Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural Basis of Ca2+-Dependent Self-Processing Activity of Repeat-in-Toxin Proteins

The Ca2+-dependent clip-and-link activity of large repeat-in-toxin (RTX) proteins is an exceptional posttranslational process in which an internal domain called a self-processing module (SPM) mediates Ca2+-dependent processing of a highly specific aspartate-proline (Asp-Pro) peptide bond and covalent linkage of the released aspartyl to an adjacent lysine residue through an isopeptide bond. Here, we report the solution structures of the Ca2+-loaded SPM (Ca-SPM) defining the mechanism of the autocatalytic cleavage of the Asp414-Pro415 peptide bond of the Neisseria meningitidis FrpC exoprotein. Moreover, deletion of the SPM domain in the ApxIVA protein, the FrpC homolog of Actinobacillus pleuropneumoniae, resulted in attenuation of virulence of the bacterium in a pig infection model, indicating that the Ca2+-dependent clip-and-link activity plays a role in the virulence of Gram-negative pathogens. ABSTRACT The posttranslational Ca2+-dependent “clip-and-link” activity of large repeat-in-toxin (RTX) proteins starts by Ca2+-dependent structural rearrangement of a highly conserved self-processing module (SPM). Subsequently, an internal aspartate-proline (Asp-Pro) peptide bond at the N-terminal end of SPM breaks, and the liberated C-terminal aspartyl residue can react with a free ε-amino group of an adjacent lysine residue to form a new isopeptide bond. Here, we report a solution structure of the calcium-loaded SPM (Ca-SPM) derived from the FrpC protein of Neisseria meningitidis. The Ca-SPM structure defines a unique protein architecture and provides structural insight into the autocatalytic cleavage of the Asp-Pro peptide bond through a “twisted-amide” activation. Furthermore, in-frame deletion of the SPM domain from the ApxIVA protein of Actinobacillus pleuropneumoniae attenuated the virulence of this porcine pathogen in a pig respiratory challenge model. We hypothesize that the Ca2+-dependent clip-and-link activity represents an unconventional strategy for Gram-negative pathogens to adhere to the host target cell surface. IMPORTANCE The Ca2+-dependent clip-and-link activity of large repeat-in-toxin (RTX) proteins is an exceptional posttranslational process in which an internal domain called a self-processing module (SPM) mediates Ca2+-dependent processing of a highly specific aspartate-proline (Asp-Pro) peptide bond and covalent linkage of the released aspartyl to an adjacent lysine residue through an isopeptide bond. Here, we report the solution structures of the Ca2+-loaded SPM (Ca-SPM) defining the mechanism of the autocatalytic cleavage of the Asp414-Pro415 peptide bond of the Neisseria meningitidis FrpC exoprotein. Moreover, deletion of the SPM domain in the ApxIVA protein, the FrpC homolog of Actinobacillus pleuropneumoniae, resulted in attenuation of virulence of the bacterium in a pig infection model, indicating that the Ca2+-dependent clip-and-link activity plays a role in the virulence of Gram-negative pathogens.
lncRNA CASC2 downregulation participates in rheumatoid arthritis, and CASC2 overexpression promotes the apoptosis of fibroblast-like synoviocytes by downregulating IL-17

lncRNA cancer susceptibility candidate 2 (CASC2) is a recently identified oncogenic lncRNA in different types of cancers. Our preliminary microarray data showed that lncRNA CASC2 was downregulated in the plasma of patients with rheumatoid arthritis (RA), indicating the involvement of this lncRNA in RA. In the present study, lncRNA CASC2 and IL-17 in plasma were detected by reverse transcription--quantitative PCR and ELISA, respectively. Diagnostic analyses were performed using receiver operating characteristic curves. Flow cytometry was performed to evaluate cell apoptosis. The effects of lncRNA CASC2 on IL-17 expression were determined via western blotting. lncRNA CASC2 was found to be downregulated, while IL-17 was upregulated in the plasma of RA patients when compared with these levels in the plasma of healthy controls. Plasma levels of lncRNA CASC2 and IL-17 were significantly and inversely correlated in both RA patients and healthy controls. Altered plasma levels of lncRNA CASC2 and IL-17 were able to differentiate RA patients from healthy controls. Overexpression of lncRNA CASC2 promoted, while treatment with IL-17 inhibited the apoptosis of human fibroblast-like synoviocytes (HFLSs) isolated from RA patients. Overexpression of lncRNA CASC2 inhibited IL-17 expression in HFLS, while treatment with IL-17 did not significantly affect the expression of lncRNA CASC2. Therefore, downregulation of lncRNA CASC2 is involved in RA and lncRNA CASC2 overexpression may promote the apoptosis of HFLS by downregulating IL-17.
Reveals of New Candidate Active Components in Hemerocallis Radix and Its Anti-Depression Action of Mechanism Based on Network Pharmacology Approach

The global depression population is showing a significant increase. Hemerocallis fulva L. is a common Traditional Chinese Medicine (TCM). Its flower buds are known to have ability to clear away heat and dampness, detoxify, and relieve depression. Ancient TCM literature shows that its roots have a beneficial effect in calming the spirit and even the temper in order to reduce the feeling of melancholy. Therefore, it is inferred that the root of Hemerocallis fulva L. can be used as a therapeutic medicine for depression. This study aims to uncover the pharmacological mechanism of the antidepressant effect of Hemerocallis Radix (HR) through network pharmacology method. During the analysis, 11 active components were obtained and screened using ADME—absorption, distribution, metabolism, and excretion— method. Furthermore, 267 HR targets and 740 depressive disorder (DD) targets were gathered from various databases. Then protein–protein interaction (PPI) network of HR and DD targets were constructed and cluster analysis was applied to further explore the connection between the targets. In addition, gene ontology (GO) enrichment and pathway analysis was applied to further verify that the biological process related to the target protein is associated with the occurrence of depression disorder. In conclusion, the most important bioactive components—anthraquinone, kaempferol, and vanillic acid—can alleviate depression symptoms by regulating MAOA, MAOB, and ESR1. The proposed network pharmacology strategy provides an integrating method to explore the therapeutic mechanism of multi-component drugs on a systematic level.
Design of a Functionalized Metal–Organic Framework System for Enhanced Targeted Delivery to Mitochondria

Mitochondria play a key role in oncogenesis and constitute one of the most important targets for cancer treatments. Although the most effective way to deliver drugs to mitochondria is by covalently linking them to a lipophilic cation, the in vivo delivery of free drugs still constitutes a critical bottleneck. Herein, we report the design of a mitochondria-targeted metal–organic framework (MOF) that greatly increases the efficacy of a model cancer drug, reducing the required dose to less than 1% compared to the free drug and ca. 10% compared to the nontargeted MOF. The performance of the system is evaluated using a holistic approach ranging from microscopy to transcriptomics. Super-resolution microscopy of MCF-7 cells treated with the targeted MOF system reveals important mitochondrial morphology changes that are clearly associated with cell death as soon as 30 min after incubation. Whole transcriptome analysis of cells indicates widespread changes in gene expression when treated with the MOF system, specifically in biological processes that have a profound effect on cell physiology and that are related to cell death. We show how targeting MOFs toward mitochondria represents a valuable strategy for the development of new drug delivery systems.
Deoxynivalenol Induces Inflammation in IPEC-J2 Cells by Activating P38 Mapk And Erk1/2

Fusarium-derived mycotoxin deoxynivalenol (DON) usually induces diarrhea, vomiting and gastrointestinal inflammation. We studied the cytotoxic effect of DON on porcine small intestinal epithelium using the intestinal porcine epithelial cell line IPEC-J2. We screened out differentially expressed genes (DEGs) using RNA-seq and identified 320 upregulated genes and 160 downregulated genes. The enrichment pathways of these DEGs focused on immune-related pathways. DON induced proinflammatory gene expression, including cytokines, chemokines and other inflammation-related genes. DON increased IL1A, IL6 and TNF-α release and DON activated the phosphorylation of extracellular signal-regulated kinase-1 and-2 (ERK1/2), JUN N-terminal kinase (JNK) and p38 MAPK. A p38 inhibitor attenuated DON-induced IL6, TNF-α, CXCL2, CXCL8, IL12A, IL1A, CCL20, CCL4 and IL15 production, while an ERK1/2 inhibitor had only a small inhibitory effect on IL15 and IL6. An inhibitor of p38 MAPK decreased the release of IL1A, IL6 and TNF-α and an inhibitor of ERK1/2 partly attenuated protein levels of IL6. These data demonstrate that DON induces proinflammatory factor production in IPEC-J2 cells by activating p38 and ERK1/2.
Effects of cisplatin on the proliferation, invasion and apoptosis of breast cancer cells following β-catenin silencing

Resistance to the chemotherapeutic drug cisplatin has been documented in various types of cancer, while the increased expression of β-catenin has been observed in cisplatin-resistant ovarian cancer. However, the involvement of β-catenin in cisplatin resistance is unclear. The present study investigated the antitumor effect of cisplatin on the proliferation, invasion and apoptosis of breast cancer (BC) cells following β-catenin silencing in BC, which is the most frequent type of malignancy among women. The expression of β-catenin in BC tissues and cell lines was measured by reverse transcription-quantitative polymerase chain reaction, and the association between expression levels and clinical characteristics was statistically analyzed. The viability of BC cell lines treated with siR-β-catenin or with siR-β-catenin and cisplatin in combination was determined using a Cell Counting Kit-8 assay. The migratory and invasive abilities of BC cells treated with both siR-β-catenin and cisplatin were examined with Transwell assays. The CD44 antigen/intercellular adhesion molecule 1 expression ratio, cell cycle distribution and apoptosis levels of BC cells treated with siR-β-catenin and cisplatin in combination were detected by flow cytometry. The expression levels of apoptosis-associated proteins, including caspase-3/9, in the BC cells treated with both siR-β-catenin and cisplatin were investigated by western blot analysis. The levels of apoptosis in the BC cells following combined treatment with siR-β-catenin and cisplatin was further quantified by Hoechst 33342 staining. β-catenin was identified to be highly expressed in BC tissues and cell lines and was associated with pathological stage and lymph node status. Following knockdown of β-catenin expression, cisplatin treatment suppressed the viabilities, and the migratory and invasive capabilities of the T47D and MCF-7 cells, and induced extensive apoptosis. β-catenin knockdown upregulated caspase-3/9 levels following cisplatin treatment and induced the apoptosis of T47D and MCF-7 cells. In conclusion, β-catenin may be of value as a therapeutic target during cisplatin treatment in patients with BC treated with cisplatin.
Mechanical, Thermal and Rheological Properties of Polyethylene-Based Composites Filled with Micrometric Aluminum Powder

Investigations related to polymer/metal composites are often limited to the analysis of the electrical and thermal conductivity of the materials. The presented study aims to analyze the impact of aluminum (Al) filler content (from 1 to 20 wt%) on the rarely investigated properties of composites based on the high-density polyethylene (HDPE) matrix. The crystalline structure, rheological (melt flow index and oscillatory rheometry), thermal (differential scanning calorimetry), as well as static (tensile tests, hardness, rebound resilience) and dynamic (dynamical mechanical analysis) mechanical properties of composites were investigated. The incorporation of 1 and 2 wt% of aluminum filler resulted in small enhancements of mechanical properties, while loadings of 5 and 10 wt% provided materials with a similar performance to neat HDPE. Such results were supported by the lack of disturbances in the rheological behavior of composites. The presented results indicate that a significant content of aluminum filler may be introduced into the HDPE matrix without additional pre-treatment and does not cause the deterioration of composites’ performance, which should be considered beneficial when engineering PE/metal composites.
A Multi-Static Radar Network with Ultra-Wideband Radio-Equipped Devices

A growing number of devices, from car key fobs to mobile phones to WiFi-routers, are equipped with ultra-wideband radios. In the network formed by these devices, communicating modules often estimate the channel impulse response to employ a matched filter to decode transmitted data or to accurately time stamp incoming messages when estimating the time-of-flight for localization. This paper investigates how such measurements of the channel impulse response can be utilized to augment existing ultra-wideband communication and localization networks to a multi-static radar network. The approach is experimentally evaluated using off-the-shelf hardware and simple, distributed filtering, and shows that a tag-free human walking in the space equipped with ultra-wideband modules can be tracked in real time. This opens the door for various location-based smart home applications, ranging from smart audio and light systems to elderly monitoring and security systems.
ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, with many more potential applications under study and in clinical trials. Here, we discuss the potential for extending PARP inhibitor therapies to tumours with deficiencies in the DNA damage-activated protein kinase, Ataxia-Telangiectasia Mutated (ATM). We highlight our recent findings that PARP inhibition alone is cytostatic but not cytotoxic in ATM-deficient cancer cells and that the combination of a PARP inhibitor with an ATR (ATM, Rad3-related) inhibitor is required to induce cell death.
Proteomics Analysis Reveals that Warburg Effect along with Modification in Lipid Metabolism Improves In Vitro Embryo Development under Low Oxygen

The molecular mechanism regulating embryo development under reduced oxygen tension remains elusive. This study aimed to identify the molecular mechanism impacting embryo development under low oxygen conditions. Buffalo embryos were cultured under 5% or 20% oxygen and were evaluated according to their morphological parameters related to embryo development. The protein profiles of these embryos were compared using iTRAQ-based quantitative proteomics. Physiological O2 (5%) significantly promoted blastocyst yield, hatching rate, embryo quality and cell count as compared to atmospheric O2 (20%). The embryos in the 5% O2 group had an improved hatching rate of cryopreserved blastocysts post-warming (p < 0.05). Comparative proteome profiles of hatched blastocysts cultured under 5% vs. 20% O2 levels identified 43 differentially expressed proteins (DEPs). Functional analysis indicated that DEPs were mainly associated with glycolysis, fatty acid degradation, inositol phosphate metabolism and terpenoid backbone synthesis. Our results suggest that embryos under physiological oxygen had greater developmental potential due to the pronounced Warburg Effect (aerobic glycolysis). Moreover, our proteomic data suggested that higher lipid degradation, an elevated cholesterol level and a higher unsaturated to saturated fatty acid ratio might be involved in the better cryo-survival ability reported in embryos cultured under low oxygen. These data provide new information on the early embryo protein repertoire and general molecular mechanisms of embryo development under varying oxygen levels.
Dietary Iron Intake in Pregnant Women in Europe: A Review of 24 Studies from 14 Countries in the Period 1991–2014

Objective Assessment of dietary iron intake in pregnant women in Europe. Design Review. Setting. Literature search of dietary surveys reporting the intake of dietary iron using the PubMed and Google Scholar databases covering the years 1990–2019. Subjects Healthy pregnant women. Results 24 dietary surveys/studies in 14 European countries were included. Nine studies (38%) used Food Frequency Questionnaires, which yielded significantly higher iron intake than studies using Dietary Records. Results from Dietary Record studies in 11 countries showed that iron intake varied between 8.3–15.4 mg/day with an estimated “median” value of 10–11 mg/day. Spain, Bosnia, and Poland reported an intake of 8.3–10.1 mg/day, Croatia, England, Norway, and Finland an intake of 10.2–11.4 mg/day, and Germany, Portugal, Czech Republic, and Greece an intake of 12.2–15.4 mg/day. The recommended iron intake in the various countries varied from 14.8–30 mg/day. In all studies, 60–100% of the women had a dietary iron intake below the recommended intake. Conclusions In Europe, the majority of pregnant women have a dietary iron intake, which is markedly below the recommended intake. This contributes to a low iron status in many pregnant women. Most guidelines do not advice routine iron supplements, while two guidelines (World Health Organization and Nordic Nutrition Recommendations) recommend routine iron supplementation during pregnancy. Within the European community, we need to reach consensus on the various guidelines and on the issue of iron supplementation. We should establish common European standardized dietary methods, uniform Dietary Reference Values, and uniform statistical methods in order to perform more reliable comparisons between studies in different countries.
Evolution and Pathogenicity of the H1 and H3 Subtypes of Swine Influenza Virus in Mice between 2016 and 2019 in China

Pigs are considered a “mixing vessel” that can produce new influenza strains through genetic reassortments, which pose a threat to public health and cause economic losses worldwide. The timely surveillance of the epidemiology of the swine influenza virus is of importance for prophylactic action. In this study, 15 H1N1, one H1N2, and four H3N2 strains were isolated from a total of 4080 nasal swabs which were collected from 20 pig farms in three provinces in China between 2016 and 2019. All the isolates were clustered into four genotypes. A new genotype represented by the H1N2 strain was found, whose fragments came from the triple reassortant H1N2 lineage, classical swine influenza virus (cs-H1N1) lineage, and 2009 H1N1 pandemic virus lineage. A/Sw/HB/HG394/2018(H1N1), which was clustered into the cs-H1N1 lineage, showed a close relationship with the 1918 pandemic virus. Mutations determining the host range specificity were found in the hemagglutinin of all isolates, which indicated that all the isolates had the potential for interspecies transmission. To examine pathogenicity, eight isolates were inoculated into 6-week-old female BALB/c mice. The isolates replicated differently, producing different viral loadings in the mice; A/Swine/HB/HG394/2018(H1N1) replicated the most efficiently. This suggested that the cs-H1N1 reappeared, and more attention should be given to the new pandemic to pigs. These results indicated that new reassortments between the different strains occurred, which may increase potential risks to human health. Continuing surveillance is imperative to monitor swine influenza A virus evolution.
Identification of Long Noncoding RNA Associated ceRNA Networks in Rosacea

Rosacea is a chronic and relapsing inflammatory cutaneous disorder with highly variable prevalence worldwide that adversely affects the health of patients and their quality of life. However, the molecular characterization of each rosacea subtype is still unclear. Furthermore, little is known about the role of long noncoding RNAs (lncRNAs) in the pathogenesis or regulatory processes of this disorder. In the current study, we established lncRNA-mRNA coexpression networks for three rosacea subtypes (erythematotelangiectatic, papulopustular, and phymatous) and performed their functional enrichment analyses using Gene Onotology, KEGG, GSEA, and WGCNA. Compared to the control group, 13 differentially expressed lncRNAs and 525 differentially expressed mRNAs were identified in the three rosacea subtypes. The differentially expressed genes identified were enriched in four signaling pathways and the GO terms found were associated with leukocyte migration. In addition, we found nine differentially expressed lncRNAs in all three rosacea subtype-related networks, including NEAT1 and HOTAIR, which may play important roles in the pathology of rosacea. Our study provided novel insights into lncRNA-mRNA coexpression networks to discover the molecular mechanisms involved in rosacea development that can be used as future targets of rosacea diagnosis, prevention, and treatment.
Highly Sensitive THz Gas-Sensor Based on the Guided Bloch Surface Wave Resonance in Polymeric Photonic Crystals

THz waves have interesting applications in refractive index sensing. A THz gas sensor based on the guided Bloch surface wave resonance (GBSWR) in a one-dimensional photonic crystal (1DPhC), which consists of periodic polycarbonate (PC) layers and polyvinylidene fluoride (PVDF) layers, has been proposed. Numerical results based on finite element method (FEM) show that the photonic band gap that confines Bloch surface waves (BSWs) lies in the regime of 11.54 to 21.43 THz, in which THz wave can transmit in both PC and PVDF with the ignored absorption. The calculated sensitivity of hazardous gas HCN in angle is found to be 118.6°/RIU (and the corresponding figure of merit (FOM) is 227) and the sensitivity in frequency is 4.7 THz/RIU (the corresponding FOM is 301.3). The proposed structure may also be used for monitoring hazardous gases which show absorption to the incident THz wave. Further results show that for N2O gas, the maximum sensitivity goes up to 644 (transmittance unit/ one unit of the imaginary part of the refractive index). The proposed design may find applications in the detection of dangerous gases.