The role of anoctamin 1 in liver disease.

Liver diseases include all types of viral hepatitis, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), cirrhosis, liver failure (LF) and hepatocellular carcinoma (HCC). Liver disease is now one of the leading causes of disease and death worldwide, which compels us to better understand the mechanisms involved in the development of liver diseases. Anoctamin 1 (ANO1), a calcium-activated chloride channel (CaCC), plays an important role in epithelial cell secretion, proliferation and migration. ANO1 plays a key role in transcriptional regulation as well as in many signalling pathways. It is involved in the genesis, development, progression and/or metastasis of several tumours and other diseases including liver diseases. This paper reviews the role and molecular mechanisms of ANO1 in the development of various liver diseases, aiming to provide a reference for further research on the role of ANO1 in liver diseases and to contribute to the improvement of therapeutic strategies for liver diseases by regulating ANO1.

Steering Electron-Induced Surface Reaction via a Molecular Assembly Approach.

Electrons not only serve as a "reactant" in redox reactions but also play a role in "catalyzing" some chemical processes. Despite the significance and ubiquitousness of electron-induced chemistry, many related scientific issues still await further exploration, among which is the impact of molecular assembly. In this work, microscopic insights into the vital role of molecular assembly in tweaking the electron-induced surface chemistry are unfolded by combined scanning tunneling microscopy and density functional theory studies. It is shown that the selective dissociation of a C-Cl bond in 4,4″-dichloro-1,1':3',1''-terphenyl (DCTP) on Cu(111) can be efficiently triggered by an electron injection via the STM tip into the unoccupied molecular orbital. The DCTP molecules are embedded in different assembly structures, including its self-assembly and coassemblies with Br adatoms. The energy threshold for the C-Cl bond cleavage increases as more Br adatoms stay close to the molecule, indicative of the sensitive response of the electron-induced surface reactivity of the C-Cl bond to the subtle change in the molecular assembly. Such a phenomenon is rationalized by the energy shift of the involved unoccupied molecular orbital of DCTP that is embedded in different assemblies. These findings shed new light on the tuning effect of molecular assembly on electron-induced reactions and introduce an efficient approach to precisely steer surface chemistry.

Unzipping Carbon Nanotubes to Sub-5-nm Graphene Nanoribbons on Cu(111) by Surface Catalysis.

Graphene nanoribbons (GNRs) are promising in nanoelectronics for their quasi-1D structures with tunable bandgaps. The methods for controllable fabrication of high-quality GNRs are still limited. Here a way to generate sub-5-nm GNRs by annealing single-walled carbon nanotubes (SWCNTs) on Cu(111) is demonstrated. The structural evolution process is characterized by low-temperature scanning tunneling microscopy. Substrate-dependent measurements on Au(111) and Ru(0001) reveal that the intermediate strong SWCNT-surface interaction plays a pivotal role in the formation of GNRs.

UBE2D1 promotes glioblastoma proliferation by modulating p21 ubiquitination.

Glioblastoma (GBM) cells exhibit aberrant proliferative abilities and resistance to conventional therapies. However, the mechanisms underlying these malignant phenotypes are poorly understood. In this study, we identified ubiquitin-conjugating enzyme E2D1 (UBE2D1) as a crucial stimulator of GBM development. It is highly expressed in GBM and closely associated with poor prognosis in patients with GBM. UBE2D1 knockdown inhibits GBM cell growth and leads to G1 cell cycle arrest. Mechanistically, UBCH5A binds to p21 at the protein level and induces the ubiquitination and degradation of p21. This negative regulation is mediated by STUB1. Our findings are the first to identify UBE2D1 as a key driver of GBM growth and provide a potential target for improving prognosis and therapy.

Prognostic value and immunological role of PD-L1 gene in pan-cancer.

OBJECTIVE: PD-L1, a target of immune checkpoint blockade, has been proven to take the role of an oncogene in most human tumors. However, the role of PD-L1 in human pan-cancers has not yet been fully investigated. MATERIALS AND METHODS: Pan-cancer analysis was conducted to analyze expression, genetic alterations, prognosis analysis, and immunological characteristics of PD-L1. Estimating the correlation between PD-L1 expression and survival involved using pooled odds ratios and hazard ratios with 95% CI. The Kaplan-Meier (K-M) technique, COX analysis, and receiver operating characteristic (ROC) curves were applied to the survival analysis. Additionally, we investigated the relationships between PD-L1 and microsatellite instability (MSI), tumor mutational burden (TMB), DNA methyltransferases (DNMTs), the associated genes of mismatch repair (MMR), and immune checkpoint biomarkers using Spearman's correlation analysis. Also, immunohistochemical analysis and qRT-PCR were employed in evaluating PD-L1's protein and mRNA expression in pan-caner. RESULTS: PD-L1 showed abnormal mRNA and protein expression in a variety of cancers and predicted prognosis in cancer patients. Furthermore, across a variety of cancer types, the aberrant PD-L1 expression was connected to the MSI, MMR, TMB, drug sensitivity, and tumor immune microenvironment (TIME). Moreover, PD-L1 was significantly correlated with infiltrating levels of immune cells (T cell CD8 + , neutrophil, and so on). CONCLUSION: Our study provides a better theoretical basis and guidance for the clinical treatment of PD-L1.

Composition, Release, and Transformation of Earthworm Tissue-Bound Residues of Tetrabromobisphenol A in Soil.

Earthworms accumulate organic pollutants to form earthworm tissue-bound residues (EBRs); however, the composition and fate of EBRs in soil remain largely unknown. Here, we investigated the fate of tetrabromobisphenol A (TBBPA)-derived EBRs in soil for 250 days using a 14C-radioactive isotope tracer and the geophagous earthworm Metaphire guillelmi. The EBRs of TBBPA in soil were rapidly transformed into nonextractable residues (NERs), mainly in the form of sequestered and ester-linked residues. After 250 days of incubation, 4.9% of the initially applied EBRs were mineralized and 69.3% were released to extractable residues containing TBBPA and its transformation products (TPs, generated mainly via debromination, O-methylation, and skeletal cleavage). Soil microbial activity and autolytic enzymes of earthworms jointly contributed to the release process. In their full-life period, the earthworms overall retained 24.1% TBBPA and its TPs in soil and thus prolonged the persistence of these pollutants. Our study explored, for the first time, the composition and fate of organic pollutant-derived EBRs in soil and indicated that the decomposition of earthworms may release pollutants and cause potential environmental risks of concern, which should be included in both environmental risk assessment and soil remediation using earthworms.

Intravenous immunoglobulin for treatment of hospitalized COVID-19 patients: an evidence mapping and meta-analysis.

BACKGROUND: The clinical efficacy and safety of intravenous immunoglobulin (IVIg) treatment for COVID-19 remain controversial. This study aimed to map the current status and gaps of available evidence, and conduct a meta-analysis to further investigate the benefit of IVIg in COVID-19 patients. METHODS: Electronic databases were searched for systematic reviews/meta-analyses (SR/MAs), primary studies with control groups, reporting on the use of IVIg in patients with COVID-19. A random-effects meta-analysis with subgroup analyses regarding study design and patient disease severity was performed. Our outcomes of interest determined by the evidence mapping, were mortality, length of hospitalization (days), length of intensive care unit (ICU) stay (days), number of patients requiring mechanical ventilation, and adverse events. RESULTS: We included 34 studies (12 SR/MAs, 8 prospective and 14 retrospective studies). A total of 5571 hospitalized patients were involved in 22 primary studies. Random-effects meta-analyses of very low to moderate evidence showed that there was little or no difference between IVIg and standard care or placebo in reducing mortality (relative risk [RR] 0.91; 95% CI 0.78-1.06; risk difference [RD] 3.3% fewer), length of hospital (mean difference [MD] 0.37; 95% CI - 2.56, 3.31) and ICU (MD 0.36; 95% CI - 0.81, 1.53) stays, mechanical ventilation use (RR 0.92; 95% CI 0.68-1.24; RD 2.8% fewer), and adverse events (RR 0.98; 95% CI 0.84-1.14; RD 0.5% fewer) of patients with COVID-19. Sensitivity analysis using a fixed-effects model indicated that IVIg may reduce mortality (RR 0.76; 95% CI 0.60-0.97), and increase length of hospital stay (MD 0.68; 95% CI 0.09-1.28). CONCLUSION: Very low to moderate certainty of evidence indicated IVIg may not improve the clinical outcomes of hospitalized patients with COVID-19. Given the discrepancy between the random- and fixed-effects model results, further large-scale and well-designed RCTs are warranted.

Assembling Surface Molecular Sierpinski Triangle Fractals via K+-Invoked Electrostatic Interaction.

Molecular Sierpinski triangles (STs), a family of elegant and well-known fractals, can be prepared on surfaces with atomic precision. Up to date, several kinds of intermolecular interactions such as hydrogen bond, halogen bond, coordination, and even covalent bond have been employed to construct molecular STs on metal surfaces. Herein a series of defect-free molecular STs have been fabricated via electrostatic attraction between potassium cations and electronically polarized chlorine atoms in 4,4″-dichloro-1,1':3',1″-terphenyl (DCTP) molecules on Cu(111) and Ag(111). The electrostatic interaction is confirmed both experimentally by scanning tunneling microscopy and theoretically by density functional theory calculations. These findings illustrate that electrostatic interaction can serve as an efficient driving force to construct molecular fractals, which enriches our toolbox for the bottom-up fabrication of complex functional supramolecular nanostructures.

CircGNB1 facilitates the malignant phenotype of GSCs by regulating miR-515-5p/miR-582-3p-XPR1 axis.

Glioma is the most common and aggressive primary malignant brain tumor. Circular RNAs (circRNAs) and RNA-binding proteins (RBPs) have been verified to mediate diverse biological behaviors in various human cancers. Therefore, the aim of this study was to explore a novel circRNA termed circGNB1 and elucidate relative molecular mechanism in functional phenotypes, which might be a potential prognostic biomarker and therapeutic approach for glioma. CircGNB1 was upregulated in glioma and closely associated with the low poor prognosis. Functional assays demonstrated that circGNB1 overexpression promoted glioma stem cells (GSCs) viability proliferation, invasion, and neurosphere formation. Mechanistically, circGNB1 upregulated the expression of oncogene XPR1 via sponging miR-515-5p and miR-582-3p. The following experiments proved XPR1 could promote the malignant phenotype of GSCs via upregulating IL6 expression and activating JAK2/STAT3 signaling. Moreover, the RNA binding protein IGF2BP3 could bind to and maintain the stability of circGNB1, thus promoting the effects of circGNB1 on GSCs. Our study reveals that circGNB1 plays a crucial role in promoting tumorigenesis and malignant progression in glioma, which provides a promising cancer biomarker.

Comprehensive analysis of the role of ICOS ( CD278 ) in pan-cancer prognosis and immunotherapy.

BACKGROUND: The immunological checkpoint known as Inducible T Cell Costimulatory Factor (ICOS, Cluster of Differentiation, CD278) is activated and expressed on T cells. Both somatic cells and antigen-presenting cells expressed its ligand, ICOSL (including tumor cells in the tumor microenvironment).It is important for immunosuppression. Uncertainty surrounds the function of ICOS in tumor immunity. METHODS: Several bioinformatics techniques were employed by us to thoroughly examine the expression and prognostic value of ICOS in 33 cancers based on data collected from TCGA and GTEx. In addition, ICOS was explored with pathological stage, tumor-infiltrating cells, immune checkpoint genes, mismatch repair (MMR) genes, DNA methyltransferases (DNMTs), microsatellite instability (MSI),and tumor mutation burden (TMB).In addition,To ascertain the level of ICOS expression in various cells, qRT-PCR was employed. RESULTS: The findings revealed that ICOS expression was up regulation in most cancer types. The high expression of ICOS in tumor samples was related to the poor prognosis of UVM and LGG; The positive prognosis was boosted by the strong expression of ICOS in OV, SARC, SKCM, THYM, UCEC, and HNSC. The result is that the expression of malignancy was revealed by the immune cells' invasion.profile of ICOS in different types of cancer. Different ways that ICOS expression is connected to immune cell infiltration account for variations in patient survival. Additionally, the TMB, MSI, MMR, and DNMT genes as well as ICOS expression are linked in many cancer types.The results of PCR showed that it is highly expressed in gastric, breast, liver and renal cell carcinoma cell lines compared with normal cells. CONCLUSION: This study suggests that ICOS may be a potential tumor immunotherapy target and prognostic marker.

Transition-Metal-Free Approach to Acridone Derivatives by TBHP-Promoted Oxidative Annulation of Isatins with Arynes.

A tert-butyl hydroperoxide-promoted oxidative annulation reaction of isatins with 2-(trimethylsilyl)aryl triflates for the convenient synthesis of acridone derivatives has been established. Mechanistic investigation suggested that the reaction may proceed via consecutive Baeyer-Villiger-type rearrangement followed by an intermolecular cyclization. This synthetic approach offers several advantages, including broad substrate scope, good functional group tolerance, and simplicity of operation. Additionally, successful late-stage modification of the obtained compounds was achieved, expanding the application potential of this methodology in organic synthesis.

Zhongfeng Capsules protects against cerebral ischemia-reperfusion injury via mediating the phosphoinositide 3-kinase/Akt and toll-like receptor 4/nuclear factor kappa B signaling pathways by regulating neuronal apoptosis and inflammation.

Inflammatory reaction and neuronal apoptosis are the major pathophysiological mechanisms involved in cerebral ischemia-reperfusion injury (CI/RI). It has been reported that Zhongfeng Capsules (ZFCs), which contain Panax notoginseng, Hirudo, Red ginseng, Eupolyphaga sinensis, Pangolin scales, Rhubarb, and Radix Salvia miltiorrhizae, have a definite therapeutic effect on CI/RI. However, the specific molecular mechanisms of ZFCs are unclear. In this study, the effects of ZFCs on middle cerebral artery occlusion were investigated in rats. Our results showed that neurological impairment and neuronal apoptosis were alleviated in ZFC-treated rats. Additionally, infarct volume and cerebral edema decreased and there was an improvement in histopathological features. Furthermore, the expression levels of IL-1ß, IL-6, and TNF-α were downregulated in ZFC-treated rats. TLR 4, NF-κB, Bax, and Caspase-3 expression also tended to decrease, whereas the expression of Bcl-2, p-PI3K, p-Akt, and I-κBα increased. The results indicate that the ZFCs effectively protected the rats against CI/RI possibly via the TLR4/NF-κB signaling pathway. Additionally, the formulation regulated the transcriptional activity of NF-κB, secretion of downstream inflammatory factors, and the expression of Bcl-2-Bax proteins in the PI3K/Akt pathway. Our findings suggest that ZFCs suppress neuronal apoptosis and inflammatory reaction via the PI3K/Akt and TLR4/NF-κB signaling pathways, respectively. Moreover, activation of the PI3K/Akt pathway may result in the inhibition of proinflammatory cytokine secretion, which may be another mechanism by which ZFCs alleviate CI/RI.

All-Nanofiber-Based Janus Epidermal Electrode with Directional Sweat Permeability for Artifact-Free Biopotential Monitoring.

Epidermal electronics have been developed with gas/sweat permeability for long-term wearable electrophysiological monitoring. However, the state-of-the-art breathable epidermal electronics ignore the sweat accumulation and immersion at the skin/device interface, resulting in serious degradation of the interfacial conformality and adhesion, leading to signal artifacts with unstable and inaccurate biopotential measurements. Here, the authors present an all-nanofiber-based Janus epidermal electrode endowed with directional sweat transport properties for artifact-free biopotential monitoring. The designed Janus multilayered membrane (≈15 µm) of superhydrophilic-hydrolyzed-polyacrylonitrile (HPAN)/polyurethane (PU)/Ag nanowire (AgNW) can quickly (less than 5 s) drive sweat away from the skin/electrode interface while resisting its penetration in the reverse direction. Along with the medical adhesive (MA)-reinforced junction-nodes, the adhesion strength among the heterogeneous interfaces can be greatly enhanced for robust mechanical-electrical stability. Therefore, their measured on-body electromyography (EMG) and electrocardiography (ECG) signals are free of sweat artifacts with negligible degradation and baseline drift compared to commercial Ag/AgCl gel electrodes and hydrophilic textile electrodes. This work paves a way to design novel directional-sweat-permeable epidermal electronics that can be conformally attached under sweaty conditions for long-term biopotential monitoring and shows the potential to apply epidermal electronics to many challenging conditions.

Observation of Biradical Spin Coupling through Hydrogen Bonds.

Investigation of intermolecular electron spin interaction is of fundamental importance in both science and technology. Here, radical pairs of all-trans retinoic acid molecules on Au(111) are created using an ultralow temperature scanning tunneling microscope. Antiferromagnetic coupling between two radicals is identified by magnetic-field-dependent spectroscopy. The measured exchange energies are from 0.1 to 1.0 meV. The biradical spin coupling is mediated through O─H⋯O hydrogen bonds, as elucidated from analysis combining density functional theory calculation and a modern version of valence bond theory.

LncCDCA3L inhibits cell proliferation via a novel RNA structure-based crosstalk with CDCA3 in hepatocellular carcinoma.

BACKGROUND & AIMS: The molecular mechanisms underlying hepatocellular carcinoma (HCC) remain poorly understood. In this study, we investigated cell division cycle-associated 3 (CDCA3) expression status and characterized a CDCA3-related long non-coding RNA (lncRNA) in HCC. METHODS: RT-qPCR and western blot were used to determine CDCA3 expression level in HCC clinical specimens. 5' and 3'-RACE, RNAscope, RNA pull-down, CRISPR/Cas9-based RNA immunoprecipitation (CRIP) and site-directed mutation experiments were used to characterize lncCDCA3L and investigate its function target. Chi-square test and Kaplan-Meier analysis were used to assess lncCDCA3L clinical significance. The effects of lncCDCA3L on HCC development were assessed by overexpression in vitro and in vivo. RESULTS: In this study, we found CDCA3 was a potential oncogenic factor in HCC and characterized the lncCDCA3L, which could inhibit CDCA3. LncCDCA3L is significantly downregulated in HCC and its expression level is associated with tumour size and can act as an independent risk factor affecting postoperative survival time in HCC patients. Mechanistically, lncCDCA3L can repress CDCA3 protein level and inhibit hepatocarcinogenesis by directly binding to CDCA3 mRNA at 1423-1455 region via a novel manner based on a hairpin structure motif. CONCLUSIONS: Our study collectively unveiled the molecular mechanisms of how lncCDCA3L repressed the tumourigenic properties of HCC cells and exhibited a tumour suppressor character in HCC in a CDCA3-dependent manner. The findings here support lncCDCA3L can be used as a candidate prognostic biomarker for HCC patients.

Robust covalent pyrazine anchors forming highly conductive and polarity-tunable molecular junctions with carbon electrodes.

In molecular electronics, electrode-molecule anchoring strategies play a crucial role in the design of stable and high-performance functional single-molecule devices. Herein, we employ aromatic pyrazine as anchors to connect a central anthracene molecule to carbon electrodes including graphene and armchair single-walled carbon nanotubes (SWCNTs), and theoretically investigate their atomic structures and electronic transport properties. These molecular junctions can be constructed via condensation reactions of the central molecules terminated with ortho-phenylenediamines with ortho-quinone-functionalized nanogaps of graphene and SWCNT electrodes. With two direct C-N covalent bonds connecting the central molecule site-selectively to carbon electrodes in a coplanar way, pyrazine anchors are advantageous for forming stable and structurally well-defined molecular junctions, being expected to reduce the uncertainty about the electrode-molecule linkage motifs. The junction transport is highly efficient due to the coplanar geometry and the ensuing strong π-type molecule-electrode electronic coupling. Furthermore, our calculations show that molecular junctions with pyrazine anchors and carbon electrodes are usually n-type electronic devices; upon hydrogenation of pyridinic nitrogen atoms, the device polarity can be tuned to p-type, indicating that the pyrazine anchors can also serve as a powerful platform for tailoring in situ the polarity of charge carriers in carbon-electrode molecular electronic devices.

Effect of Cu2+ on the Laccase-Inducted Formation of Non-Extractable Residues of Tetrabromobisphenol A in Humic Acids.

We used 14 C-radiolabelling to study the non-extractable residues (NERs) formation of tetrabromobisphenol A (TBBPA) in a humic acid (HA) suspension under catalysis of laccase in the presence of copper. When entering the suspension after TBBPA adsorbing to HA supramolecular associates, Cu2+ at low concentrations (even without toxicity to laccase) significantly reduced the amount and first-order kinetic constant of the NER formation, while Cu2+ had no significant effect on the formation after it was complexed with HA. The inhibition effect of Cu2+ on the NER formation is explained to be attributed to the prevention of laccase-induced oxidation of TBBPA in the voids of HA associates by complexation of Cu2+ with periphery molecules of the associates. The results provide insights into varying effects of heavy metals on the environmental fate of organic contaminants and suggest that co-existing heavy metals could increase their environmental risk by reducing their NER formation.

Packing Biomolecules into Sierpinski Triangles with Global Organizational Chirality.

Fractals are found in nature and play important roles in biological functions. However, it is challenging to controllably prepare biomolecule fractals. In this study, a series of Sierpinski triangles with global organizational chirality is successfully constructed by the coassembly of l-tryptophan and 1,3-bi(4-pyridyl)benzene molecules on Ag(111). The chirality is switched when replacing l-tryptophan by d-tryptophan. The fractal structures are characterized by low-temperature scanning tunneling microscopy at the single-molecule level. Density functional theory calculations reveal that intermolecular hydrogen bonds stabilize the Sierpinski triangles.

Identification of WRKY transcription factors responding to abiotic stresses in Brassica napus L.

MAIN CONCLUSION: A total of 278 BnWRKYs were identified and analyzed. Ectopic expression of BnWRKY149 and BnWRKY217 suggests that they function in the ABA signaling pathway. WRKY transcription factors play an important role in plant development, however, their function in Brassica napus L. abiotic stress response is still unclear. In this study, a total of 278 BnWRKY transcription factors were identified from the B. napus genome data, and they were subsequently distributed in three main groups. The protein motifs and classification of BnWRKY transcription factors were analyzed, and the locations of their corresponding encoding genes were mapped on the chromosomes of B. napus. Transcriptome analysis of rapeseed seedlings exposed to drought, salt, heat, cold and abscisic acid treatment revealed that 99 BnWRKYs responded to at least one of these stresses. The expression profiles of 12 BnWRKYs were examined with qPCR and the result coincided with RNA-seq analysis. Two genes of interest, BnWRKY149 and BnWRKY217 (homologs of AtWRKY40), were overexpressed in Arabidopsis, and the corresponding proteins were located to the nucleus. Transgene plants of BnWRKY149 and BnWRKY217 were less sensitive to ABA than Arabidopsis Col-0 plants, suggesting they might play important roles in the responses of rapeseed to abiotic stress.

Using Weakly Supervised Deep Learning to Classify and Segment Single-Molecule Break-Junction Conductance Traces.

In order to design molecular electronic devices with high performance and stability, it is crucial to understand their structure-to-property relationships. Single-molecule break junction measurements yield a large number of conductance-distance traces, which are inherently highly stochastic. Here we propose a weakly supervised deep learning algorithm to classify and segment these conductance traces, a method that is mainly based on transfer learning with the pretrain-finetune technique. By exploiting the powerful feature extraction capabilities of the pretrained VGG-16 network, our convolutional neural network model not only achieves high accuracy in the classification of the conductance traces, but also segments precisely the conductance plateau from an entire trace with very few manually labeled traces. Thus, we can produce a more reliable estimation of the junction conductance and quantify the junction stability. These findings show that our model has achieved a better accuracy-to-manpower efficiency balance, opening up the possibility of using weakly supervised deep learning approaches in the studies of single-molecule junctions.