molecular mechanism of H. pylori infection in RA progression. RESULTS: The DAS-28 and ACPA levels of patients with RA in the H. pylori-positive group were significantly higher than those in the H. pylori-negative group. Polyclonal ACPA derived from H. pylori-positive patients promoted cell proliferation and induced secretion of IL-6 and IL-8. For the first time, we found that H. pylori infection induces cellular protein citrullination by upregulating protein arginine deiminase type 4 (PAD4). Furthermore, we confirmed a direct functional binding of hypoxia-inducible factor 1α on the PADI4 gene promoter. We demonstrated that PAD4 interacts with and citrullinates keratin 1 (K1), and serum and synovial fluid levels of anti-Cit-K1 antibody were markedly increased in H. pylori-infected patients with RA. CONCLUSION: Our findings reveal a novel mechanism by which H. pylori infection contributes to RA progression. Therapeutic interventions targeting H. pylori may be a viable strategy for the management of RA.

Aggregation of gold nanoclusters in amyloid fibers: a luminescence assay for amyloid fibrillation detection and inhibitor screening.

Amyloid fibrillation is associated with a great variety of human diseases, such as Alzheimer's and Huntington's diseases. A fluorescence assay for amyloid fibrillation detection and inhibitor screening was developed based on the fact that the fluorescence emission of gold nanoclusters (Au NCs) is largely enhanced upon adding amyloids, such as lysozyme amyloid fibers. A good linear relationship exists between the enhanced fluorescence intensity of Au NCs and lysozyme fiber within the concentration range of 0-0.05 mg mL-1. This ultra-sensitive method can detect the protein fiber earlier than thioflavin T (THT), allowing more time for disease treatment. Furthermore, Au NCs have many advantages over the classical probe (i.e., THT), such as large Stokes shifts and low toxicity. We selected ascorbic acid as a representative inhibitor and used this method to screen inhibitors. If inhibitors are added when incubating lysozyme, the lysozyme fibrosis process will be crimped, decreasing the amount of lysozyme fibers.

Copper Electrocatalyst Produced by Cu2(OH)2CO3-Mediated In Situ Deposition for Diluted CO2 Reduction to Multicarbon Products.

Pure CO2 is commonly used in most of the current studies for electrochemical CO2 reduction which will need a further cost of gas purification and separation. However, the limited works on diluted CO2 reduction are focused on CO or CH4 production other than C2 products. In this work, copper electrocatalysts were prepared by Cu2(OH)2CO3-mediated in situ deposition for diluted CO2 reduction to multicarbon products. Using in situ Raman spectroscopy, constant amounts of CO and OH* were observed on the catalyst surface, which could effectively suppress the high kinetics of hydrogen evolution and promote C-C coupling, especially under the condition of diluted CO2 reduction. The optimized Cu catalyst achieves a C2 Faradaic efficiency as high as 60.72% in the presence of merely 25% CO2, which is almost equivalent to that observed with pure CO2.

Surface Reconstruction for Selective Oxidation of Tetrahydroisoquinoline.

Integration of hydrogen evolution with the oxidation of organic substances in one electrochemical system is highly desirable. However, achieving selective oxidation of organic substances in the integrated system is still highly challenging. In this study, a phosphorylated NiMoO4 nanoneedle-like array was designed as the catalytic active electrode for the integration of highly selective electrochemical dehydrogenation of tetrahydroisoquinolines (THIQs) with hydrogen production. The leaching of anions, including MoO42- and PO43-, facilitates the reconstruction of the catalyst. As a result, nickel oxyhydroxides with the doping of PO43- and richness of defects are in situ formed. In situ Raman and density functional theory calculations have shown that the high catalytic activity is attributed to the in situ formed PO43- involved NiOOH substance. In the dehydrogenation process, the involved C-H bond but not the N-H bond is first destroyed. A two-electrode system was then fabricated with the optimized electrode that shows a benchmark current density of 10 mA cm-2 at 1.783 V, providing a yield of 70% for dihydroisoquinolines. A robust stability was also shown for this integrated electrochemical system. The understanding of the reconstruction behavior and the achievement of selective dehydrogenation will provide some hints for electrochemical synthesis.

SUV39H1 is a novel biomarker targeting oxidative phosphorylation in hepatitis B virus-associated hepatocellular carcinoma.

BACKGROUND: As a histone methyltransferase, suppressor of variegation 3-9 homolog 1 (SUV39H1) plays an important role in the occurrence and development of cancer. To explore the mechanism and biological function of SUV39H1 in hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) can gain an insight into the pathogenesis of HBV-HCC. METHODS: The effect of HBV infection on SUV39H1 in hepatoma cells was detected. CCK-8, colony growth assay and wound healing assay were used to assess the proliferation and migration of HBV-positive hepatoma cells. RNA sequencing (RNA-seq) was applied to find differential genes and enriched pathways. The serum SUV39H1 level in HBV-HCC patients was detected and its correlation with clinical indicators was analyzed. RESULTS: SUV39H1 was increased by HBV infection and promoted the proliferation and migration of hepatoma cells. SUV39H1 could upregulate the expression of mitochondrial oxidative phosphorylation (OXPHOS) pathway-related genes. OXPHOS pathway inhibitors could reduce the capacity of proliferation and migration of hepatoma cells after overexpressing SUV39H1. Serum SUV39H1 levels were higher in chronic hepatitis B (CHB) patients than in healthy controls and higher in HBV-HCC patients than in CHB patients. In the diagnosis of HCC, the predictive value of SUV39H1 combined with alpha-fetoprotein (AFP) was better than that of AFP alone. CONCLUSION: SUV39H1 is regulated by HBV infection and promotes the proliferation and migration of hepatoma cells by targeting OXPHOS pathway. It indicates that SUV39H1 may be a new biomarker of the diagnosis of HCC.

Linear epitopes on the capsid protein of norovirus commonly elicit high antibody response among past-infected individuals.

BACKGROUND: Human norovirus (HuNoV) is the leading cause of acute nonbacterial gastroenteritis globally, and its infection is usually self-limited, so most people become past Norovirus (NoV)-infected individuals. It is known that some antibody responses may play a critical role in preventing viral infection and alleviating disease; however, the characteristics and functions of particular antibody responses in persons with previous infections are not fully understood. Capsid proteins, including VP1 and VP2, are crucial antigenic components of NoV and may regulate antibody immune responses, while epitope-specific antibody responses to capsid proteins have not been comprehensively characterized. METHODS: We prepared purified VP1 and VP2 proteins by ion exchange chromatography and measured serum antigen-specific IgG levels in 398 individuals by ELISA. Overlapping 18-mer peptides covering the full length of VP1 and VP2 were synthesized, and then we identified linear antigenic epitopes from 20 subjects with strong IgG positivity. Subsequently, specific antibody responses to these epitopes were validated in 185 past infected individuals, and the conservation of epitopes was analyzed. Finally, we obtained epitope-specific antiserum by immunizing mice and expressed virus-like particles (VLPs) in an insect expression system for a blockade antibody assay to evaluate the receptor-blocking ability of epitope-specific antibodies. RESULTS: The IgG responses of VP1 were significantly stronger than those of VP2, both of which had high positive rates of over 80%. The overall positive rate of VP1-IgG and/or VP2-IgG was approximately 94%, which may be past NoV-infected individuals. Four linear antigenic B-cell epitopes of capsid proteins were identified, namely, VP1199-216, VP1469-492, VP297-120, and VP2241-264, all of which were conserved. The IgG response rates of the above epitopes in past NoV-infected individuals were 38.92%, 22.16%, 8.11% and 28.11%, respectively. In addition, VP1199-216- and VP1469-492-specific antibodies can partially block the binding of VLPs to the receptor histo-blood group antigen (HBGA). CONCLUSION: This is the first study to describe specific antibody responses of VP2 and to identify its B-cell epitopes. Our findings offer data for a more thorough understanding of norovirus capsid protein-specific IgG responses and could provide useful information for designing and developing vaccines.

Unveiling the Structural Self-Reconstruction and Identifying the Reactive Center of a V, Fe Co-Doped Cobalt Precatalyst toward Enhanced Overall Water Splitting by Operando Raman Spectroscopy.

The development of efficient and stable bifunctional electrocatalysts based on non-noble metals for water electrolysis is both urgent and challenging. However, unresolved issues remain regarding the challenge of identifying the active phase and gaining a comprehensive understanding of its surface reconstruction and functionality throughout the reaction process. In this study, we have combined doping and heterostructure construction by a one-step electrodeposition and a subsequent activation treatment to synthesize Fe, V co-doped Co3O4/Co(OH)2 and Co/Co(OH)2 heterointerfaces (referred to as A-Co60Fe1.1V). These heterointerfaces, composed of Co/Co(OH)2 and Co3O4/Co(OH)2, are proposed to facilitate charge transfer process during catalysis. X-ray photoelectron spectroscopy (XPS) analysis demonstrates that the introduction of V and Fe dopants increases the valence state of Co centers in Co3O4 and Co(OH)2. Further operando Raman spectroscopy reveals that Co(OH)2 and Co3O4 with the high-valence Co centers remain stable during the hydrogen evolution reaction (HER) process. These high-valence Co centers are believed to promote the crucial water dissociation step and therefore enhance the overall HER catalysis. On the other hand, during the oxygen evolution reaction (OER), Fe, V co-doping leads to an earlier formation of the active CoOOH species, while Fe doping can further help stabilize the more reactive ß-CoOOH species instead of the less reactive γ-CoOOH. As a result, the A-Co60Fe1.1V catalyst exhibits significantly improved catalytic activity for both HER and OER that it requires low overpotentials of 51 and 250 mV, respectively, to attain a current density of 10 mA cm-2. Moreover, when utilized as both the cathode and anode in alkaline water electrolysis, the A-Co60Fe1.1V catalyst can operate at a mere 1.54 V voltage while maintaining 10 mA cm-2, surpassing the majority of non-noble metal catalysts. Remarkably, it also exhibits stability for at least 40 h at ∼100 mA cm-2.

Densifying Crystalline-Amorphous Ni3S2/NiOOH Interfacial Sites To Boost Electrocatalytic O2 Production.

The development of an efficient and low-cost electrocatalyst for oxygen evolution reaction (OER) is the key to improving the overall efficiency of water electrolysis. Here, we report the design of a three-dimensional (3-D) heterostructured Ni9S8/Ni3S2 precatalyst composed of unstable Ni9S8 and inert Ni3S2 components, which undergoes in situ electrochemical activation to generate an amorphous-NiOOH/Ni3S2 heterostructured catalyst. In situ Raman spectroscopy combined with ex situ characterizations, such as X-ray diffraction, X-ray photoelectron spectroscopy, and transmission electron microscopy, reveals that during the activation, Ni9S8 loses the sulfur element to form nickel oxides and eventually transforms to amorphous NiOOH at O2-evolving potentials, while the Ni3S2 component is rather inert that its majority in the bulk remains, thus forming a 3-D congee-like NiOOH/Ni3S2 heterostructure with the Ni3S2 crystalline particles randomly dispersed among amorphous NiOOH species. Unlike the sparse heterostructure that consists of a layer of NiOOH on top of Ni3S2, our unique congee-like NiOOH/Ni3S2 heterostructure provides plentiful reactive amorphous-crystalline interfacial sites. Moreover, the partial electron transfer between the NiOOH and remaining Ni3S2, benefiting from their dense interfacial sites, contributes to a higher valence state of the Ni3+ active centers in NiOOH, hence optimizing the adsorption of OER intermediates. Density functional theory calculations further disclose that the electronic structure regulation not only optimizes the Gibbs free energy of intermediate adsorption but also tunes the OH* absorption behavior to be exothermic, elucidating the spontaneous occurrence of OH* absorption and hence improves the OER. Therefore, a low overpotential of only 197 mV at an O2-evolving current density of 10 mA/cm2, a small Tafel slope of 38.8 mV/dec, and good stability are achieved on the amorphous-NiOOH/crystalline-Ni3S2 heterostructured catalyst.

Facet Control of Nickel Nitride Nano-Framework for Efficient Hydrogen Evolution Electrocatalysis via Auxiliary Cooling Assisted Plasma Engineering.

The precise facet modulation of transition metal nitrides (TMNs) has been regarded as an essential issue in boosting electrocatalytic H2 production. Compared to thermal nitridation, the plasma technique serves as a favorable alternative to directly achieve TMNs, but the apparent surface heating effect during plasma treatment inevitably causes the thermally stabilized nitride formation, resulting in the deterioration of the highly reactive facet. To optimize the hydrogen evolution reaction (HER) behavior, an auxiliary cooling assisted plasma system to selectively expose Ni3 N (2-10) with favorable activity by controlling surface heating during plasma nitridation is designed. The resultant nickel nitride (cp-Ni3 N) nano-framework delivers exceptional catalytic performance, evidenced by its low overpotential of 58 and 188 mV at the current density of 10 and 100 mA cm-2 for HER, in stark comparison with that of normal plasma and thermally fabricated Ni3 N. Operando plasma diagnostics along with numerical simulation further confirm the effect of surface heating on typical plasma parameters as well as the Ni3 N nanostructure, indicating the key factor responsible for the high-performance nitride electrocatalyst.

Development and validation of an efficient nomogram for risk assessment of norovirus infection in pediatric patients.

This study aimed to establish a predictive model and nomogram based on routine laboratory blood indicators and clinical symptoms, subsequently providing a rapid risk assessment of norovirus (NoV) infection in children. This retrospective study enrolled 307 pediatric patients with symptoms of acute gastroenteritis and detected NoV using real-time quantitative polymerase chain reaction. Significant indicators selected by multivariate logistic regression, including routine blood tests and consultation symptoms, were used to develop the nomogram. We divided the sample into training and internal validation sets and performed external validation of the final model. Furthermore, we evaluated the clinical performance using the Akaike information criterion (AIC), area under the curve (AUC), calibration curve, decision curve analysis (DCA), sensitivity, specificity, concordance rate, positive predictive value, and negative predictive value. Overall, 153 cases were NoV-PCR-positive, and 154 were negative. The multivariate logistic regression included five predictors of NoV infection, including symptoms of vomiting, upper respiratory tract infection, and indicators of white blood cells, lymphocyte absolute counts, and platelet counts. The nomogram showed a significant predictive value with overall internal set diagnosis, with an AUC of 0.827 (95% confidence interval (CI): 0.785-0.868), and 0.812 (95% CI: 0.755-0.869) with 0.799 (95% CI: 0.705-0.894) in the training and internal validation sets, respectively. Nevertheless, the AUC in the external validation set was higher (0.915; 95% CI: 0.862-0.968). This nomogram is a useful tool for risk assessment for NoV infection. Moreover, the evaluated indicators are accessible, substantially reducing the time for laboratory testing.

Spontaneous Dissolution of Oxometalates Boosting the Surface Reconstruction of CoMOx (M = Mo, V) to Achieve Efficient Overall Water Splitting in Alkaline Media.

Bimetallic materials have been regarded as promising catalysts for efficient alkaline water splitting. However, the spontaneous reconstruction of the surface structures of the catalysts before catalysis has long been overlooked. Here, we present that in situ dissolution of MoO42- in CoMoO4 boosts spontaneous surface reconstruction in an alkaline medium. Our results reveal that CoMoO4 microrod arrays function as precatalysts that undergo spontaneous surface reconstruction under alkaline conditions, forming a layer of Co3O4/CoMoO4 and CoOOH/CoMoO4 heterostructures. X-ray photoelectron spectroscopy (XPS) combined with in situ Raman spectroscopy reveals that in such activated CoMoO4 (A-CoMoO4), the partial electron transfer from Co to Mo sites helps induce a higher valence state of Co centers and the heterostructure of Co3O4/CoMoO4 may promote the generation of CoOOH, which is very likely the precursor to the active Co4+ species for oxygen evolution reaction (OER) catalysis. During the hydrogen evolution reaction (HER), Co3O4 generated after surface reconstruction can promote the dissociation of water, which is considered the rate-determining step of the alkaline HER. Hence, A-CoMoO4 exhibits superior bifunctional electrocatalytic activities that the overpotentials at a working current density of 10 mA cm-2 for the HER and OER are only 13 and 264 mV, respectively. Inspired by the remarkable bifunctionality, the electrolytic cell employing A-CoMoO4 as both anode and cathode shows an appealing potential of 1.51 V to deliver 10 mA cm-2 for overall water splitting. Similarly, CoVOx also shows the spontaneous surface reconstruction behavior in the alkaline medium, which we propose can be extended to a series of oxometalate catalysts.

Selective CO2 Reduction to Ethylene Over a Wide Potential Window by Copper Nanowires with High Density of Defects.

Electrochemical reduction of CO2 to ethylene using renewable electricity is an attractive approach for sustainable carbon recycling. In situ generation of defects in catalysts is found to be a promising method to guarantee high ethylene production from CO2 with high stability. In this study, copper nanowires are prepared in situ with a high density of defects for electrocatalytic CO2 reduction. These defects effectively improve C-C coupling, thus realizing a remarkable performance toward CO2 reduction to C2 products. The obtained copper nanowires showed a high selectivity of ∼79% for C2 products and >58% for C2H4. More importantly, a significantly wide potential window of 500 mV was realized for the selective production of C2H4 with FE(C2H4) >55%. Finally, in situ Raman spectroscopy revealed that Cu0 is the real reactive site for the electrocatalytic CO2 reduction reaction.

NiFe Layered Double Hydroxide/FeOOH Heterostructure Nanosheets as an Efficient and Durable Bifunctional Electrocatalyst for Overall Seawater Splitting.

Electrolysis of seawater can not only desalinate seawater but also produce high-purity hydrogen. Nevertheless, the presence of chloride ions in seawater will cause electrode corrosion and also undergo a chlorine oxidation reaction (ClOR) that competes with the oxygen evolution reaction (OER). Therefore, highly efficient and long-term stable electrocatalysts are needed in this field. In this work, an advanced bifunctional electrocatalyst based on NiFe layered double hydroxide (LDH)/FeOOH heterostructure nanosheets (NiFe LDH/FeOOH) was synthesized on nickel-iron foam (INF) via a simple electrodeposition method. The NiFe LDH/FeOOH electrode demonstrates excellent electrocatalytic activity and stability, which results from the strong interaction between FeOOH and NiFe LDH. Furthermore, ex situ X-ray photoelectron spectroscopy (XPS) and in situ Raman spectroscopy revealed the catalytic process and also demonstrated that the NiFe LDH/FeOOH heterostructure could facilitate the formation of active NiOOH species in the reaction. The obtained NiFe LDH/FeOOH catalyst displays low overpotentials of 181.8 mV at 10 mA·cm-2 for hydrogen evolution reaction (HER) and 286.2 mV at 100 mA·cm-2 for OER in the 1.0 M KOH + 0.5 M NaCl electrolyte. Furthermore, it also exhibits a low voltage of 1.55 V to achieve the current density of 10 mA·cm-2 and works steadily for 105 h at 100 mA·cm-2 for overall alkaline simulated seawater splitting. This work will afford a valid strategy for designing a non-noble metal catalyst for seawater splitting.

Protective Effects of Oridonin on Acute Liver Injury via Impeding Posttranslational Modifications of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) in the Toll-Like Receptor 4 (TLR4) Signaling Pathway.

OBJECTIVE: Recent researches have demonstrated that inflammation-related diseases are effectively regulated by posttranslational modifications (PTMs) including phosphorylation and acetylation. Our previous study found a new acetyltransferase inhibitor, oridonin, which had a protective effect on acute liver injury (ALI). In the present study, we further investigated its protective mechanism against D-galactosamine (D-Gal) combined with lipopolysaccharide- (LPS-) induced ALI in mice. METHODS: Intraperitoneal injections of LPS (40 µg/mouse)/D-Gal (5 mg/mouse) were given to the mice, and the experimental group was pretreated with intraperitoneal injection of oridonin (0.2 mg/mouse). To elucidate the protective mechanism of oridonin, we collected liver specimens and used RNA-sequencing (RNA-Seq) analysis. We focused on the genes that were upregulated by LPS/D-Gal and downregulated after pretreatment with oridonin. The downregulated genes examined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were further verified by real-time polymerase chain reaction (PCR) and western blot. RESULTS: GO analysis showed that genes that were downregulated after pretreatment with oridonin were extremely concentrated in immune response, chemotaxis, and inflammatory response. Real-time PCR confirmed that the expression of these genes was upregulated by LPS/D-Gal induction and reduced after treatment with oridonin, which was consistent with RNA-Seq results. KEGG pathway analysis showed a significantly enriched downregulated gene that was present in the Toll-like receptor (TLR) 4 signaling cascade. Our results manifested that phosphorylation levels of upstream signaling molecules in the TLR4 signaling cascade, including extracellular signal-regulated kinase (ERK), P38, and IκB, were significantly inhibited by oridonin. Furthermore, LPS/D-Gal stimulation triggered posttranslational modifications of related gene loci in the TLR4 signaling pathway, including phosphorylation of IL-1 receptor-associated kinase 4 (IRAK4 T345/S346) and acetylation of IRAK4 (K34). However, after treatment with oridonin, the modification pattern of IRAK4 expression stimulated by LPS/D-Gal was suggestively attenuated. CONCLUSION: Our study revealed that the protective effects of oridonin on LPS/D-Gal-induced ALI mediated by inhibition of the PTMs of IRAK4, including phosphorylation of T345/S346 and acetylation of K34.

Rational Optimization of Tumor Suppressor-Derived Peptide Inhibitor Selectivity between Oncogene Tyrosine Kinases ErbB1 and ErbB2.

The tumor-suppressor protein Mig-6 has been found to directly target and inhibit the human ErbB receptor tyrosine kinases ErbB1 and ErbB2. Despite their highly homologous nature, these two kinases are separately involved in the development of different types of human cancer. Here, we utilized a rational strategy to iteratively optimize the interaction specificity of the two kinases with a Mig-6 derived peptide by exploiting structural diversity space. Instead of traditionally improving the peptide binding potency, the optimization attempts to maximize the affinity difference between peptides binding to ErbB1 and ErbB2. The computational design was also substantiated by using fluorescence-based assays. Consequently, we successfully designed three peptides, HSLTPTQSF, THLMNLLRI, and NSGCPMHK, with high or moderate selectivity for ErbB1 over ErbB2 (3.1-, 6.3-, and 3.0-fold, respectively) and two peptides, PCMTDFLFT and WVIFPSQTN, with moderate or modest selectivity for ErbB2 over ErbB1 (3.5- and 1.6-fold, respectively). The method is expected to be used for the rational molecular design of selective peptide entities for other protein systems.

Characteristics of Norovirus capsid protein-specific CD8+ T-Cell responses in previously infected individuals.

Norovirus (NV) infection causes acute gastroenteritis in children and adults. Upon infection with NV, specific CD8+ T cells, which play an important role in anti-infective immunity, are activated in the host. Owing to the NV's wide genotypic variability, it is challenging to develop vaccines with cross-protective abilities against infection. To aid effective vaccine development, we examined specific CD8+ T-cell responses towards viral-structural protein (VP) epitopes, which enable binding to host susceptibility receptors. We isolated peripheral blood mononuclear cells from 196 participants to screen and identify predominant core peptides towards NV main and small envelope proteins using ex vivo and in vitro intracellular cytokine staining assays. Human leukocyte antigen (HLA) restriction characteristics were detected using next-generation sequencing. Three conservative immunodominant VP-derived CD8+ T-cell epitopes, VP294-102 (TDAARGAIN), VP2153-161 (RGPSNKSSN), and VP1141-148 (FPHIIVDV), were identified and restrictively presented by HLA-Cw * 0102, HLA-Cw * 0702, and HLA-A *1101 alleles, separately. Our findings provide useful insights into the development of future vaccines and treatments for NV infection.

AGEs induce MMP-9 promoter demethylation through the GADD45α-mediated BER pathway to promote breast cancer metastasis in patients with diabetes.

Scientific evidence has linked diabetes to a higher incidence and increased aggressiveness of breast cancer; however, mechanistic studies of the numerous regulators involved in this process are insufficiently thorough. Advanced glycation end products (AGEs) play an important role in the chronic complications of diabetes, but the mechanisms of AGEs in breast cancer are largely unexplored. In this study, we first demonstrate that high AGE levels in breast cancer tissues are associated with the diabetic state and poor patient outcomes. Furthermore, AGEs interact with the receptor for AGEs (RAGE) to promote breast cancer cell migration and invasion. Mechanistically, based on RNA sequencing (RNA-seq) analysis, we reveal that growth arrest and DNA damage gene 45α (GADD45α) is a vital protein upregulated by AGEs through a P53-dependent pathway. Next, GADD45α recruits thymine DNA glycosylase for base excision repair to form the demethylation complex at the promoter region of MMP-9 and enhance MMP-9 transactivation through DNA demethylation. Overall, our results indicate a critical regulatory role of AGEs in patients with breast cancer and diabetes and reveal a novel mechanism of epigenetic modification in promoting breast cancer metastasis.

Efficient electrocatalyst for solar-driven electrolytic water splitting: Phosphorus (P) and niobium (Nb) co-doped NiFe2O4 nanosheet.

In the context of hydrogen production through water electrolysis, the development of efficient and stable electrocatalysts is of paramount importance. However, the creation of cost-effective electrocatalysts poses a significant challenge. In this study, a P and Nb co-doped NiFe2O4 nanosheet is designed and grown on Fe foam (referred to as P, Nb-NiFe2O4/FF). The P, Nb-NiFe2O4/FF exhibits a distinctive crystalline/amorphous heterostructure, and the co-doping of P and Nb in the material leads to the exposure of additional catalytic active sites, optimization of the electronic structure, and enhancement of charge conductivity. Additionally, the P, Nb-NiFe2O4/FF possesses a superhydrophilic surface for the enhancement of charge/mass transfer at interface and a superaerophobic surface, facilitating the efficient release of gas. The P, Nb-NiFe2O4/FF demonstrates remarkable oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) activities, achieving overpotential as low as 247 mV and 127 mV, respectively, to attain the current density response of 100 mA cm-2. Based on the high bifunctional activities, the P, Nb-NiFe2O4/FF requires only a working voltage of 1.56 V to obtain the current density of 10 mA cm-2 in overall water splitting. Furthermore, the overall water splitting device of P, Nb-NiFe2O4/FF is integrated with a commercial solar cell to simulate a solar-powered water splitting system, resulting in as superior solar-to-hydrogen conversion efficiency of 15.11%.

Bioinformatics analysis of human kallikrein 5 (KLK5) expression in metaplastic triple-negative breast cancer.

Background: Metaplastic breast carcinoma (MBC) is a rare breast cancer subtype; most cases are triple-negative breast cancers (TNBCs) and are poorly responsive to conventional systemic therapy. Few potential diagnostic and prognostic markers for distinguishing between metaplastic TNBC and nonmetaplastic TNBC have been discovered. We performed bioinformatic analysis to explore the underlying mechanism by which metaplastic TNBC differs from nonmetaplastic TNBC and provides potential pathogenic genes of metaplastic TNBC. Methods: Differentially expressed genes (DEGs) in metaplastic tumors and nonmetaplastic tumors from TNBC patients were screened using GSE165407. The GSE76275 data set and The Cancer Genome Atlas (TCGA) database were used to screen DEGs in TNBC and non-TNBC. Metascape and DAVID were used for the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Gene Ontology (GO) analysis of DEGs. Online databases, including UALCAN, GEPIA, HPA, Breast Cancer Gene-Expression Miner, and quantitative PCR and western blot, were used to examine KLK5 messenger RNA and protein expression in breast cancer. Analysis of KLK5­associated genes was performed with TCGA data, and the LinkedOmics database was used to detect the genes co-expressed with KLK5. STRING (Search Tool for the Retrieval of Interacting Genes) and Cytoscape were used to screen for hub genes. Kaplan­Meier plotter was used for survival analysis. Results: KLK5 was identified among the DEGs in nonmetaplastic TNBC and metaplastic TNBC. The KLK5 gene was overexpressed in nonmetaplastic TNBC but downregulated in metaplastic TNBC. KEGG and GO analyses revealed that epithelial-to-mesenchymal transition was a pathogenic mechanism in metaplastic TNBC and an important pathway by which KLK5 and its associated genes DSG1 and DSG3 influence metaplastic TNBC progression. Prognosis analysis showed that only low expression of KLK5 in metaplastic TNBC had clinical significance. Conclusion: Our research indicated that KLK5 may be a pivotal molecule with a key role in the mechanism of tumorigenesis in metaplastic TNBC.

Crystalline Ni-Fe phosphide/amorphous P doped Fe-(oxy)hydroxide heterostructure as a multifunctional electrocatalyst for solar cell-driven hydrogen production.

Hydrogen production by electrocatalytic water splitting is considered to be an effective and environmental method, and the design of an electrocatalyst with high efficiency, low cost, and multifunction is of great importance. Herein, we developed a crystalline NiFe phosphide (NiFeP)/amorphous P-doped FeOOH (P-FeOOH) heterostructure (defined as P-NiFeOxHy) as a high-efficiency multifunctional electrocatalyst for water electrolysis. The NiFeP nanocrystals provide remarkable electronic conductivity and plenty of active sites, the amorphous P-FeOOH improves the adsorption energy of oxygen-containing species, and the crystalline/amorphous heterostructure with superhydrophilic and superaerophobic surface generates synergistic effects, providing plentiful active sites and efficient charge/mass transfer. Benefiting from this, the designed P-NiFeOxHy displays ultralow overpotentials of 159.2 and 20.8 mV to achieve 10 mA cm-2 for oxygen evolution reaction and hydrogen evolution reaction, and also shows the superior performance of urea oxidation reaction with a low voltage of 1.37 V at 10 mA cm-2 in 1 M KOH with 0.33 M urea. In-situ Raman spectra and ex-situ XPS analysis were also used to investigate the catalytic process and reveal the surface structure evolution of P-NiFeOxHy under electrochemical oxidation. Accordingly, the designed P-NiFeOxHy is employed as both cathode and anode to assemble into the urea-assisted water electrolysis device, which can reach 10 mA cm-2 with a low 1.36 V and could be further driven by a solar cell. The work reveals a design of superior activity, cost-effective and multifunctional electrocatalysts for water splitting.