This study aimed to determine long non‐coding RNA (lncRNA) small nucleolar RNA host gene 14 (SNHG14) expression in pancreatic cancer and to explore the potential molecular actions of SNHG14 in ...mediating pancreatic cancer progression. Gene expression was detected by quantitative real‐time PCR. Cell proliferation, growth and invasion were detected by respective CCK‐8, colony formation, and transwell invasion assays. Protein levels were measured by Western blotting. Cell apoptosis and caspase‐3 activity were detected by flow cytometry and caspase‐3 activity assay. The link between miR‐613 and its targets was evaluated by luciferase reporter assay. In vivo tumour growth was evaluated using a xenograft model of nude mice. SNHG14 expression was up‐regulated in cancerous tissues from pancreatic cancer patients. High expression of SNHG14 was associated with poor tumour differentiation, advanced TNM stage and nodal metastasis. SNHG14 overexpression enhanced cell proliferative, growth and invasive abilities, and suppressed apoptotic rates and caspase‐3 activity in pancreatic cancer cells, while SNHG14 knockdown exerted opposite effects. Mechanistic studies revealed that miR‐613 was targeted by SNHG14, and Annexin A2 (ANXA2) was targeted and inversely regulated by miR‐613 in pancreatic cancer cells. In vivo studies showed that SNHG14 knockdown attenuated tumour growth. MiR‐613 was down‐regulated and ANXA2 was up‐regulated in the pancreatic cancer tissues, and SNHG14 expression levels were inversely correlated with miR‐613 expression levels and positively correlated with the ANXA2 mRNA expression levels. Collectively, our results suggest that SNHG14 potentiates pancreatic cancer progression through modulation of annexin A2 expression via acting as a competing endogenous RNA for miR‐613.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Sphingosine-1-phosphate receptor 1 (S1PR1) is a master regulator of lymphocyte egress from the lymph node and an established drug target for multiple sclerosis (MS). Mechanistically, therapeutic ...S1PR1 modulators activate the receptor yet induce sustained internalization through a potent association with β-arrestin. However, a structural basis of biased agonism remains elusive. Here, we report the cryo-electron microscopy (cryo-EM) structures of G
-bound S1PR1 in complex with S1P, fingolimod-phosphate (FTY720-P) and siponimod (BAF312). In combination with functional assays and molecular dynamics (MD) studies, we reveal that the β-arrestin-biased ligands direct a distinct activation path in S1PR1 through the extensive interplay between the PIF and the NPxxY motifs. Specifically, the intermediate flipping of W269
and the retained interaction between F265
and N307
are the key features of the β-arrestin bias. We further identify ligand-receptor interactions accounting for the S1PR subtype specificity of BAF312. These structural insights provide a rational basis for designing novel signaling-biased S1PR modulators.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Chronic inflammation-promoted metastasis has been considered as a major challenge in cancer therapy. Pro-inflammatory cytokine TNFα can induce cancer invasion and metastasis associated with ...epithelial-mesenchymal transition (EMT). However, the underlying mechanisms are not entirely clear. In this study, we showed that TNFα induces EMT in human HCT116 cells and thereby promotes colorectal cancer (CRC) invasion and metastasis. TNFα-induced EMT was characterized by acquiring mesenchymal spindle-like morphology and increasing the expression of N-cadherin and fibronectin with a concomitant decrease of E-cadherin and Zona occludin-1(ZO-1). TNFα treatment also increased the expression of transcription factor Snail, but not Slug, ZEB1 and Twist. Overexpression of Snail induced a switch from E-cadherin to N-cadherin expression in HCT116 cells, which is a characteristic of EMT. Conversely, knockdown of Snail significantly attenuated TNFα-induced EMT in HCT116 cells, suggesting that Snail plays a crucial role in TNFα-induced EMT. Interestingly, exposure to TNFα rapidly increased Snail protein expression and Snail nuclear localization but not mRNA level upregulation. Finally, we demonstrated that TNFα elevated Snail stability by activating AKT pathway and subsequently repressing GSK-3β activity and decreasing the association of Snail with GSK-3β. Knockdown of GSK-3β further verified our finding. Taken together, these results revealed that AKT/GSK-3β-mediated stabilization of Snail is required for TNFα-induced EMT in CRC cells. Our study provides a better understanding of inflammation-induced CRC metastasis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recently, a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage called B.1.1.7 (variant of concern: VOC 202012/01), which is reported to spread more efficiently and faster than ...other strains, emerged in the United Kingdom. This variant has an unusually large number of mutations, with 10 amino acid changes in the spike (S) protein, raising concerns that its recognition by neutralizing antibodies may be affected. In this study, we tested SARS-CoV-2-S pseudoviruses bearing either the Wuhan reference strain or the B.1.1.7 lineage spike protein with sera of 40 participants who were vaccinated in a previously reported trial with the messenger RNA-based COVID-19 vaccine BNT162b2. The immune sera had slightly reduced but overall largely preserved neutralizing titers against the B.1.1.7 lineage pseudovirus. These data indicate that the B.1.1.7 lineage will not escape BNT162b2-mediated protection.
After cerebral infarction, the regeneration of microvascular played an important role in the recovery. Ginsenoside Rg1 (Rg1) had good effects on promoting angiogenesis and neuro-protection in ...cerebral infarction treatment. However, the blood-brain barrier (BBB) restricted Rg1 to enter into cerebral tissue. Transferrin receptor (TfR) was over-expressed in the BBB. In this study, we fabricated a TfR targeting nano-carrier (PATRC) to penetrate the BBB for treatment of cerebral infarction. A TfR targeted peptide was conjugated with the nano-carrier wrapped hydrophobic Rg1. The nanoscale size (132 ± 12 nm), polydispersity index (PDI =0.29) and the zeta potential (−38mv) were tested with dynamic light scattering optical system. Surface morphology (ellipse, mean diameter 122 ± 26 nm) was detected by transmission electron microscope (TEM). PATRC implement cell targeting ability on rat brain microvascular endothelial cells RBE4 in vitro detected by immunofluorescence and flow cytometry methods. Comparing with Rg1 threated group, the PATRC exhibited more prominent ability on the tube formation ability (p < .05) in vitro. Comparing with the Rg1 treated group, PATRC penetrated BBB in vivo detected by HPLC, decreased the brain infarction volume tested with TTC staining and promoted regeneration of microvascular in infarction zone detected by CD31 immunofluorescence. PATRC has great potentiality for wide application in clinic.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This paper examines the mechanism through which HRM practices promote firms' innovation and how this relationship differs across cultures. Based on a data-set of 3755 firms from 13 countries, this ...study finds that in most countries employee-oriented HRM practices that dedicate attention to employee needs and interests are positively related to firms' market-sensing capability, which is the capability to continuously learn about their markets. Market-sensing capability is in turn significantly related to firms' product and process innovation. Cross-country examination further reveals that in high power distance countries employee-oriented HRM practices have a stronger positive effect than in low power distance countries. This study highlights the importance of HRM in supporting the use organizations make of external knowledge, which is critical for organizational innovation. Bringing an external perspective, we complement existing literature that emphasizes the role of HRM in integrating internal knowledge. Our cross-cultural findings contribute to the understanding of cultural contingency in HRM theories.
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BFBNIB, IZUM, KILJ, NUK, PILJ, SAZU, UL, UM, UPUK
Circular RNAs (circRNAs) play important roles in cancer development and progression. The purpose of this study is to identify aberrantly expressed circRNAs in gastric cancer (GC), unravel their roles ...in GC progression, and provide new targets for GC diagnosis and therapy.
Bioinformatic analyses were performed to identify the aberrantly expression of hsa_circ_0061137 (termed as circDIDO1) in GC. Gain- and loss-of-function studies were performed to examine the biological roles of circDIDO1 in GC progression. Tagged RNA affinity purification, mass spectrometry, immunofluorescence, co-immunoprecipitation, and Western blot were used to identify circRNA-interacting and circRNA-encoded proteins. RNA sequencing, qRT-PCR, and Western blot were performed to analyze circRNA-regulated downstream target genes and signaling pathways. Mouse tumor models were used to analyze the effects of circDIDO1 on GC growth and metastasis.
CircDIDO1 was transcribed from human DIDO1 (death-inducer obliterator 1) gene and formed by back-splicing of exons 2-6 of the linear transcript. circDIDO1 was down-regulated in GC tissues and its low levels were associated with larger tumor size, distal metastasis, and poor prognosis. CircDIDO1 overexpression inhibited while knockdown promoted GC cell proliferation, migration and invasion. CircDIDO1 overexpression suppressed GC growth and metastasis in mouse tumor models. Mechanistically, circDIDO1 encoded a novel 529aa protein that directly interacted with poly ADP-ribose polymerase 1 (PARP1) and inhibited its activity. CircDIDO1 also specifically bound to peroxiredoxin 2 (PRDX2) and promoted RBX1-mediated ubiquitination and degradation of PRDX2, which led to the inactivation of its downstream signaling pathways.
CircDIDO1 is a new circRNA that has tumor suppressor function in GC and it may serve as a potential prognostic biomarker and therapeutic target for GC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Environmental and plant factors (soil condition, variety, season, and maturity) and exposure risks of aluminum (Al), manganese (Mn), lead (Pb), cadmium (Cd), and copper (Cu) in tea leaves were ...investigated. The concentrations of these metals in tea leaves could not be predicted by their total concentrations in the soil. During any one season, there were differences in Al, Mn, and Cd levels between tea varieties. Seasonally, autumn tea and/or summer tea had far higher levels of Al, Mn, Pb, and Cd than did spring tea. Tea leaf maturity positively correlated with the concentrations of Al, Mn, Pb, and Cd, but negatively with Cu. The calculated average daily intake doses (mg/ kg•d) for these metal elements were 0.14 (Al), 0.11 (Mn), 2.70 × 10−3 (Cu), 2.80 × 10−4 (Pb), and 2.88 × 10−6 (Cd). The hazard quotient values of each metal were all significantly lower than risk level (=1), suggesting that, for the general population, consumption of tea does not result in the intake of excessive amounts of Al, Mn, Pb, Cd, or Cu. This study identified the factors that can be monitored in the field to decrease consumer exposure to Al and Mn through tea consumption.
Practical Application
Environmental and plant factors influence aluminum and heavy metal accumulation in tea leaves. Consumers of tea are not ingesting excessive Al, Mn, Pb, Cd, or Cu. Trackable factors were identified to manage exposure levels.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
An eco-friendly and economical approach for the photocatalytic oxidation of organic inter-mediates by air under mild conditions is highly desirable in green and sustainable chemistry, where the ...photogeneration of active oxygen species plays a key role in improving conversion efficiency and selectivity. By using pyridinium derivatives as molecular mediators for electron transfer and energy transfer, the simultaneous activation of O
2
from air into superoxide radicals and singlet oxygen species can be achieved, and a photoinduced electron transfer catalytic system for the oxidation of alcohols has been developed. Thus, we have successfully simplified the complicated catalytic system into a single molecular catalyst without any additional noble metals and co-catalysts/additives. The current photocatalytic system shows high catalytic efficiency not only for aromatic alcohols but also for aliphatic alcohols that are generally difficult to undergo aerobic oxidation at room temperature under air atmosphere, representing an ideal photocatalytic platform for green and economical organic syntheses.
Pyridinium molecules are developed as electron- and energy-transfer mediators to boost the activity of air oxygen and thus achieve highly efficient photocatalytic oxidation of alcohols without any noble metal and additional co-catalysts/additives under mild conditions.
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