Solving the maximum duo-preservation string mapping problem with linear programming
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Here we report that Prostate Cancer (PCa) cell-lines DU145, PC3, LNCaP and RWPE-1 grown in 3D matrices in contrast to conventional 2D monolayers, display distinct differences in cell morphology, proliferation and expression of important biomarker proteins associated with cancer progression. Consistent with in vivo growth rates, in 3D cultures, all PCa cell-lines were found to proliferate at significantly lower rates in comparison to their 2D counterparts. Moreover, when grown in a 3D matrix, metastatic PC3 cell-lines were found to mimic more precisely protein expression patterns of metastatic tumour formation as found in vivo. In comparison to the prostate epithelial cell-line RWPE-1, metastatic PC3 cell-lines exhibited a down-regulation of E-cadherin and {alpha}6 integrin expression and an up-regulation of N-cadherin, Vimentin and {beta}1 integrin expression and re-expressed non-transcriptionally active AR. In comparison to the non-invasive LNCaP cell-lines, PC3 cells were found to have an up-regulation of chemokine receptor CXCR4, consistent with a metastatic phenotype. In 2D cultures, there was little distinction in protein expression between metastatic, non-invasive and epithelial cells. These results suggest that 3D cultures are more representative of in vivo morphology and may serve as a more biologically relevant model in the drug discovery pipeline. -- Highlights: Black-Right-Pointing-Pointer We developed and optimised 3D culturing techniques for Prostate Cancer cell-lines. Black-Right-Pointing-Pointer We investigated biomarker expression in 2D versus 3D culture techniques. Black-Right-Pointing-Pointer Metastatic PC3 cells re-expressed non-transcriptionally active androgen receptor. Black-Right-Pointing-Pointer Metastatic PCa cell lines retain in vivo-like antigenic profiles in 3D cultures.
Hepatic stellate cells (HSC) are well known initiators of hepatic fibrosis. After liver cell damage, HSC transdifferentiate into proliferative myofibroblasts, representing the major source of extracellular matrix in the fibrotic organ. Recent studies also demonstrate a role of HSC as progenitor or stem cell like cells in liver regeneration. Lhx2 is described as stem cell maintaining factor in different organs and as an inhibitory transcription factor in HSC activation. Here we examined whether a continuous expression of Lhx2 in HSC could attenuate their activation and whether Lhx2 could serve as a potential target for antifibrotic gene therapy. Therefore, we evaluated an adenoviral mediated overexpression of Lhx2 in primary HSC and investigated mRNA expression patterns by qRT-PCR as well as the activation status by different in vitro assays. HSC revealed a marked increase in activation markers like smooth muscle actin alpha (αSMA) and collagen 1α independent from adenoviral transduction. Lhx2 overexpression resulted in attenuated cell viability as shown by a slightly hampered migratory and contractile phenotype of HSC. Expression of stem cell factors or signaling components was also unaffected by Lhx2. Summarizing these results, we found no antifibrotic or stem cell maintaining effect of Lhx2 overexpression in primary HSC. - Highlights: • We performed adenoviral overexpression of Lhx2 in primary hepatic stellate cells. • Hepatic stellate cells expressed stem cell markers during cultivation. • Cell migration and contractility was slightly hampered upon Lhx2 overexpression. • Lhx2 overexpression did not affect stem cell character of hepatic stellate cells.
Highlights: • CCR7 promotes the progression of HCC and is associated with poor survival. • HDAC inhibition induces EMT in HCC cells via up-regulating CCR7. • HDAC inhibition up-regulates CCR7 via reversing the promoter hypoacetylation and increasing CCR7 transcription. The effects of Histone deacetylase (HDAC) inhibition on epithelial-mesenchymal transition (EMT) differs in various types of cancers. However, its function in hepatocellular carcinoma (HCC) is not well-explored. In this study, we investigated the effect of HDAC inhibition on EMT in HCC cells by using trichostatin A (TSA) and valproic acid (VPA). The results showed that TSA/VPA significantly induced EMT phenotype, as demonstrated by the decreased level of E-cadherin, increased level of N-cadherin, vimentin, Twist and snail, and enhanced capacity of cell migration and invasion. In addition, CCR7 was speculated and confirmed as a function target of HDAC inhibition. CCR7 promotes the progression of HCC and is associated with poor survival. Knockdown of CCR7 significantly attenuated the effect of TSA on EMT. Moreover, our results demonstrated that HDAC inhibition up-regulates CCR7 via reversing the promoter hypoacetylation and increasing CCR7 transcription. Taken together, our study has identified the function of HDAC in EMT of HCC and suggested a novel mechanism through which TSA/VPA exerts its carcinogenic roles in HCC. HDAC inhibitors require careful caution before their application as new anticancer drugs.
Highlights: • VP deleted B epitope and reduced atherosclerosis. • VP maintained anti-T1DM function. • VP maintained β cell function and anti-inflammatory. P277 is a 24 amino-acids peptide, residues 437–460 of human heat shock protein 60 (HSP60). P277 or sequence repeated 6 × P277 was previously found showing potency preventive and therapeutic anti-diabetes functions in NOD mice, but aroused atherosclerosis due to the induction of anti-HSP65 autoantibodies as reported. To determine the intrinsic B epitope sequence, we screened P277 with pepscan method and then proved by detection of sera IgG from peptide fragments vaccinated mouse and rabbits. Results indicated HSP60 443–448 (ALLRCI) is potential intrinsic B epitope sequence of P277. We modified P277 by deleting the former three amino acids of ALLRCI (VP) or replacing these six with alanine (AP). The detection of serum lipid parameter in NOD mice and aorta endothelial damage levels in high-cholesterol diets fed rabbits demonstrated that VP induced higher anti-diabetes efficacy and caused less arteriosclerosis-liked diseases separately. With less TLR2/4 activation of dendritic cells and macrophages, VP treatment reduced Th1 related P277 specific pro-inflammatory cytokines production and increased regulatory immune responses both in vivo and in vitro. These results indicated that optimized VP peptide might serve as a promising candidate for mouse type 1 diabetes therapy.
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The bulk phase of transition metal nitrides (TMNs) has long been a subject of extensive investigation due to their utility as coating materials, electrocatalysts, and diffusion barriers, attributed to their high conductivity and refractory properties. Downscaling TMNs into two-dimensional (2D) forms would provide valuable members to the existing 2D materials repertoire, with potential enhancements across various applications. Moreover, calculations have anticipated the emergence of uncommon physical phenomena in TMNs at the 2D limit. Here, in this study, we use the atomic substitution approach to synthesize 2D W 5 N 6 with tunable thicknesses from tens of nanometers down to 2.9 nm. The obtained flakes exhibit high crystallinity and smooth surfaces. Electrical measurements on 15 samples show an average electrical conductivity of 161.1 S/cm, which persists while thickness decreases from 45.6 to 2.9 nm. The observed weak gate-tuning effect suggests the semimetallic nature of the synthesized 2D W 5 N 6 . Further investigation of the conversion mechanism elucidates the crucial role of chalcogen vacancies in the precursor for initiating the reaction and strain in propagating the conversion. Our work introduces a desired semimetallic crystal to the 2D material library with mechanistic insights for future design of the synthesis.
Ball milling is used for size reduction of biomass for isolating lignin. However, it is known that it can lead to some structural alteration of lignin. Fibrillation using ultrafriction grinding is a newer size reduction technology which was applied to poplar for isolating cellulolytic enzyme lignin. Compositional analysis of poplar, enzymatic hydrolysis yield, water retention value, lignin yield, lignin structural characterization, and lignin molecular weight analysis were carried out to compare lignin isolated from fibrillated and ball milled poplar. By using fibrillation instead of planetary ball milling for size reduction of poplar, higher β-O-4' linkage content, lignin yield, and molecular weight were obtained. Replacing ball milling with fibrillation for size reduction allows recovery of lignin whose structure is closer to that of lignin in biomass.
We report a quenching-triggered reversible single-crystalto- single-crystal (SC-SC) phase transition was discovered in a metal–organic framework (MOF) PCN-526. During the phase transition, the one-dimensional channel of PCN-526 distorts from square to rectangular in shape while maintaining single crystallinity. Although SC-SC transformations have been frequently observed in MOFs, most reports have focused on describing the resulting structural alterations without shedding light on the mechanism for the transformation. Interestingly, modifying the occupancy or species of metal ions in the extraframework sites, which provides mechanistic insight into the causes for the transformation, can forbid this phase transition. Moreover, as a host scaffold, PCN-526 presents a platform for modulation of the photoluminescence properties by encapsulation of luminescent guest molecules. Through judicious choice of these guest molecules, responsive luminescence caused by SC-SC transformations can be detected, introducing a new strategy for the design of novel luminescent MOF materials.
Abstract Stratospheric aerosol injection (SAI) has been shown in climate models to reduce some impacts of global warming in the Arctic, including the loss of sea ice, permafrost thaw, and reduction of Greenland Ice Sheet (GrIS) mass; SAI at high latitudes could preferentially target these impacts. In this study, we use the Community Earth System Model to simulate two Arctic‐focused SAI strategies, which inject at 60°N latitude each spring with injection rates adjusted to either maintain September Arctic sea ice at 2030 levels (“Arctic Low”) or restore it to 2010 levels (“Arctic High”). Both simulations maintain or restore September sea ice to within 10% of their respective targets, reduce permafrost thaw, and increase GrIS surface mass balance by reducing runoff. Arctic High reduces these impacts more effectively than a globally focused SAI strategy that injects similar quantities of SO 2 at lower latitudes. However, Arctic‐focused SAI is not merely a “reset button” for the Arctic climate, but brings about a novel climate state, including changes to the seasonal cycles of Northern Hemisphere temperature and sea ice and less high‐latitude carbon uptake relative to SSP2‐4.5. Additionally, while Arctic‐focused SAI produces the most cooling near the pole, its effects are not confined to the Arctic, including detectable cooling throughout most of the northern hemisphere for both simulations, increased mid‐latitude sulfur deposition, and a southward shift of the location of the Intertropical Convergence Zone. For these reasons, it would be incorrect to consider Arctic‐focused SAI as “local” geoengineering, even when compared to a globally focused strategy.