Light-responsive transcription factors VvHYH and VvGATA24 mediate wax terpenoid biosynthesis in Vitis vinifera.

The cuticular wax that covers the surfaces of plants is the first barrier against environmental stresses and increasingly accumulates with light exposure. However, the molecular basis of light-responsive wax biosynthesis remains elusive. In grape (Vitis vinifera), light exposure resulted in higher wax terpenoid content and lower decay and abscission rates than controls kept in darkness. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA-seq data were integrated to draw the chromatin accessibility and cis-elements regulatory map to identify the potential action sites. Terpenoid synthase 12 (VvTPS12) and 3-Hydroxy-3-methylglutaryl-CoA reductase 2 (VvHMGR2) were identified as grape wax biosynthesis targets, while VvHYH and VvGATA24 were identified as terpenoid biosynthesis activators, as more abundant wax crystals and higher wax terpenoid content were observed in transiently overexpressed grape berries and Nicotiana benthamiana leaves. The interaction between VvHYH and the open chromatin of VvTPS12 was confirmed qualitatively using a dual luciferase assay and quantitatively using surface plasma resonance, with an equilibrium dissociation constant of 2.81 nM identified via the latter approach. Molecular docking simulation implied the structural nature of this interaction, indicating that 24 amino acid residues of VvHYH, including Arg106A, could bind to the VvTPS12 G-box cis-element. VvGATA24 directly bound to the open chromatin of VvHMGR2, with an equilibrium dissociation constant of 8.59 nM. 12 amino acid residues of VvGATA24, including Pro218B, interacted with the VvHMGR2 GATA-box cis-element. Our work characterizes the mechanism underlying light-mediated wax terpenoid biosynthesis and provides gene targets for future molecular breeding.

Identification of necroptosis-related genes in ankylosing spondylitis by bioinformatics and experimental validation.

The pathogenesis of ankylosing spondylitis (AS) remains unclear, and while recent studies have implicated necroptosis in various autoimmune diseases, an investigation of its relationship with AS has not been reported. In this study, we utilized the Gene Expression Omnibus database to compare gene expressions between AS patients and healthy controls, identifying 18 differentially expressed necroptosis-related genes (DENRGs), with 8 upregulated and 10 downregulated. Through the application of three machine learning algorithms-least absolute shrinkage and selection operation, support vector machine-recursive feature elimination and random forest-two hub genes, FASLG and TARDBP, were pinpointed. These genes demonstrated high specificity and sensitivity for AS diagnosis, as evidenced by receiver operating characteristic curve analysis. These findings were further supported by external datasets and cellular experiments, which confirmed the downregulation of FASLG and upregulation of TARDBP in AS patients. Immune cell infiltration analysis suggested that CD4+ T cells, CD8+ T cells, NK cells and neutrophils may be associated with the development of AS. Notably, in the group with high FASLG expression, there was a significant infiltration of CD8+ T cells, memory-activated CD4+ T cells and resting NK cells, with relatively less infiltration of memory-resting CD4+ T cells and neutrophils. Conversely, in the group with high TARDBP expression, there was enhanced infiltration of naïve CD4+ T cells and M0 macrophages, with a reduced presence of memory-resting CD4+ T cells. In summary, FASLG and TARDBP may contribute to AS pathogenesis by regulating the immune microenvironment and immune-related signalling pathways. These findings offer new insights into the molecular mechanisms of AS and suggest potential new targets for therapeutic strategies.

Three-Motif Molecular Junction Type Covalent Organic Frameworks for Efficient Photocatalytic Aerobic Oxidation.

Covalent organic frameworks (COFs), with the features of flexible structure regulation and easy introduction of functional groups, have aroused broad interest in the field of photocatalysis. However, due to the low light absorption intensity, low photoelectron conversion efficiency, and lack of suitable active sites, it remains a great challenge to achieve efficient photocatalytic aerobic oxidation reactions. Herein, based on reticular chemistry, we rationally designed a series of three-motif molecular junction type COFs, which formed dual photosensitizer coupled redox molecular junctions containing multifunctional COF photocatalysts. Significantly, due to the strong light adsorption ability of dual photosensitizer units and integrated oxidation and reduction features, the PY-BT COF exhibited the highest activity for photocatalytic aerobic oxidation. Especially, it achieved a photocatalytic benzylamine conversion efficiency of 99.9% in 2.5 h, which is much higher than that of the two-motif molecular junctions with only one photosensitizer or redox unit lacking COFs. The mechanism of selective aerobic oxidation was studied through comprehensive experiments and density functional theory calculations. The results showed that the photoinduced electron transfer occurred from PY and then through triphenylamine to BT. Furthermore, the thermodynamics energy for benzylamine oxidation on PY-BT COF was much lower than that for others, which confirmed the synergistic effect of dual photosensitizer coupled redox molecular junction COFs. This work provided a new strategy for the design of functional COFs with three-motif molecular junctions and also represented a new insight into the multifunctional COFs for organic catalytic reactions.

Altered Genome-Wide DNA Methylation in the Duodenum of Common Variable Immunodeficiency Patients.

PURPOSE: A large proportion of Common variable immunodeficiency (CVID) patients has duodenal inflammation with increased intraepithelial lymphocytes (IEL) of unknown aetiology. The histologic similarities to celiac disease, lead to confusion regarding treatment (gluten-free diet) of these patients. We aimed to elucidate the role of epigenetic DNA methylation in the aetiology of duodenal inflammation in CVID and differentiate it from true celiac disease. METHODS: DNA was isolated from snap-frozen pieces of duodenal biopsies and analysed for differences in genome-wide epigenetic DNA methylation between CVID patients with increased IEL (CVID_IEL; n = 5) without IEL (CVID_N; n = 3), celiac disease (n = 3) and healthy controls (n = 3). RESULTS: The DNA methylation data of 5-methylcytosine in CpG sites separated CVID and celiac diseases from healthy controls. Differential methylation in promoters of genes were identified as potential novel mediators in CVID and celiac disease. There was limited overlap of methylation associated genes between CVID_IEL and Celiac disease. High frequency of differentially methylated CpG sites was detected in over 100 genes nearby transcription start site (TSS) in both CVID_IEL and celiac disease, compared to healthy controls. Differential methylation of genes involved in regulation of TNF/cytokine production were enriched in CVID_IEL, compared to healthy controls. CONCLUSION: This is the first study to reveal a role of epigenetic DNA methylation in the etiology of duodenal inflammation of CVID patients, distinguishing CVID_IEL from celiac disease. We identified potential biomarkers and therapeutic targets within gene promotors and in high-frequency differentially methylated CpG regions proximal to TSS in both CVID_IEL and celiac disease.

Correlation of distribution characteristics and dynamic changes of gut microbiota with the efficacy of immunotherapy in EGFR-mutated non-small cell lung cancer.

BACKGROUND: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS: The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.

Circulating cytokines levels and osteoarthritis: A Mendelian randomization study.

BACKGROUND: Previous traditional observational studies have suggested the contribution of several cytokines and growth factors to the development of osteoarthritis (OA). This study aimed to determine the association of circulating cytokine and growth factor levels with OA. METHODS: We used two-sample Mendelian randomization (MR) to explore the causality between circulating cytokine and growth factor levels and OA [including knee or hip OA (K/HOA), knee OA (KOA), and hip OA (HOA)]. Summary level data for circulating cytokine and growth factor levels were sourced from a genome-wide association study (GWAS) involving 8,293 participants of Finnish ancestry. Single-nucleotide polymorphisms related to K/HOA (39,427 cases and 378,169 controls), KOA (24,955 cases and 378,169 controls), and HOA (15,704 cases and 378,169 controls) were obtained from a previous GWAS. The inverse variance weighted (IVW) method was primarily used for our MR analysis. For exposures to only one relevant SNP as IV, we used the Wald ratio as the major method to assess causal effects. We also conducted a series of sensitivity analyses to improve the robustness of the results. RESULTS: Circulating vascular endothelial growth factor levels were suggestively associated with an increased risk of K/HOA (odds ratio (OR) = 1.034; 95 % confidence interval (CI) = 1.013-1.055; P = 0.001), KOA (OR = 1.034; 95 % CI = 1.014-1.065; P = 0.002), and HOA (OR = 1.039; 95 % CI = 1.003-1.067; P = 0.034). Circulating interleukin (IL)-12p70 levels was suggestively associated with K/HOA (OR = 1.047; 95 % CI = 1.018-1.077; P = 0.001), KOA (OR = 1.058; 95 % CI = 1.022-1.095; P = 0.001), and HOA (OR = 1.044; 95 % CI = 1.000-1.091; P = 0.048). Circulating IL-18 levels were suggestively associated with HOA (OR = 1.068; 95 % CI = 1.014-1.125; P = 0.012). However, limited evidence exists to support causal genetic relationships between other circulating cytokines, growth factor levels and K/HOA, KOA, and HOA. CONCLUSIONS: Our MR analysis provides suggestive evidence of causal relationships between circulating cytokines and growth factors levels and OA, providing new insights into the etiology of OA.

The genetic causal relationship between type 2 diabetes, glycemic traits and venous thromboembolism, deep vein thrombosis, pulmonary embolism: a two-sample Mendelian randomization study.

OBJECTIVE: To investigate the genetic underpinnings of the association between type 2 diabetes (T2D), glycemic indicators such as fasting glucose (FG), fasting insulin (FI), and glycated hemoglobin (GH), and venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), thereby contributing novel insights to the scholarly discourse within this domain. METHODS: Genome-wide association study (GWAS) summary data pertaining to exposures (T2D, FG, FI, GH) and outcomes (VTE, DVT, PE) were acquired from the IEU Open GWAS database, encompassing participants of European descent, including both male and female individuals. Two-sample Mendelian randomization (MR) analyses were conducted utilizing the TwoSampleMR and MRPRESSO packages within the R programming environment. The primary analytical approach employed was the random-effects inverse variance weighted (IVW) method. Heterogeneity was assessed via Cochran's Q statistic for MR-IVW and Rucker's Q statistic for MR-Egger. Horizontal pleiotropy was evaluated using the intercept test of MR Egger and MR pleiotropy residual sum and outlier (MR-PRESSO) analysis, with the latter also employed for outlier detection. Additionally, a "Leave one out" analysis was conducted to ascertain the influence of individual single nucleotide polymorphisms (SNPs) on MR results. RESULTS: The random-effects IVW analysis revealed a negative genetic causal association between T2D) and VTE (P = 0.008, Odds Ratio [OR] 95% confidence interval [CI] = 0.896 [0.827-0.972]), as well as between FG and VTE (P = 0.002, OR 95% CI = 0.655 [0.503-0.853]), GH and VTE (P = 0.010, OR 95% CI = 0.604 [0.412-0.884]), and GH and DVT (P = 0.002, OR 95% CI = 0.413 [0.235-0.725]). Conversely, the random-effects IVW analysis did not detect a genetic causal relationship between FI and VTE (P > 0.05), nor between T2D, FG, or FI and DVT (P > 0.05), or between T2D, FG, FI, or GH and PE (P > 0.05). Both the Cochran's Q statistic for MR-IVW and Rucker's Q statistic for MR-Egger indicated no significant heterogeneity (P > 0.05). Moreover, the intercept tests of MR Egger and MR-PRESSO suggested the absence of horizontal pleiotropy (P > 0.05). MR-PRESSO analysis identified no outliers, while the "Leave one out" analysis underscored that the MR analysis was not influenced by any single SNP. CONCLUSION: Our investigation revealed that T2D, FG, and GH exhibit negative genetic causal relationships with VTE at the genetic level, while GH demonstrates a negative genetic causal relationship with DVT at the genetic level. These findings furnish genetic-level evidence warranting further examination of VTE, DVT, and PE, thereby making a contribution to the advancement of related research domains.

Duodenal inflammation in common variable immunodeficiency has altered transcriptional response to viruses.

BACKGROUND: A substantial proportion of common variable immunodeficiency (CVID) patients has duodenal inflammation of largely unknown etiology. However, because of its histologic similarities with celiac disease, gluten sensitivity has been proposed as a potential mechanism. OBJECTIVE: We aimed to elucidate the role of the duodenal microenvironment in the pathogenesis of duodenal inflammation in CVID by investigating the transcriptional, proteomic, and microbial signatures of duodenal biopsy samples in CVID. METHODS: DNA, total RNA, and protein were isolated from snap-frozen pieces of duodenal biopsy samples from CVID (with and without duodenal inflammation), healthy controls, and patients with celiac disease (untreated). RNA sequencing, mass spectrometry-based proteomics, and 16S ribosomal DNA sequencing (bacteria) were then performed. RESULTS: CVID separated from controls in regulation of transcriptional response to lipopolysaccharide and cellular immune responses. These differences were independent of mucosal inflammation. Instead, CVID patients with duodenal inflammation displayed alterations in transcription of genes involved in response to viral infections. Four proteins were differently regulated between CVID patients and healthy controls-DBNL, TRMT11, GCHFR, and IGHA2-independent of duodenal inflammation. Despite similar histology, there were major differences in CVID with duodenal inflammation and celiac disease both at the RNA and protein level. No significant difference was observed in the bacterial gut microbial signature between CVID, celiac, and healthy controls. CONCLUSION: Our findings suggest the existence of altered functions of the duodenal epithelium, particularly in response to lipopolysaccharide and viruses. The latter finding was related to duodenal inflammation, suggesting that viruses, not gluten sensitivity, could be related to duodenal inflammation in CVID.

Heterogeneity in the immune microenvironment of bone metastasis in driver-positive non-small cell lung cancer.

Mutations in epidermal growth factor receptor and anaplastic lymphoma kinase are common driver events in non-small cell lung cancer (NSCLC), which are associated with a high frequency of bone metastases (BMs). While the bone marrow represents a specialized immune microenvironment, the immune repertoire of BMs remains unknown. Considering the higher incidence of BMs in driver gene-positive NSCLCs, and the unique biology of the bone, herein, we assessed the infiltrating immune cells and T cell receptor (TCR) profile of BMs in driver-positive NSCLCs. Immune profile of BMs in driver gene-positive NSCLC were assessed in 10 patients, where 6 had driver gene-positive mutation. TCR and bulk RNA sequencing were performed on malignant bone samples. The diversity and clonality of the TCR repertoire were analyzed. The cellular components were inferred from bulk gene expression profiles computationally by CIBERSORT. Although BMs were generally regarded as immune-cold tumors, immune cell composition analyses showed co-existence of cytotoxic and suppressor immune cells in driver-positive BM samples, as compared to primary lung. Analysis of the TCR repertoire indicated a trend of higher diversity and similar clonality in the driver-positive compared with the driver-negative subsets. In addition, we identified two cases that showed the opposite response to immune checkpoint blockade. A comparison of these two patients' BM samples showed more highly amplified clones, fewer M2 macrophages and more activated natural killer cells in the responder. In summary, BMs in NSCLC are heterogeneous in their immune microenvironment, which might be related to differential clinical outcomes to immune checkpoint blockade.

Identification of the potential regulatory interactions in rheumatoid arthritis through a comprehensive analysis of lncRNA-related ceRNA networks.

OBJECTIVE: This study aimed at constructing a network of competing endogenous RNA (ceRNA) in the synovial tissues of rheumatoid arthritis (RA). It seeks to discern potential biomarkers and explore the long non-coding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) axes that are intricately linked to the pathophysiological mechanisms underpinning RA, and providing a scientific basis for the pathogenesis and treatment of RA. METHODS: Microarray data pertaining to RA synovial tissue, GSE103578, GSE128813, and GSE83147, were acquired from the Gene Expression Omnibus (GEO) database ( http://www.ncbi.nlm.nih.gov/geo ). Conducted to discern both differentially expressed lncRNAs (DELncRNAs) and differentially expressed genes (DEGs). A ceRNA network was obtained through key lncRNAs, key miRNAs, and key genes. Further investigations involved co-expression analyses to uncover the lncRNA-miRNA-mRNA axes contributing to the pathogenesis of RA. To delineate the immune-relevant facets of this axis, we conducted an assessment of key genes, emphasizing those with the most substantial immunological correlations, employing the GeneCards database. Finally, gene set enrichment analysis (GSEA) was executed on the identified key lncRNAs to elucidate their functional implications in RA. RESULTS: The 2 key lncRNAs, 7 key miRNAs and 6 key genes related to the pathogenesis of RA were obtained, as well as 2 key lncRNA-miRNA-mRNA axes (KRTAP5-AS1-hsa-miR-30b-5p-PNN, XIST-hsa-miR-511-3p/hsa-miR-1277-5p-F2RL1). GSEA of two key lncRNAs obtained biological processes and signaling pathways related to RA synovial lesions. CONCLUSION: The findings of this investigation hold promise in furnishing a foundational framework and guiding future research endeavors aimed at comprehending the etiology and therapeutic interventions for RA.

Sediment source fingerprinting and the temporal variability of source contributions.

Sediment source fingerprinting has been progressively developed and refined over the past 40 years or more and now represents a widely used and valuable technique, with important practical applications. However, relatively little attention has been given to the target samples and the extent to which they are able to provide meaningful information on short- or longer-term relative source contributions for a given study catchment. A key issue here is the inherent short- and longer-term temporal variability of source contributions and the extent to which such variability is taken into account by the target samples. The objective of this study was to investigate the temporal variation of source contributions from the Qiaozi West catchment, a small (1.09 km2) gully catchment located within the Loess Plateau of China. The target samples represented a suite of 214 spot suspended sediment samples collected during eight representative wet season rainfall events occurring over two years. A suite of geochemical properties was used as fingerprints and standard source apportionment calculations indicated that the gully walls contributed the most sediment (load-weighted mean 54.5%) and, together with cropland (load-weighted mean 37.3%), and gully slopes (load-weighed mean 6.6%) were the main sediment sources. The 214 individual target samples indicated that the contribution of cropland sources varied between 8.3% and 60.4%, gully walls between 22.9% and 85.8% and gully slopes between 1.1% and 30.7%, representing ranges of 52.1%, 62.9% and 29.6% respectively. In order to explore whether the temporal variability of source contributions demonstrated by the study catchment should be seen as typical, equivalent information was abstracted from 14 published studies for other catchments of varying size and located in different environments worldwide. This information demonstrated similar temporal variability of the relative contributions of the major sources, which were typically characterized by ranges of the order of 30-70%. The temporal variability associated with the estimates of relative source contributions provided by target samples has important implications for the uncertainty associated with such estimates derived using source fingerprinting techniques based on a limited number of target samples. Further attention needs to be directed to the design of sampling programmes used to collect such samples and to taking account of such uncertainty in source apportionment calculations.

Iron, copper, zinc and magnesium on rheumatoid arthritis: a two-sample Mendelian randomization study.

This study aimed to elucidate the causal genetic relationships between iron, copper, zinc, magnesium, and rheumatoid arthritis (RA). A two-sample Mendelian randomization (MR) analysis was conducted using the "TwoSampleMR" and "MendelianRandomization" packages in R. The random-effects inverse variance-weighted (IVW) method was used as the primary approach. We performed sensitivity analyses to test the reliability of the results. The random-effects IVW analysis revealed that there was no genetic causal relationship between iron (P = 0.429, odds ratio [OR] 95% confidence interval [CI] = 0.919 [0.746-1.133]), copper (P = 0.313, OR 95% CI = 0.973 [0.921-1.027]), zinc (P = 0.633, OR 95% CI = 0.978 [0.891-1.073]), or magnesium (P = 0.218, OR 95% CI = 0.792 [0.546-1.148]) and RA. Sensitivity analysis verified the reliability of the results. Therefore, there is no evidence to support a causal relationship between iron, copper, zinc, and magnesium intake at the genetic level and the development of RA.

Dual Photosensitizer Coupled Three-Dimensional Metal-Covalent Organic Frameworks for Efficient Photocatalytic Reactions.

In this work, we innovatively assembled two types of traditional photosensitizers, that is pyridine ruthenium/ferrum (Ru(bpy)3 2+ /Fe(bpy)3 2+ ) and porphyrin/metalloporphyrin complex (2HPor/ZnPor) by covalent linkage to get a series of dual photosensitizer-based three-dimensional metal-covalent organic frameworks (3D MCOFs), which behaved strong visible light-absorbing ability, efficient electron transfer and suitable band gap for highly efficient photocatalytic hydrogen (H2 ) evolution. Rubpy-ZnPor COF achieved the highest H2 yield (30 338 µmol g-1 h-1 ) with apparent quantum efficiency (AQE) of 9.68 %@420 nm, which showed one of the best performances among all reported COF based photocatalysts. Furthermore, the in situ produced H2 was successfully tandem used in the alkyne hydrogenation with ≈99.9 % conversion efficiency. Theoretical calculations reveal that both the two photosensitizer units in MCOFs can be photoexcited and thus contribute optimal photocatalytic activity. This work develops a general strategy and shows the great potential of using multiple photosensitive materials in the field of photocatalysis.

Relative Local Electron Density Tuning in Metal-Covalent Organic Frameworks for Boosting CO2 Photoreduction.

The high local electron density and efficient charge carrier separation are two important factors to affect photocatalytic activity, especially for the CO2 photoreduction reaction. However, the systematic studies on the structure-functional relationship regarding the above two factors based on precisely structure model are rarely reported. Herein, as a proof-of-concept, we developed a new strategy on the evaluation of local electron density by controlling the relative electron-deficient (ED) and electron-rich (ER) intensity of monomer at a molecular level based on three rational-designed vinylene-linked sp2 carbon-covalent organic frameworks (COFs). As expected, the as-prepared vinylene-linked sp2 carbon-conjugated metal-covalent organic framework (MCOFs) (VL-MCOF-1) with molecular junction exhibited excellent activities for CO2 -to-HCOOH conversion (283.41 µmol g-1 h-1 ) and high selectivity of 97.1 %, much higher than the VL-MCOF-2 and g-C34 N6 -COF, which is due to the synergistic effect of the multi-electronic metal clusters (Cu3 (PyCA)3 ) (PyCA=pyrazolate-4-carboxaldehyde) as strong ER roles and cyanopyridine units as ED roles and active sites, as well as the boosted photo-induced charge separation efficiency of vinyl connection and increased light utilization ability. These results not only provide a strategy for regulating the electron-density distribution of photocatalysts at the molecular level but also offers profound insights for metal clusters-based COFs to effective CO2 conversion.

abc4pwm: affinity based clustering for position weight matrices in applications of DNA sequence analysis.

BACKGROUND: Transcription factor (TF) binding motifs are identified by high throughput sequencing technologies as means to capture Protein-DNA interactions. These motifs are often represented by consensus sequences in form of position weight matrices (PWMs). With ever-increasing pool of TF binding motifs from multiple sources, redundancy issues are difficult to avoid, especially when every source maintains its own database for collection. One solution can be to cluster biologically relevant or similar PWMs, whether coming from experimental detection or in silico predictions. However, there is a lack of efficient tools to cluster PWMs. Assessing quality of PWM clusters is yet another challenge. Therefore, new methods and tools are required to efficiently cluster PWMs and assess quality of clusters. RESULTS: A new Python package Affinity Based Clustering for Position Weight Matrices (abc4pwm) was developed. It efficiently clustered PWMs from multiple sources with or without using DNA-Binding Domain (DBD) information, generated a representative motif for each cluster, evaluated the clustering quality automatically, and filtered out incorrectly clustered PWMs. Additionally, it was able to update human DBD family database automatically, classified known human TF PWMs to the respective DBD family, and performed TF motif searching and motif discovery by a new ensemble learning approach. CONCLUSION: This work demonstrates applications of abc4pwm in the DNA sequence analysis for various high throughput sequencing data using ~ 1770 human TF PWMs. It recovered known TF motifs at gene promoters based on gene expression profiles (RNA-seq) and identified true TF binding targets for motifs predicted from ChIP-seq experiments. Abc4pwm is a useful tool for TF motif searching, clustering, quality assessment and integration in multiple types of sequence data analysis including RNA-seq, ChIP-seq and ATAC-seq.

Peroxiredoxin 4 regulates tumor-cell-like characteristics of fibroblast-like synoviocytes in rheumatoid arthritis through PI3k/Akt signaling pathway.

Peroxiredoxin-4 (PRDX4), a member of PRDX family, which played an important role in scavenging reactive oxygen species (ROS). The up-regulation of PRDX4 in synovial tissue and synovial fluid from rheumatoid arthritis (RA) patients has been reported. However, the biological functions of PRDX4 in fibroblast-like synoviocytes (RA-FLS) remains unclear. In this research, we reveal that expression of PRDX4 was notably increased in RA synovial tissue, especially in hyperplastic synovial tissue. PRDX4 silencing significantly inhibited the tumor cell-like behaviors and mRNA expression of matrix metalloproteinases (MMPs) in RA-FLS. Furthermore, overexpression of PRDX4 markedly activated PI3K/Akt signaling pathway, which can be reverted by Akt inhibitor MK-2206. These observations identified elevated PRDX4 may regulates the tumor cell-like biological characteristic of RA-FLS via Pi3k/Akt pathway. Targeting PRDX4 and its downstream signaling pathway might provide a potential diagnostic markers and therapeutic target for RA.

Covalent Organic Framework Based Functional Materials: Important Catalysts for Efficient CO2 Utilization.

As hot topics in the chemical conversion of CO2 , the photo-/electrocatalytic reduction of CO2 and use of CO2 as a supporter for energy storage have shown great potential for the utilization of CO2 . However, many obstacles still exist on the road to realizing highly efficient chemical CO2 conversion, such as inefficient uptake/activation of CO2 and mass transport in catalysts. Covalent organic frameworks (COFs), as a kind of porous material, have been widely explored as catalysts for the chemical conversion of CO2 owing to their unique features. In particular, COF-based functional materials containing diverse active sites (such as single metal sites, metal nanoparticles, and metal oxides) offer great potential for realizing CO2 conversion and energy storage. This Minireview discusses recent breakthroughs in the basic knowledge, mechanisms, and pathways of chemical CO2 conversion strategies that use COF-based functional catalysts. In addition, the challenges and prospects of COF-based functional catalysts for the efficient utilization of CO2 are also introduced.

Comparison of the clinical efficacy of a femoral neck system versus cannulated screws in the treatment of femoral neck fracture in young adults.

BACKGROUND: To compare the clinical efficacy of a femoral neck system (FNS) and cannulated screws (CS) in the treatment of femoral neck fracture in young adults. METHODS: Data from 69 young adults, who were admitted for femoral neck fracture between March 2018 and June 2020, were retrospectively analyzed. Patients were divided into two groups according to surgical method: FNS and CS. The number of intraoperative fluoroscopies, operative duration, length of hospital stay, fracture healing time, Harris score of hip function, excellent and good rate of hip function, and postoperative complications (infection, cut out the internal fixation, nail withdrawal, and femoral neck shortening) were compared between the two groups. Hip joint function was evaluated using the Harris Hip Scoring system. RESULTS: All 69 patients had satisfactory reduction and were followed up for 12-24 months, with a mean follow-up of 16.91 ± 3.01 months. Mean time to fracture healing was13.82 ± 1.59 and 14.03 ± 1.78 weeks in the FNS and CS groups, respectively. There was a statistical difference in the number of intraoperative fluoroscopies between the 2 groups (P = 0.000). There were no significant differences, in operation duration, hospital length of stay, fracture healing time, complications, Harris Hip Score for hip function and excellent and good rate between the two groups (P > 0.05). The incidence of complications was 6.1%(2/33) in the FNS group lower than 25%(9/36) in the CS group, a difference that was statistically significant (P = 0.032). At the last follow-up, the Harris Hip Score of the hip joint in the FNS group was 90.42 ± 4.82and 88.44 ± 5.91 in the CS group. CONCLUSIONS: Both treatment methods resulted in higher rates of fracture healing and excellent hip function. Compared with CS, the FNS reduced the number of intraoperative fluoroscopies, radiation exposure to medical staff and patients, and short-term complications including femoral neck shortening and bone nonunion.

Novel UCHL1 mutations reveal new insights into ubiquitin processing.

Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 has been implicated in early-onset progressive neurodegeneration (MIM no. 615491), so far only in one family. In this study a second family is characterized, and the functional consequences of the identified mutations in UCHL1 are explored. Three siblings developed childhood-onset optic atrophy, followed by spasticity and ataxia. Whole exome sequencing identified compound heterozygous variants in UCHL1, c.533G > A (p.Arg178Gln) and c.647C > A (p.Ala216Asp), cosegregating with the phenotype. Enzymatic activity of purified recombinant proteins analysed by ubiquitin hydrolase assays showed a 4-fold increased hydrolytic activity of the recombinant UCHL1 mutant Arg178Gln compared to wild type, whereas the Ala216Asp protein was insoluble. Structural 3D analysis of UCHL1 by computer modelling suggests that Arg178 is a rate-controlling residue in catalysis which is partly abolished in the Arg178Gln mutant and, consequently, the Arg178Gln mutant increases the enzymatic turnover. UCHL1 protein levels in fibroblasts measured by targeted mass spectrometry showed a total amount of UCHL1 in control fibroblasts about 4-fold higher than in the patients. Hence, studies of the identified missense variants reveal surprisingly different functional consequences as the insoluble Ala216Asp variant leads to loss of function, whereas the Arg178Gln leads to increased enzyme activity. The reported patients have remarkably preserved cognition, and we propose that the increased enzyme activity of the Arg178Gln variant offers a protective effect on cognitive function. This study establishes the importance of UCHL1 in neurodegeneration, provides new mechanistic insight about ubiquitin processing, and underlines the complexity of the different roles of UCHL1.

Exogenous Melatonin and Abscisic Acid Expedite the Flavonoids Biosynthesis in Grape Berry of Vitis vinifera cv. Kyoho.

Grape polyphenols contributing to more than half of the global polyphenol market were well studied; however, how melatonin (MLT), a potential plant hormone, and abscisic acid (ABA) affects polyphenols profile is still poorly understood. To explore whether these hormones are involved in polyphenolic biosynthesis, grape (Vitis vinifera cv. Kyoho) was exposed to MLT, ABA, and NDGA (nordihydroguaiaretic acid, an ABA biosynthesis inhibitor) treatments, and 16 polyphenols were identified from grape extracts by high performance liquid chromatography quadrupole time of flight mass spectrometry (HPLC-Q-TOF-MS). Both exogenous MLT and ABA significantly enhanced the biosynthesis of each flavonol and flavanol component, especially catechin, which was almost increased double by 200 µM of MLT treatment. Furthermore, the expression of genes involved in flavonoid biosynthesis, including 4-coumaroyl-CoA synthase, chalcone synthase, flavonoid 3'-hydroxylase, anthocyanin 3'-methyltransferase, flavonol synthase, flavonoid-3-O-glucosyltransferase, and flavonoid 3',5'-methyltransferase were highly up-regulated as well but were down-regulated by NDGA. The present study provided new insights for improving flavonoids accumulation in agricultural production and its underlying mechanism.