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Lysyl oxidase (LOX) is upregulated in highly stiff aggressive tumors, correlating with metastasis, resistance, and worse survival; however, there are currently no potent, safe, and orally bioavailable small molecule LOX inhibitors to treat these aggressive desmoplastic solid tumors in clinics. Here we discovered bi-thiazole derivatives as potent LOX inhibitors by robust screening of drug-like molecules combined with cell/recombinant protein-based assays. Structure-activity relationship analysis identified a potent lead compound (LXG6403) with ∼3.5-fold specificity for LOX compared to LOXL2 while not inhibiting LOXL1 with a competitive, time- and concentration-dependent irreversible mode of inhibition. LXG6403 shows favorable pharmacokinetic properties, globally changes ECM/collagen architecture, and reduces tumor stiffness. This leads to better drug penetration, inhibits FAK signaling, and induces ROS/DNA damage, G1 arrest, and apoptosis in chemoresistant triple-negative breast cancer (TNBC) cell lines, PDX organoids, and in vivo. Overall, our potent and tolerable bi-thiazole LOX inhibitor enhances chemoresponse in TNBC, the deadliest breast cancer subtype. [Display omitted] • A cell-based HTS identifies bi-thiazole derivatives as potent LOX inhibitors • LXG6403 is a well-tolerated potent LOX inhibitor with favorable drug-like features • LXG6403 rewires collagen architecture/signaling to overcome chemoresistance in TNBC • LXG6403 is a promising lead candidate for highly stiff drug resistant tumors Cetin-Saatci et al. identified a potent and well-tolerated bi-thiazole LOX inhibitor LXG6403, overcoming chemoresistance in TNBC, the deadliest breast cancer subtype, by rewiring collagen architecture/signaling and increasing drug penetration. LXG6403 has great potential for optimization for future clinical testing in LOX-driven diseases, including chemoresistant TNBC. [ABSTRACT FROM AUTHOR]

The role of long non‐coding RNAs in fibroid pathogenesis remains largely unexplored. In a previous study, we found elevated XIST (X‐inactive specific transcript) levels in fibroids, which sponged miR‐29c and miR‐200c, leading to the overexpression of their target genes. This study aimed to assess the therapeutic potential of XIST downregulation in fibroid treatment. Ovariectomized SCID (severe combined immunodeficiency) mice were implanted with fibroid tumors transduced with XIST siRNA or a control via lentivirus. After 1 month, animals were sacrificed and the xenografts were removed for further analysis. XIST knockdown reduced tumor weight by 15% and increased miR‐29c and miR‐200c expression by 3.9‐fold and 2.2‐fold, respectively. The mRNA expression of miR‐29c targets (COL3A1, TGF‐β3, CDK2, SPARC) and miR‐200c targets (CDK2, FN1, TDO2), as well as PRL, E2F1, and EZH2, was significantly decreased. Protein abundance of collagen, COL3A1, FN1, CDK2, SPARC, and EZH2 was also reduced. IHC analysis of xenograft sections using the markers of Ki67 for cell proliferation and cleaved caspase 3 for apoptosis showed decreased cell proliferation and no changes in apoptosis in the XIST knockdown xenografts. This analysis also revealed decreased collagen and E2F1 staining nuclei in the XIST knockdown xenografts. These results indicate that downregulation of XIST in fibroids has beneficial therapeutic effects, by reducing tumor growth and the expression of genes involved in cell proliferation, inflammation, and extracellular matrix regulation. [ABSTRACT FROM AUTHOR]

Existing evidence indicates that LINCMD1 regulates muscle differentiation-related gene expression in skeletal muscle by acting as a miRNA sponge, though its role in leiomyoma development is still unknown. This study investigated LINCMD1′s involvement in leiomyoma by analyzing paired myometrium and leiomyoma tissue samples (n = 34) from patients who had not received hormonal treatments for at least three months prior to surgery. Myometrium smooth muscle cells (MSMCs) were isolated, and gene expression of LINCMD1 and miR-135b was assessed via qRT-PCR, while luciferase assays determined the interaction between LINCMD1 and miR-135b. To examine the effects of LINCMD1 knockdown, siRNA transfection was applied to a 3D MSMC spheroid culture, followed by qRT-PCR and Western blot analyses of miR-135b, APC, β-Catenin and COL1A1 expression. The results showed that leiomyoma tissues had significantly reduced LINCMD1 mRNA levels, regardless of patient race or MED12 mutation status, while miR-135b levels were elevated compared to matched myometrium samples. Luciferase assays confirmed LINCMD1′s role as a sponge for miR-135b. LINCMD1 knockdown in MSMC spheroids increased miR-135b levels, reduced APC expression, and led to β-Catenin accumulation and higher COL1A1 expression. These findings highlight LINCMD1 as a potential therapeutic target to modulate aberrant Wnt/β-Catenin signaling in leiomyoma. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effect of reducing Lysyl oxidase (LOX) overexpression on retinal ganglion cells (RGCs) apoptosis in an acute ocular hypertension (AOH) rat model. Methods: AOH rat model was performed by anterior chamber perfusion and either received an intravitreal injection with β-aminopropionitrile (BAPN) or normal saline. After 2wk, Quantification of survival RGCs in the retina was performed using Retrograde FluoroGold labeling. The mRNA expression levels of LOX, LOXL1-4, collagen 1a1 (Col1a1), collagen 3a1 (Col3a1), collagen4a1 (Col4a1), elastin (Eln), fibronectin1 (Fbn1), fibronectin4 (Fbn4) were determined by RT-qPCR. LOX expression was determined by Western blot (WB) analysis and immunohistochemistry. The RNA expression of LOX, Eln and Col1a1 in RGCs retrograde-labeled with 1,1'-dioctadecyl-3,3,3',3' tetra-methylindocarbocyanine perchlorate(DiI)that selected through FACS sorting were determined by RT-qPCR analysis. Changes of the retinal function were detected by Electroretinogram (ERG) analysis. Results: Results showed that significant LOX overexpression and loss of RGCs related to IOP exposure in AOH retinas. PCR analysis indicated significant increased mRNA level of Col1a1, Col3al and Eln in AOH retinas. Significant increase mRNA expression of LOX, Col1a1 and Eln in the RGCs were observed in AOH group compared with CON group. AOH rats injected with BAPN showed a significant decrease in LOX expression, reduced the loss of RGCs and retinal function damage. Conclusions: The results demonstrated that changes of LOX and specific ECM components in retina were correlated with AOH. Findings from this study indicated that preventing LOX over-expression may be protective against RGCs loss and retinal function damage in AOH animal model. [ABSTRACT FROM AUTHOR]

• ECM synthesis poses significant demands for biomass generation with requirements different from cell proliferation. • With its high glycine and proline content, collagen synthesis imposes unique biosynthetic demands. • Pro-fibrotic signaling cascades mediate metabolic rewiring in activated fibroblasts. • Targeting the metabolic pathways supporting collagen synthesis provides opportunities for treating fibrotic conditions. • Nutrient availability influences metabolic pathways regulating collagen synthesis and creates new vulnerabilities. The extracellular matrix (ECM) is present in all tissues and crucial in maintaining normal tissue homeostasis and function. Defects in ECM synthesis and remodeling can lead to various diseases, while overproduction of ECM components can cause severe conditions like organ fibrosis and influence cancer progression and therapy resistance. Collagens are the most abundant core ECM proteins in physiological and pathological conditions and are predominantly synthesized by fibroblasts. Previous efforts to target aberrant collagen synthesis in fibroblasts by inhibiting pro-fibrotic signaling cascades have been ineffective. More recently, metabolic rewiring downstream of pro-fibrotic signaling has emerged as a critical regulator of collagen synthesis in fibroblasts. Here, we propose that targeting the metabolic pathways involved in ECM biomass generation provides a novel avenue for treating conditions characterized by excessive collagen accumulation. This review summarizes the unique metabolic challenges collagen synthesis imposes on fibroblasts and discusses how underlying metabolic networks could be exploited to create therapeutic opportunities in cancer and fibrotic disease. Finally, we provide a perspective on open questions in the field and how conceptual and technical advances will help address them to unlock novel metabolic vulnerabilities of collagen synthesis in fibroblasts and beyond. [ABSTRACT FROM AUTHOR]

The brain's extracellular matrix (ECM) regulates neuronal plasticity and animal behavior. ECM staining shows a net-like structure around a subset of neurons, a ring-like structure at the nodes of Ranvier, and diffuse staining in the interstitial matrix. However, understanding the structural features of ECM deposition across various neuronal types and subcellular compartments remains limited. To visualize the organization pattern and assembly process of the hyaluronan-scaffolded ECM in the brain, we fused a HaloTag to hyaluronan proteoglycan link protein 1, which links hyaluronan and proteoglycans. Expression or application of the probe in primary rat neuronal cultures enables us to identify spatial and temporal regulation of ECM deposition and heterogeneity in ECM aggregation among neuronal populations. Dual-color birthdating shows the ECM assembly process in culture and in vivo. Sparse expression in mouse brains of either sex reveals detailed ECM architectures around excitatory neurons and developmentally regulated dendritic ECM. Our study uncovers extensive structural features of the brain's ECM, suggesting diverse roles in regulating neuronal plasticity. [ABSTRACT FROM AUTHOR]

The purpose of this research is to investigate the use of cross-hedging in the South African soybean market, by using the JSE BEAN contract as a cross-hedge instrument for the JSE SOYA contract. The research study involves a detailed assessment of the data, which includes the use of stationarity tests such as the Phillips-Perron and Augmented Dickey-Fuller, as well as the Johansen co-integration approach to analyse long-term relationships between the variables. To evaluate the efficiency of cross-hedging strategies, three distinct hedging models are used: the ordinary least squares (OLS) model, error correction model (ECM) and EC-GARCH. The results demonstrate that these models produce significant hedge ratios. Through back-testing and the application of hedging strategies, it is determined that the JSE BEAN contract holds the potential to serve as a cross-hedge for the JSE SOYA contract in the South African soybean market. This study provides useful information for market participants and model selection in the context of cross-hedging. [ABSTRACT FROM AUTHOR]

The reconstruction of a heart valve through in situ tissue engineering remains a formidable challenge, particularly for patients with diabetes mellitus, because the pathophysiological alterations associated with diabetes substantially impair the cardiovascular system's intrinsic repair capacity. In this study, reactive oxygen species (ROS) regulation are integrated into the fabrication of pro‐endothelialization interfaces to counteract the adverse repair environment. Specifically, a heparin‐mimicking alginate‐derived glycopeptide and the natural ROS scavenger melanin are modified onto the surface of a decellularized extracellular matrix (dECM). This tailored interface significantly enhances endothelial cell (EC) adhesion while reducing platelet adhesion. The incorporation of melanin effectively suppresses ROS elevation in ECs and macrophages under hyperglycemic conditions. Consequently, this intervention promotes EC rejuvenation by enhancing proliferation, migration, and anti‐apoptotic capabilities, while concurrently attenuating the release of inflammatory and pro‐fibrotic factors by macrophages. The dECM is intravascularly implanted in a diabetic rabbit model after being fabricated into a covered stent, demonstrating favorable remodeling characteristics such as enhanced endothelialization and reduced fibrotic deposition. This scaffold design, specifically tailored to the pathological conditions of diabetes, offers a precise biomaterial strategy for in situ heart valve tissue engineering. [ABSTRACT FROM AUTHOR]

Background: Renal interstitial fibrosis (RIF) is a common feature of chronic kidney diseases (CKD), with epithelial-mesenchymal transition (EMT) being one of its important mechanisms. S100A2 is a protein associated with cell proliferation and differentiation, but its specific functions and molecular mechanisms in RIF remain to be determined. Methods: S100A2 levels were evaluated in three mouse models, including unilateral ureteral obstruction (UUO), ischemia-reperfusion injury (IRI), and aristolochic acid nephropathy (AAN), as well as in TGF-β1- treated HK-2 cells and in kidney tissue samples. Furthermore, the role of S100A2 and its interaction with FoxO1 was investigated using RT-qPCR, immunoblotting, immunofluorescence staining, co-immunoprecipitation (Co-IP), transcriptome sequencing, and gain- or loss-of-function approaches in vitro. Results: Elevated expression levels of S100A2 were observed in three mouse models and TGF-β1-treated HK2 cells, as well as in kidney tissue samples. Following siRNA silencing of S100A2, exposure to TGF-β1 in cultured HK-2 cells suppressed EMT process and extracellular matrix (ECM) accumulation. Conversely, Overexpression of S100A2 induced EMT and ECM deposition. Notably, we identified that S100A2-mediated EMT depends on FoxO1. Immunofluorescence staining indicated that S100A2 and FoxO1 colocalized in the nucleus and cytoplasm, and their interaction was verified in Co-IP assay. S100A2 knockdown decreased TGF-β1-induced phosphorylation of FoxO1 and increased its protein expression, whereas S100A2 overexpression hampered FoxO1 activation. Furthermore, pharmacological blockade of FoxO1 rescued the induction of TGF-β1 on EMT and ECM deposition in S100A2 siRNA-treated cells. Conclusion: S100A2 activation exacerbates interstitial fibrosis in kidneys by facilitating FoxO1-mediated EMT. A schematic diagram of the underlying mechanisms by which S100A2 regulates EMT and renal fibrosis. Following injury, the cytoplasmic expression of S100A2 in renal tubular epithelial cells is markedly elevated. This increase promotes the phosphorylation of FoxO1, preventing its translocation into the nucleus and enhances EMT and extracellular matrix ECM deposition, thereby exacerbating renal interstitial fibrosis. [ABSTRACT FROM AUTHOR]

Reduced PALMD expression is strongly associated with the development of calcified aortic valve stenosis; however, the role of PALMD in vascular calcification remains unknown. Calcified arteries were collected from mice to detect PALMD expression. Heterozygous Palmd knockout (Palmd+/-) mice were established to explore the role of PALMD in subtotal nephrectomyinduced vascular calcification. RNA sequencing was applied to detect molecular changes in aortas from Palmd+/- mice. Primary Palmd +/- vascular smooth muscle cells (VSMCs) or PALMD-silenced VSMCs by short interfering RNA were used to analyze PALMD function in phenotypic changes and calcification. PALMD haploinsufficiency aggravated subtotal nephrectomyinduced vascular calcification. RNA sequencing analysis showed that loss of PALMD disturbed the synthesis and degradation of the extracellular matrix (ECM) in aortas, including collagens and matrix metalloproteinases (Col6a6, Mmp2, Mmp9, etc.). In vitro experiments revealed that PALMD-deficient VSMCs were more susceptible to high phosphate-induced calcification. Downregulation of SMAD6 expression and increased levels of p-SMAD2 were detected in Palmd+/- VSMCs, suggesting that transforming growth factor-β signaling may be involved in PALMD haploinsufficiency-induced vascular calcification. Our data revealed that PALMD haploinsufficiency causes ECM dysregulation in VSMCs and aggravates vascular calcification. Our findings suggest that reduced PALMD expression is also linked to vascular calcification, and PALMD may be a potential therapeutic target for this disease. [ABSTRACT FROM AUTHOR]

Liver cancer represents a substantial global health challenge, contributing significantly to worldwide morbidity and mortality. It has long been understood that tumors are not composed solely of cancerous cells, but also include a variety of normal cells within their structure. These tumor-associated normal cells encompass vascular endothelial cells, fibroblasts, and various inflammatory cells, including neutrophils, monocytes, macrophages, mast cells, eosinophils, and lymphocytes. Additionally, tumor cells engage in complex interactions with stromal cells and elements of the extracellular matrix (ECM). Initially, the components of what is now known as the tumor microenvironment (TME) were thought to be passive bystanders in the processes of tumor proliferation and local invasion. However, recent research has significantly advanced our understanding of the TME's active role in tumor growth and metastasis. Tumor progression is now known to be driven by an intricate imbalance of positive and negative regulatory signals, primarily influenced by specific growth factors produced by both inflammatory and neoplastic cells. This review article explores the latest developments and future directions in understanding how the TME modulates liver cancer, with the aim of informing the design of novel therapies that target critical components of the TME. [ABSTRACT FROM AUTHOR]

Modern molecular microbiology elucidates the organizational principles of bacterial biofilms via detailed examination of the interplay between signaling and gene regulation. A complementary biophysical approach studies the mesoscopic dependencies at the cellular and multicellular levels with a distinct focus on intercellular forces and mechanical properties of whole biofilms. Here, motivated by recent advances in biofilm research and in other, seemingly unrelated fields of biology and physics, we propose a perspective that links the biofilm, a dynamic multicellular organism, with the physical processes occurring in the extracellular milieu. Using Bacillus subtilis as an illustrative model organism, we specifically demonstrate how such a rationale explains biofilm architecture, differentiation, communication, and stress responses such as desiccation tolerance, metabolism, and physiology across multiple scales--from matrix proteins and polysaccharides to macroscopic wrinkles and water-filled channels. [ABSTRACT FROM AUTHOR]

This research paper presents an innovative approach to fabricating enhanced-quality hierarchical surface micro-textures on Ti6Al4V alloy by synergistically employing in situ electrical discharge machining (EDM) and electrochemical machining (ECM) processes. The hierarchical structure encompasses three levels: a primary level at a few hundred micrometers, a secondary level at a few tens of micrometers, and a ternary level at sub-micrometer scales. Despite the precision achieved in generating the primary-level texture through EDM using a chemically patterned tool, inherent thermal damages and surface defects, such as micro-craters and irregularities, pose challenges. Unlike usual ex situ chemical or electrochemical post-processing methods, this study introduces in situ ECM post-processing (ECM) with the same patterned tool. This approach enhances the quality of EDMed surfaces without compromising geometrical accuracy, offering anisotropic dissolution along the feature depth. To ensure geometrical accuracy, an experimentally validated finite element method-based transient numerical simulation model is developed. This model accurately predicts the evolution of the feature profile during the ECM operation. Furthermore, ECM with a fluoride ion–containing electrolyte introduces additional secondary and ternary levels of hierarchical textures. Fluoride ions play a pivotal role in augmenting material removal during ECM, particularly in areas around micro-crevices and pores, shaping the secondary-level texture. [ABSTRACT FROM AUTHOR]

Bluetongue virus (BTV) infection induces profound and intricate changes in the transcriptional profile of the host to facilitate its survival and replication. However, there have been no whole-transcriptome studies on ovine lung microvascular endothelial cells (OLMECs) infected with BTV. In this study, we comprehensively analysed the whole-transcriptome sequences of BTV-1 serotype-infected and mock-infected OLMECs and subsequently performed bioinformatics differential analysis. Our analysis revealed 1215 differentially expressed mRNA transcripts, 82 differentially expressed long noncoding RNAs (lncRNAs) transcripts, 63 differentially expressed microRNAs (miRNAs) transcripts, and 42 differentially expressed circular RNAs (circRNAs) transcripts. Annotation from Gene Ontology, enrichment from the Kyoto Encyclopedia of Genes and Genomes, and construction of endogenous competing RNA network analysis revealed that the differentially expressed RNAs primarily participated in viral sensing and signal transduction pathways, antiviral and immune responses, inflammation, and extracellular matrix (ECM)-related pathways. Furthermore, protein‒protein interaction network analysis revealed that BTV may regulate the conformation of ECM receptor proteins and change their biological activity through a series of complex mechanisms. Finally, on the basis of real-time fluorescence quantitative polymerase chain reaction results, the expression trends of the differentially expressed RNA were consistent with the whole-transcriptome sequencing data, such as downregulation of the expression of COL4A1, ITGA8, ITGB5, and TNC and upregulation of the expression of CXCL10, RNASEL, IRF3, IRF7, and IFIHI. This study provides a novel perspective for further investigations of the mechanism of the ECM in the BTV-host interactome and the pathogenesis of lung microvascular endothelial cells. [ABSTRACT FROM AUTHOR]

The potential of micro electrochemical slotting is significant due to its adaptability and usefulness across diverse manufacturing applications. This technique holds potential, particularly for handling advanced engineering materials like superalloys, with a focus on applications requiring high strength, i.e., micro-cutting for gas-turbine parts, biomedical applications, etc. With this view, this article has been attempted to explore the influence of various considered machining factors, namely as; applied potential difference, tool feed rate (TFR), pulse supply, and modes of tool insulation on the performance measures, i.e. material removal rate (MRR) and surface roughness (Ra) while attempting micro-slotting in Nimonic-263 superalloy work samples. The entire experimentation was conducted on the in-house fabricated 3-axis micro-electrochemical setup designed for performing various complex machining operations at a miniature scale. Furthermore, this study has also been focused toward investigating the impact of varying the electrical conductivity by employing different tool materials (i.e. copper and SS304) on the process characteristics measured. The observed effects of the tool electrode's conductivity have also been expressed and supported by performing the simulation for electric field distribution using COMSOL Multiphysics software. The experimental results have revealed that the process input variables remarkably influence MRR and Ra, mainly applied voltage and TFR. The best values of MRR and Ra attained with SS304 and copper tool electrodes were 1.521 mg/min and 0.721 mg/min, and 0.038 µm and 0.029 µm, correspondingly. The microstructure analysis has further been conducted on machined micro-slotted work samples that provided detailed insights into various surface integrity aspects, which are essential for microdevice applications. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs), fundamental constituents of the tumor microenvironment (TME), significantly influence cancer development, primarily by promoting epithelial-mesenchymal transition (EMT). EMT endows cancer cells with increased motility, invasiveness, and resistance to therapies, marking a pivotal juncture in cancer progression. The review begins with a detailed exposition on the origins of TAMs and their functional heterogeneity, providing a foundational understanding of TAM characteristics. Next, it delves into the specific molecular mechanisms through which TAMs induce EMT, including cytokines, chemokines and stromal cross-talking. Following this, the review explores TAM-induced EMT features in select cancer types with notable EMT characteristics, highlighting recent insights and the impact of TAMs on cancer progression. Finally, the review concludes with a discussion of potential therapeutic targets and strategies aimed at mitigating TAM infiltration and disrupting the EMT signaling network, thereby underscoring the potential of emerging treatments to combat TAM-mediated EMT in cancer. This comprehensive analysis reaffirms the necessity for continued exploration into TAMs' regulatory roles within cancer biology to refine therapeutic approaches and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Elevated extracellular matrix (ECM) accumulation is a major contributing factor to the pathogenesis of fibrotic diseases. Recent studies have indicated that N6‐methyladenosine (m6A) RNA modification plays a pivotal role in modulating RNA stability and contribute to the initiation of various pathological conditions. Howbeit, the precise mechanism by which m6A influences ECM deposition remains unclear. Methods: In this study, we used hypertrophic scars (HTSs) as a paradigm to investigate ECM‐related diseases. We focused on the role of ALKBH5‐mediated m6A demethylation within the pathological progression of HTSs and examined its correlation with clinical stages. The effects of ALKBH5 ablation on ECM components were studied both in vivo and in vitro. Downstream targets of ALKBH5, along with their underlying mechanisms, were identified using integrated high‐throughput analysis, RNA‐binding protein immunoprecipitation and RNA pull‐down assays. Furthermore, the therapeutic potential of exogenous ALKBH5 overexpression was evaluated in fibrotic scar models. Results: ALKBH5 was decreased in fibroblasts derived from HTS lesions and was negatively correlated with their clinical stages. Importantly, ablation of ALKBH5 promoted the expression of COL3A1, COL1A1, and ELN, leading to pathological deposition and reconstruction of the ECM both in vivo and in vitro. From a therapeutic perspective, the exogenous overexpression of ALKBH5 significantly inhibited abnormal collagen deposition in fibrotic scar models. As determined by integrated high‐throughput analysis, key ECM components including COL3A1, COL1A1, and ELN are direct downstream targets of ALKBH5. By means of its mechanism, ALKBH5 inhibits the expression of COL3A1, COL1A1, and ELN by removing m6A from mRNAs, thereby decreasing their stability in a YTHDF1‐dependent manner. Conclusions: Our study identified ALKBH5 as an endogenous suppressor of pathological ECM deposition, contributing to the development of a reprogrammed m6A‐targeted therapy for HTSs. [ABSTRACT FROM AUTHOR]

The kidney is an essential excretory organ that works as a filter of toxins and metabolic by-products of the human body and maintains osmotic pressure throughout life. The kidney undergoes several physiological, morphological, and structural changes with age. As life expectancy in humans increases, cell senescence in renal aging is a growing challenge. Identifying age-related kidney disorders and their cause is one of the contemporary public health challenges. While the structural abnormalities to the extracellular matrix (ECM) occur, in part, due to changes in MMPs, EMMPRIN, and Meprin-A, a variety of epigenetic modifiers, such as DNA methylation, histone alterations, changes in small non-coding RNA, and microRNA (miRNA) expressions are proven to play pivotal roles in renal pathology. An aged kidney is vulnerable to acute injury due to ischemia-reperfusion, toxic medications, altered matrix proteins, systemic hemodynamics, etc., non-coding RNA and miRNAs play an important role in renal homeostasis, and alterations of their expressions can be considered as a good marker for AKI. Other epigenetic changes, such as histone modifications and DNA methylation, are also evident in AKI pathophysiology. The endogenous production of gaseous molecule hydrogen sulfide (H2S) was documented in the early 1980s, but its ameliorative effects, especially on kidney injury, still need further research to understand its molecular mode of action in detail. H2S donors heal fibrotic kidney tissues, attenuate oxidative stress, apoptosis, inflammation, and GFR, and also modulate the renin–angiotensin–aldosterone system (RAAS). In this review, we discuss the complex pathophysiological interplay in AKI and its available treatments along with future perspectives. The basic role of H2S in the kidney has been summarized, and recent references and knowledge gaps are also addressed. Finally, the healing effects of H2S in AKI are described with special emphasis on epigenetic regulation and matrix remodeling. [ABSTRACT FROM AUTHOR]

Candida albicans has been listed in the critical priority group by the WHO in 2022 depending upon its contribution in invasive candidiasis and increased resistance to conventional drugs. Drug repurposing offers an efficient, rapid, and cost-effective solution to develop alternative therapeutics against pathogenic microbes. Alexidine dihydrochloride (AXD) and hexachlorophene (HCP) are FDA approved anti-cancer and anti-septic drugs, respectively. In this study, we have shown antifungal properties of AXD and HCP against the wild type (reference strain) and clinical isolates of C. albicans. The minimum inhibitory concentrations (MIC50) of AXD and HCP against C. albicans ranged between 0.34 and 0.69 µM and 19.66–24.58 µM, respectively. The biofilm inhibitory and eradication concentration of AXD was reported comparatively lower than that of HCP for the strains used in the study. Further investigations were performed to understand the antifungal mode of action of AXD and HCP by studying virulence features like cell surface hydrophobicity, adhesion, and yeast to hyphae transition, were also reduced upon exposure to both the drugs. Ergosterol content in cell membrane of the wild type strain was upregulated on exposure to AXD and HCP both. Biochemical analyses of the exposed biofilm indicated reduced contents of carbohydrate, protein, and e-DNA in the extracellular matrix of the biofilm when compared to the untreated control biofilm. AXD exposure downregulated activity of tissue invading enzyme, phospholipase in the reference strain. In wild type strain, ROS level, and activities of antioxidant enzymes were found elevated upon exposure to both drugs. FESEM analysis of the drug treated biofilms revealed degraded biofilm. This study has indicated mode of action of antifungal potential of alexidine dihydrochloride and hexachlorophene in C. albicans. [ABSTRACT FROM AUTHOR]

The removal of metal in the form of sludge can be termed an ECM process, having primary salient features consisting of the tool, workpiece, power supply and electrolyte solution. ECM is a potential nontraditional machining process that includes too many factors contributing to process performance. Therefore, obtaining optimal factor combinations for higher efficiency is complex. In this research work, machining parameters are voltage, powder concentration and electrolyte concentration, based on which material removal rate (MRR) and surface roughness (SR) are derived. Regression analysis, signal-to-noise ratios and analysis of variance (ANOVA) are performed to determine the optimal levels and to examine the effects of machining parameters on MRR and SR. The results derived from the experiments noticed that the MRR decreases when the voltage level is increased and surface roughness decreases for the applied voltage. In case of an increase in powder concentration, MRR decreases from range 4 to 6 and further reduces to 6–8. In case of SR, it additionally decreases on the maximum level of powder concentration. In electrolyte concentration, the MRR decreases on the increment of electrolyte and increases after a short period of time; simultaneously SR is increased from range value 10–20 and decreased with a maximum level 20–30 of NaCl solution. A comparison of MOORA-PCA and TOPSIS-PCA demonstrates the superiority of TOPSIS over MOORA technique. Statistical results (95% confidence level) indicate that the voltage, powder concentration, and electrolyte concentration affect the surface roughness by 69.50%, 8.67% and 14.59% in the electrochemical machining of d3 die steel. Therefore, the optimum combination of process parameters corresponding to voltage: 45 V, powder concentration: 4 g/L, and electrolyte concentration: 10 NaCl/L, respectively, were found to yield the desired result. The prediction accuracy of the TOPSIS-PCA hybrid approach model is found better than MOORA-PCA technique. [ABSTRACT FROM AUTHOR]

The paper deals with the issue of engineering change management (ECM). ECM has received much less attention in the literature than general change management. Moreover, due to their specifics (complexity and multifaceted nature), hitherto developed ECM models are difficult to implement in companies. The paper aims to develop a simplified, universal, and hence easily applicable model of ECM. We based our assumptions on a case study of a manufacturing company with low-volume production, representing a high-mix type, posing the following research question: how to improve the ECM process to make it simpler and more quickly adaptable in companies with the analyzed type of production when compared to the existing models? To answer this question, an exploratory qualitative study was conducted in late 2021/early 2022 using in-depth personal interviews. The research sample included 31 employees involved in ECM processes. Conventional qualitative content analysis was the primary technique for analyzing and interpreting the data. The study identified gaps and bottlenecks in the existing ECM model. On this basis, a proposal for a new ECM model was developed, distinguished by its simplicity and versatility (it can be implemented in companies operating in various industries). Particular emphasis was placed on ensuring the flow of information and circulation of technical documentation between the departments involved and clarifying the role of the change administrator. The paper sheds new light on how to implement engineering changes in organizations and has considerable application value. [ABSTRACT FROM AUTHOR]

The availability of innovative payment services and the growing popularity of smartphone-based payment services (SBPS), particularly among youth, recognise India's potential to emerge as less cash or cashless economy in the near future. The influence of pre-adoption expectancies, usage experience, and conventional inhibitions on Indian youth's continuance intention to use SBPS has been investigated by integrating both adoption (UTAUT2) and post-adoption (ECM) models. PLS-SEM results show that satisfaction and facilitating conditions significantly influence continuance intention to use SBPS, whereas conventional inhibitions do not. Trust, habit, confirmation, facilitating conditions, and price value are the significant contributors to customer satisfaction. The outcome of the study reiterates the importance of strengthening the payment infrastructure and ensuring satisfaction so as to motivate young users to continue using SBPS. [ABSTRACT FROM AUTHOR]

Introduction: Microperforated panels (MPPs), often considered as potential replacements for fiber absorbers, have a significant limitation in their absorption bandwidth, particularly around the natural frequency. This study aims to address this challenge by focusing on the optimization and modeling of sound absorption in a manufactured MPP. Material and Methods: The study employed Response Surface Methodology (RSM) with a Central Composite Design (CCD) approach using Design Expert software to determine the average normal absorption coefficient within the frequency range of 125 to 2500 Hz. Numerical simulations using the Finite Element Method (FEM) were conducted to validate the RSM findings. An MPP absorber was then designed, manufactured, and evaluated for its normal absorption coefficient using an impedance tube. Additionally, a theoretical Equivalent Circuit Model (ECM) was utilized to predict the normal absorption coefficient for the manufactured MPP. Results: The optimization process revealed that setting the hole diameter to 0.3 mm, the percentage of perforation to 2.5%, and the air cavity depth behind the panel to 25 mm resulted in maximum absorption within the specified frequency range. Under these optimized conditions, the average absorption coefficient closely aligned with the predictions generated by RSM across numerical, theoretical, and laboratory assessments, demonstrating a 13.8% improvement compared to non-optimized MPPs. Conclusion: This study demonstrates the effectiveness of using RSM to optimize the parameters affecting MPP performance. The substantial correlation between the FEM numerical model, ECM theory model, and impedance tube results positions these models as both cost-effective and reliable alternatives to conventional laboratory methods. The consistency of these models with the experimental outcomes validates their potential for practical applications.

Abstract Bluetongue virus (BTV) infection induces profound and intricate changes in the transcriptional profile of the host to facilitate its survival and replication. However, there have been no whole-transcriptome studies on ovine lung microvascular endothelial cells (OLMECs) infected with BTV. In this study, we comprehensively analysed the whole-transcriptome sequences of BTV-1 serotype-infected and mock-infected OLMECs and subsequently performed bioinformatics differential analysis. Our analysis revealed 1215 differentially expressed mRNA transcripts, 82 differentially expressed long noncoding RNAs (lncRNAs) transcripts, 63 differentially expressed microRNAs (miRNAs) transcripts, and 42 differentially expressed circular RNAs (circRNAs) transcripts. Annotation from Gene Ontology, enrichment from the Kyoto Encyclopedia of Genes and Genomes, and construction of endogenous competing RNA network analysis revealed that the differentially expressed RNAs primarily participated in viral sensing and signal transduction pathways, antiviral and immune responses, inflammation, and extracellular matrix (ECM)-related pathways. Furthermore, protein‒protein interaction network analysis revealed that BTV may regulate the conformation of ECM receptor proteins and change their biological activity through a series of complex mechanisms. Finally, on the basis of real-time fluorescence quantitative polymerase chain reaction results, the expression trends of the differentially expressed RNA were consistent with the whole-transcriptome sequencing data, such as downregulation of the expression of COL4A1, ITGA8, ITGB5, and TNC and upregulation of the expression of CXCL10, RNASEL, IRF3, IRF7, and IFIHI. This study provides a novel perspective for further investigations of the mechanism of the ECM in the BTV-host interactome and the pathogenesis of lung microvascular endothelial cells.

Silicon carbide particle reinforced aluminum matrix composites (SiCp/Al), combine the properties of aluminum matrix materials and reinforced silicon carbide (SiC) particles, finding widespread application in aerospace, optics, and electronics. The increased hardness and electrochemical inertness of SiC particles present significant challenges in their processing. This research investigates the impact of photocatalytic processes on machining accuracy in electrochemical processing (ECM). The dissolution characteristics of SiCp/Al during ECM and photocatalytic-assisted electrochemical machining (PAECM) were analyzed with varying electrolyte compositions, using polarization curves and oxidation–reduction potential (ORP). Validation of improved machining accuracy and surface quality in PAECM was achieved through no-feeding machining. According to theoretical principles and laboratory analyses of the workpiece surface, it was found that PAECM, through its photocatalytic reaction, generated more oxides, blocked stray currents and stray corrosion effectively, and attained accuracy in profile creation. Through a comparative analysis it revealed that PAECM exhibited smoother profiles and reduced Overcut Ratio (OCR) in hole and groove machining compared to ECM, particularly in groove machining. Adjusting machining gaps as well as reducing abrasive particle size in PAECM influenced groove depth and width, which achieved optimal morphology with a 0.4 mm gap and a 2–3 nm abrasive particle size, resulting in a 370 μm depth. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a severe renal disorder that arises as a complication of diabetes. Liraglutide, an analogue of a glucagon‐like peptide 1 (GLP‐1) receptor agonist, has been shown to decrease diabetes‐caused renal damage. Nevertheless, the complete understanding of the roles and mechanism remains unclear. In our study, diabetic rat models were created through a single intraperitoneal injection of streptozotocin (STZ). The level of fasting blood glucose, 24‐h urine protein, serum creatinine (Scr) and blood urea nitrogen (BUN) were assessed. Periodic acid‐Schiff (PAS) staining was applied to examine the pathological changes in renal tissues. Reactive oxygen species (ROS) formation was measured via dichloro‐dihydro‐fluorescein diacetate (DCFH‐DA) probes. Western blot was conducted to examine the levels of oxidative stress‐related and extracellular matrix (ECM)‐associated proteins. The nuclear translocation of NRF2 was investigated through immunofluorescence and Western blot assays. We demonstrated that liraglutide attenuated DN‐induced oxidative stress and ECM deposition in vitro and in vivo. Liraglutide exerted a reno‐protective effect by promoting nuclear translocation of NRF2 in mesangial cells. ML385, an NRF2 inhibitor, counteracted the beneficial impact of liraglutide. [ABSTRACT FROM AUTHOR]

Background: Fibulin-2 (FBLN2) is a secreted extracellular matrix (ECM) glycoprotein and has been identified in the mouse mammary gland, in cap cells of terminal end buds (TEBs) during puberty, and around myoepithelial cells during early pregnancy. It is required for basement membrane (BM) integrity in mammary epithelium, and its loss has been associated with human breast cancer invasion. Herein, we attempted to confirm the relevance of FBLN2 to myoepithelial phenotype in mammary epithelium and to assess its expression in molecular subtypes of human breast cancer. Methods: The relationship between FBLN2 expression and epithelial markers was investigated in pubertal mouse mammary glands and the EpH4 mouse mammary epithelial cell line using immunohistochemistry, immunocytochemistry, and immunoblotting. Human breast cancer mRNA data from the METABRIC and TCGA datasets from Bioportal were analyzed to assess the association of Fbln2 expression with epithelial markers, and with molecular subtypes. Survival curves were generated using data from the METABRIC dataset and the KM databases. Results: FBLN2 knockdown in mouse mammary epithelial cells was associated with a reduction in KRT14 and an increase in KRT18. Further, TGFβ3 treatment resulted in the upregulation of FBLN2 in vitro. Meta-analyses of human breast cancer datasets from Bioportal showed a higher expression of Fbln2 mRNA in claudin-low, LumA, and normal-like breast cancers compared to LumB, Her2 +, and Basal-like subgroups. Fbln2 mRNA levels were positively associated with mesenchymal markers, myoepithelial markers, and markers of epithelial–mesenchymal transition. Higher expression of Fbln2 mRNA was associated with better prognosis in less advanced breast cancer and this pattern was reversed in more advanced lesions. Conclusion: With further validation, these observations may offer a molecular prognostic tool for human breast cancer for more personalized therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: The Murrah buffalo, pivotal in Asian agriculture, faces challenges in maximizing milk production despite significant breeding efforts. Recognizing its economic importance, this study investigates mtDNA D-loop variations in Murrah buffalo as potential indicators of milk production variability, addressing challenges in maximizing yield despite significant breeding efforts. Methods and results: Analyzing mtDNA D-loop sequences from 50 buffaloes, we categorized them into Low (Group 1), Medium (Group 2), and High ECM (Group 3) groups based on milk yields, fat and protein percentage of a 30-day period data. Somatic cell mtDNA D-loop analysis revealed distinct genetic variations, with significant differences among ECM groups. Group 2 showed higher SNP prevalence, group 3 had more insertions/deletions, and Group 1 exhibited the highest transition frequency. Notably, a consistent "C" deletion at the 714th position occurred in Groups 1 and 3, prevalent in 68% of Group 2. A G-A variation at the 93rd position was specific to the medium ECM group. Negative Tajima D values indicated unique variations in each group, with Group 1 having the highest number, and a specific SNP linked to Group 2 was identified. These SNPs in the D-loop region could impact mtDNA replication, influencing mitochondrial content among animals. Our results provide valuable insights into the role of mtDNA D-loop polymorphisms in milk production traits in Murrah buffalo. Conclusions: Our research highlights the potential for valuable markers of cellular energy efficiency in Murrah buffalo. Exploring diverse cytoplasmic backgrounds opens avenues for mtDNA-based selection strategies, enhancing milk production and optimizing genetic traits for the dairy industry. [ABSTRACT FROM AUTHOR]

Abstract Remodeling (re-engineering) of a tumor’s stroma has been shown to improve the efficacy of anti-tumor therapies, without destroying the stroma. Even though it still remains unclear which stromal component/-s and what characteristics hinder the reach of nanoparticles deep into cancer cells, we hypothesis that mechanisms behind stroma’s resistance to the penetration of nanoparticles rely heavily on extrinsic mechanical forces on stromal cells and cancer cells. Our hypothesis has been formulated on the basis of our previous study which has shown that changes in extracellular matrix (ECM) stiffness with tumor growth influence stresses exerted on fibroblasts and cancer cells, and that malignant cancer cells generate higher stresses on their stroma. This study attempts to establish a distinct identification of the components’ remodeling on the distribution and magnitude of stress within a tumor tissue which ultimately will impact the resistance of stroma to treatment. In this study, our objective is to construct a three-dimensional in silico model of a pancreas tumor tissue consisting of cancer cells, stromal cells, and ECM to determine how stromal remodeling alters the stresses distribution and magnitude within the pancreas tumor tissue. Our results show that changes in mechanical properties of ECM significantly alter the magnitude and distribution of stresses within the pancreas tumor tissue. Our results revealed that these stresses are more sensitive to ECM properties as we see the stresses reaching to a maximum of 22,000 Pa for softer ECM with Young’s modulus of 250 Pa. The stress distribution and magnitude within the pancreas tumor tissue does not show high sensitivity to the changes in mechanical properties of stromal cells surrounding stiffer cancer cells (PANC-1 with Young’s modulus of 2400 Pa). However, softer cancer cells (MIA-PaCa-2 with (Young’s modulus of 500 Pa) increase the stresses experienced by stiffer stromal cells and for stiffer ECM. By providing a unique platform to dissect and quantify the impact of individual stromal components on the stress distribution within a tumor tissue, this study serves as an important first step in understanding of which stromal components are vital for an efficient remodeling. This knowledge will be leveraged to overcome a tumor’s resistance against the penetration of nanoparticles on a per-patient basis.

Abstract This study aimed to investigate the expression and significance of insulin-like growth factor binding protein 5 (IGFBP5) and extracellular matrix (ECM) related proteins in anterior vaginal wall tissues among aged pelvic organ prolapse (POP) patients. Tissues from the anterior vaginal wall were collected from 28 patients with POP and 20 patients without POP. The expression of protein and mRNA levels of IGFBP5 and ECM related proteins were evaluated in the vaginal wall tissues using immunohistochemistry, western blotting, and RT-qPCR techniques. The expression levels were then compared with clinical parameters. The expression levels of protein and mRNA of IGFBP5, collagen I, and collagen III were significantly lower in the POP group. Protein and mRNA expression levels of MMP2 were significantly higher in the POP group. IGFBP5 protein and mRNA expression levels were negatively correlated with age and significantly lower in older POP patients (≥ 65 years old) compared to younger POP patients (

A nation’s economic growth plays a pivotal role in determining its level of national economic integration and participation in global value chains. This research investigates the impact of urbanization and ruralization on economic growth in the case of Tunisia, utilizing annual data spanning from 1965 to 2019. The findings, derived from the estimation of an autoregressive distributed lag model and an error correction model, reveal a negative correlation between urbanization and Tunisian economic growth. Conversely, ruralization is found to have a positive impact, suggesting that Tunisia may not have reached a stage of urban saturation. The study implies that urbanization, without concurrent industrialization, has encountered limitations. Consequently, Tunisia, having developed without due industrial progress, is no longer perceived as a privileged locale but at times faces exclusion. In addressing the urban crisis, ’urban exodus’ becomes, at times, the sole response.

Abstract Intestinal fibrosis is a prevalent complication of IBD that that can frequently be triggered by prolonged inflammation. Fibrosis in the gut can cause a number of issues, which continue as an ongoing challenge to healthcare systems worldwide. The primary causes of intestinal fibrosis are soluble molecules, G protein-coupled receptors, epithelial-to-mesenchymal or endothelial-to-mesenchymal transition, and the gut microbiota. Fresh perspectives coming from in vivo and in vitro experimental models demonstrate that fibrogenic pathways might be different, at least to some extent, independent of the ones that influence inflammation. Understanding the distinctive procedures of intestinal fibrogenesis should provide a realistic foundation for targeting and blocking specific fibrogenic pathways, estimating the risk of fibrotic consequences, detecting early fibrotic alterations, and eventually allowing therapy development. Here, we first summarize the inflammatory and non-inflammatory components of fibrosis, and then we elaborate on the underlying mechanism associated with multiple cytokines in fibrosis, providing the framework for future clinical practice. Following that, we discuss the relationship between modernization and disease, as well as the shortcomings of current studies. We outline fibrosis diagnosis and therapy, as well as our recommendations for the future treatment of intestinal fibrosis. We anticipate that the global review will provides a wealth of fresh knowledge and suggestions for future fibrosis clinical practice. Graphical Abstract

Abstract Sesame is a major annual oil crop that is grown practically everywhere in tropical and subtropical Asia, as well as Africa, for its very nutritious and tasty seeds. Rising temperatures, droughts, floods, desertification, and weather all have a significant impact on agricultural production, particularly in developing countries like Ethiopia. Therefore, the main objective of this study is to examine the influence of climate change on the sesame yield in North Gondar, North Ethiopia, by using the autoregressive distributed Lag (ARDL) time series model. This study employed climate data from the Bahirdar Agrometeorological Center and secondary data on sesame production from the Ethiopian Statistical Service, spanning 36 years, from 1987 to 2023. Autoregressive Distributed LAG (ARDL) includes diagnostic tests for both short- and long-term autoregressive models. The results for the long-run and short-run elastic coefficients show a significant positive association between temperatures and sesame yield. Sesame yield and rainfall have a significant negative long-run and short-run relationship in North Gondar, North Ethiopia. ARDL results confirm that temperature and rainfall have significant effects on sesame productivity. Temperature had a considerable favorable effect on sesamen production, but rainfall had a negative effect in North Gondar, Ethiopia. Based on the evidence acquired from our study, we made several policy recommendations and suggestions to government officials, policymakers, new technologies, researchers, policy development planners, and other stakeholders in order to develop or implement new technology to halt its production and direct adaptation measures in light of the certainty of global warming and the characteristics of climate-dependent agricultural production.

Remodeling (re-engineering) of a tumor's stroma has been shown to improve the efficacy of anti-tumor therapies, without destroying the stroma. Even though it still remains unclear which stromal component/-s and what characteristics hinder the reach of nanoparticles deep into cancer cells, we hypothesis that mechanisms behind stroma's resistance to the penetration of nanoparticles rely heavily on extrinsic mechanical forces on stromal cells and cancer cells. Our hypothesis has been formulated on the basis of our previous study which has shown that changes in extracellular matrix (ECM) stiffness with tumor growth influence stresses exerted on fibroblasts and cancer cells, and that malignant cancer cells generate higher stresses on their stroma. This study attempts to establish a distinct identification of the components' remodeling on the distribution and magnitude of stress within a tumor tissue which ultimately will impact the resistance of stroma to treatment. In this study, our objective is to construct a three-dimensional in silico model of a pancreas tumor tissue consisting of cancer cells, stromal cells, and ECM to determine how stromal remodeling alters the stresses distribution and magnitude within the pancreas tumor tissue. Our results show that changes in mechanical properties of ECM significantly alter the magnitude and distribution of stresses within the pancreas tumor tissue. Our results revealed that these stresses are more sensitive to ECM properties as we see the stresses reaching to a maximum of 22,000 Pa for softer ECM with Young's modulus of 250 Pa. The stress distribution and magnitude within the pancreas tumor tissue does not show high sensitivity to the changes in mechanical properties of stromal cells surrounding stiffer cancer cells (PANC-1 with Young's modulus of 2400 Pa). However, softer cancer cells (MIA-PaCa-2 with (Young's modulus of 500 Pa) increase the stresses experienced by stiffer stromal cells and for stiffer ECM. By providing a unique platform to dissect and quantify the impact of individual stromal components on the stress distribution within a tumor tissue, this study serves as an important first step in understanding of which stromal components are vital for an efficient remodeling. This knowledge will be leveraged to overcome a tumor's resistance against the penetration of nanoparticles on a per-patient basis. [ABSTRACT FROM AUTHOR]

Laminins are essential components of the basement membranes, expressed in a tissue- and cell-specific manner under physiological conditions. During inflammatory circumstances, such as atherosclerosis, alterations in laminin composition within vessels have been observed. Our study aimed to assess the influence of tumor necrosis factor-alpha (TNF), a proinflammatory cytokine abundantly found in atherosclerotic lesions, on endothelial laminin gene expression and the effects of laminin-332 (LN332) on endothelial cells' behavior. We also evaluated the expression of LN332-encoding genes in human carotid atherosclerotic plaques. Our findings demonstrate that TNF induces upregulation of LAMB3 and LAMC2, which, along with LAMA3, encode the LN332 isoform. Endothelial cells cultured on recombinant LN332 exhibit decreased claudin-5 expression and display a loosely connected phenotype, with an elevated expression of chemokines and leukocyte adhesion molecules, enhancing their attractiveness and adhesion to leukocytes in vitro. Furthermore, LAMB3 and LAMC2 are upregulated in human carotid plaques and show a positive correlation with TNF expression. In summary, TNF stimulates the expression of LN332-encoding genes in human endothelial cells and LN332 promotes an endothelial phenotype characterized by compromised junctional integrity and increased leukocyte interaction. These findings highlight the importance of basement membrane proteins for endothelial integrity and the potential role of LN332 in atherosclerosis. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the expression and significance of insulin-like growth factor binding protein 5 (IGFBP5) and extracellular matrix (ECM) related proteins in anterior vaginal wall tissues among aged pelvic organ prolapse (POP) patients. Tissues from the anterior vaginal wall were collected from 28 patients with POP and 20 patients without POP. The expression of protein and mRNA levels of IGFBP5 and ECM related proteins were evaluated in the vaginal wall tissues using immunohistochemistry, western blotting, and RT-qPCR techniques. The expression levels were then compared with clinical parameters. The expression levels of protein and mRNA of IGFBP5, collagen I, and collagen III were significantly lower in the POP group. Protein and mRNA expression levels of MMP2 were significantly higher in the POP group. IGFBP5 protein and mRNA expression levels were negatively correlated with age and significantly lower in older POP patients (≥ 65 years old) compared to younger POP patients (< 65 years old). IGFBP5 protein and mRNA expression levels were also significantly lower in POP-Q stage IV patients compared to POP-Q stage III patients. IGFBP5 expression level is negatively correlated with the age and severity of prolapse. The significant decrease in IGFBP5 expression may play a crucial part in the aging process and the occurrence of POP. [ABSTRACT FROM AUTHOR]

In the midst of the rising popularity of Subscription Video On Demand (SVOD), the industry faces significant challenges. The high churn rate and the abundance of competitors in the SVOD industry necessitate that service providers develop strategies to maintain consumer interest. Consumers who significantly contribute to the high churn rate are Generation Y and Generation Z, also known as digital natives. This study aims to analyze how factors within the Expectancy Confirmation Model can influence the Continuance Intention of SVOD users. This descriptive study employs a cross- sectional design. The respondents of this study consist of 159 active SVOD users. The findings reveal that confirmation and individual mobility significantly influence perceived usefulness. Additionally, confirmation, perceived usefulness, and perceived enjoyment significantly affect satisfaction. Furthermore, satisfaction, perceived usefulness, and habit are significant predictors of continuance intention. However, the influence of individual mobility and perceived enjoyment on continuance intention is not significant. Practically, this study provides insights for SVOD service providers to develop marketing strategies that enhance consumer habit and satisfaction. Academically, this study combines two models from previous researchs making the model and variables used more comprehensive in explaining the predictors of continuance intention. [ABSTRACT FROM AUTHOR]

The main component of human skin is a collagen-rich extracellular matrix (ECM), known as the matrisome. The matrisome is essential for maintaining the structural integrity and mechanical properties of the skin. Recently, we reported notable decreases in matrisome proteins in natural aging and photoaging human skin. This study aims to investigate the mRNA expression of the core matrisome proteins in human skin, comparing young versus aged and sun-protected versus sun-exposed skin by quantitative real-time PCR and immunostaining. Our findings reveal a notable decrease in core matrisome transcription in aged skin. The mRNA expression of the core matrisome, such as collagen 1A1 (COL1A1), decorin, and dermatopontin, is significantly reduced in aged skin compared to its young skin. Yet, the majority of collagen mRNA expression levels of aged sun-exposed skin are similar to those found in young sun-exposed skin. This discrepancy is primarily attributable to a substantial decrease in collagen transcription in young sun-exposed skin, suggesting early molecular changes in matrisome transcription due to sun exposure, which preceded the emergence of clinical signs of photoaging. These findings shed light on the mRNA transcript profile of major matrisome proteins and their alterations in naturally aged and photoaged human skin, offering valuable insights into skin matrisome biology. [ABSTRACT FROM AUTHOR]

In RNA-seq data analysis, condensing the gene count matrix size is pivotal for downstream investigations, particularly pathway analysis. For this purpose, harnessing machine learning attracts increasing interest, while conventional methodologies depend on p-value comparisons. In this study, 20 tissue samples from real-world cervical cancers were subjected to sequencing, followed by the application of the Mclust algorithm to delineate an optimal cluster. By stratifying tumor budding into high and low groups and quantifying the epithelial-to-mesenchymal transition (EMT) score to scrutinize tumor budding, we discerned 24 EMT-related genes, with 5 showing strong associations with cervical cancer prognosis. Our observations elucidate a biological flow wherein EMT, Matrix Metallopep-tidase 2 (MMP2), and extracellular matrix (ECM) degradation are interconnected, ultimately leading to collagen type VI and exacerbating the prognosis of cervical cancer. The present study underscores an alternative method for selecting useful EMT-related genes by employing an appropriate clustering algorithm, thereby avoiding classical methods while unveiling novel insights into cervical cancer etiology and prognosis. Moreover, when comparing high and low tumor budding, collagen type VI emerges as a potential gene marker for the prognosis of cervical cancer. [ABSTRACT FROM AUTHOR]

In this paper, a study was conducted on the electrochemical machining (ECM) of titanium-shaped grid holes. Firstly, the polarization characteristic curves of titanium alloy TC4 in different electrolytes were measured by an electrochemical workstation, and the mechanism of action was analyzed. The electrolyte formula was developed for 11%NaCl + 5%NaNO3 saturated ethylenediaminetetraacetic acid (EDTA). Secondly, the equal clearance method was used to design the cathode, gap flow field simulation was used to analyze five different structures of through-liquid slots, and the structural form and size of the through-liquid slots were preferred. The voltage range of ECM was determined to be 14 ~ 22 V by the multi-physical field coupling simulation analysis. Finally, through the process test, the Taguchi algorithm and gray correlation degree method were used to optimize the process objectives; to obtain the degree of influence of different factors on the experimental process objectives, machining voltage > feed velocity > duty ratio > inlet pressure; and to obtain the optimal combination of machining parameters, machining voltage of 20 V, duty ratio of 35%, inlet pressure of 0.7 MPa, and feed velocity of 0.55 mm/min. The titanium-shaped grid holes machined by the optimal process parameters have a dimension error of 0.14 mm and a surface roughness of 0.812 μm, which meet the actual production requirements. Using this process parameter for ECM of the more difficult shaped blind holes (hole depth of 10 mm), the dimension error and roughness meet the processing requirements, which further verifies the feasibility of the optimal parameters. The research results show the ECM can realize high-efficiency and high-quality processing of the titanium-shaped grid hole. It also provides process technology reference for the machining of other complex-shaped hole parts to promote the technical progress of the industry. [ABSTRACT FROM AUTHOR]

The passivation characteristics of titanium alloys in electrolytes are often the main reason that impede the electrochemical reaction process. Hence, maintaining uniform electrochemical dissolution is a prerequisite for stable electrochemical machining (ECM) of titanium alloys. In this study, a novel cathode structure with built-in insulator is proposed, whichimproves machining stability of titanium alloys in ECM. Flow dynamics simulation results show that the cathodes with built-in insulator 1 or insulator 3 demonstrate more uniform flow effect. ECM experiments reveal that the optimized cathode can reduce the time of current from transition section to balance section, presenting a optimal transition time of 180 s. Compared with the original cathode, the sample surface machined using the optimized cathode is smooth without defects. Additionally, the optimal width of the non-processing stray corrosion area decreases from 603.47 μm to 214.54 μm, and 1010.47 μm to 349.25 μm. The optimal machining taper angle is 9.85°. [ABSTRACT FROM AUTHOR]

The current study explores the effectiveness of the ECM process when machining newly developed high entropy alloy (HEA)-reinforced magnesium composites. To evaluate the machinability, the study focuses on two key output constraints: surface roughness (Ra) and material removal rate (MRR). Experimental trials involve adjusting variables such as feed rate (FR), current, Electrolyte concentration (EC), & voltage in which experiment design is done through Taguchi method. Results highlights voltage as the most important input parameter governing Ra, followed by current. Similarly, voltage emerges as the primary influencer for MRR, with current being the second most influential. Furthermore, artificial neural networks (ANN) yielded predictions closely aligns with the experimental data. The optimal parameter set identified through CRITIC-WASPAS method included 5 Wt.% HEA, 15 V Voltage, 2 Amps current, 0.3 mm/min feed, and 25 g/lit electrolyte concentrations, resulting in a surface finish of 3.47 µm and a production rate of 0.039 mg/min. [ABSTRACT FROM AUTHOR]

The study aims to identify which main macroeconomic determinants affect investment in a circular economy. The main purpose of the investment determinants in a circular economy is to determine how macroeconomic determinants such as real GDP per capita, government expenditure, unemployment, inflation, tax revenue, and interest rate affect an investment in the circular economy in the European Union for the period 2004–2022. Using an error correction model, empirical findings confirmed that government expenditure, inflation, and tax revenue have positive effects on investment in the circular economy in the short run and long run. Conversely, unemployment and interest rate negatively affect investment in the circular economy for both the short term and long term. The contribution of the paper is providing valuable insights into the determinants driving investment in the circular economy, which may help with developing sustainable business policies and practices in the European Union. [ABSTRACT FROM AUTHOR]

Understanding the tumor microenvironment (TME) and extracellular matrix (ECM) is crucial in cancer research due to their impact on tumor progression. Collagens, major ECM components, regulate cell signaling and behavior. Of the 28 reported collagens, type XII collagen is known to be vital for ECM organization. Over-produced by cancer-associated fibroblasts (CAFs), its upregulation correlates with poor survival in various cancers. This study aimed to develop an ELISA for quantifying circulating type XII collagen as a cancer biomarker. A specific ELISA targeting the C-terminal of type XII collagen was developed and used to analyze serum samples from cancer patients (n = 203) and healthy controls (n = 33). Additionally, type XII collagen expression was assessed in CAFs and normal fibroblasts (NFs) from different tissues, both under TGF-β stimulated and non-stimulated conditions. The nordicPRO-C12 ELISA demonstrated robustness and specificity for type XII collagen. PRO-C12 levels were significantly elevated in patients with various cancers compared to healthy controls and effectively distinguished between cancer patients and controls. Findings were validated using gene expression data. Furthermore, Western blot analysis revealed increased type XII collagen expression in both CAFs and NFs upon TGF-β1 stimulation, suggesting a potential role of TGF-β1 in modulating the expression of type XII collagen in cancerous and normal tissue microenvironments. This study unveils a promising avenue for harnessing PRO-C12 as a non-invasive serum biomarker, enabling the quantification of type XII collagen fragments in cancer patients. Further investigations are warranted to explore the potential of PRO-C12 across different cancer types and disease stages, shedding light on its multifaceted role in cancer development. [ABSTRACT FROM AUTHOR]

The development of biomaterials tailored for various tissue engineering applications has been increasingly researched in recent years; however, stimulating cells to synthesise the extracellular matrix (ECM) is still a significant challenge. In this study, we investigate the use of ECM-like hydrogel materials composed of Gelatin methacryloyl (GelMA) and glycosaminoglycans (GAG), such as hyaluronic acid (HA) and chondroitin sulphate (CS), to provide a biomimetic environment for tissue repair. These hydrogels are fully characterised in terms of physico-chemical properties, including compression, swelling behaviour, rheological behaviour and via 3D printing trials. Furthermore, porous scaffolds were developed through freeze drying, producing a scaffold morphology that better promotes cell proliferation, as shown by in vitro analysis with fibroblast cells. We show that after cell seeding, freeze-dried hydrogels resulted in significantly greater amounts of DNA by day 7 compared to the GelMA hydrogel. Furthermore, freeze-dried constructs containing HA or HA/CS were found to have a significantly higher metabolic activity than GelMA alone. [ABSTRACT FROM AUTHOR]

Biofilms, comprised of cells embedded in extracellular matrix (ECM), enable bacterial surface colonization and contribute to pathogenesis and biofouling. Yet, antibacterial surfaces are mainly evaluated for their effect on bacterial cells rather than the ECM. Here, a method is presented to separately quantify amounts and distribution of cells and ECM in Salmonella biofilms grown on electroactive poly(3,4‐ethylenedioxythiophene):polystyrenesulfonate (PEDOT:PSS). Within a custom‐designed biofilm reactor, biofilm forms on PEDOT:PSS surfaces electrically addressed with a bias potential and simultaneous recording of the resulting current. The amount and distribution of cells and ECM in biofilms are analyzed using a fluorescence‐based spectroscopic mapping technique and fluorescence confocal microscopy combined with advanced image processing. The study shows that surface charge leads to upregulated ECM production, leaving the cell counts largely unaffected. An altered texture is also observed, with biofilms forming small foci or more continuous structures. Supported by mutants lacking ECM production, ECM is identified as an important target when developing antibacterial strategies. Also, a central role for biofilm distribution is highlighted that likely influences antimicrobial susceptibility in biofilms. This work provides yet a link between conductive polymer materials and bacterial metabolism and reveals for the first time a specific effect of electrochemical addressing on bacterial ECM formation. [ABSTRACT FROM AUTHOR]

Screw drill is one of the most widely used power drilling tools in the field of deep sea drilling because of its excellent performance such as low drilling speed, high torque, and strong overload capacity. However, it has the problems of complex internal structure and long processing stroke of screw drill stator. In this paper, the electrochemical machining (ECM) technology is used to solve the problem of internal spiral curved surface special-shaped deep hole machining. Firstly, the initial cathode structure with spirally increasing tooth surface of six machining teeth is designed, and the gas-liquid two-phase flow field model of the gap is established to simulate and analyze it. The simulation results show that the flow field distribution of the electrolyte in the machining gap is not uniform and the bubble concentration is high. Secondly, the initial cathode structure is optimized by adding different numbers of liquid-increasing grooves on the tooth surface of the machined tooth, and the gas-liquid two-phase flow field is simulated. The simulation results show that the cathode structure with four additional baths on each tooth surface results in a better overall flow of electrolyte in the machining gap, a flow rate of more than 3 m/s in the machining area, and a significant reduction in the concentration of electrolyte bubbles, with a reduced rate of 18.7% and a smaller distribution area for the highest bubble concentration, ensure the machining accuracy. Finally, the orthogonal experiment of 4 factors and 4 levels was designed, and the optimized processing parameters were obtained by gray correlation analysis method, that is, inlet pressure of 0.4 MPa, machining voltage of 11 V, duty cycle of 40%, and cathode feed rate of 0.9 mm/min, under which the deviation of the large end diameter of the deep special-shaped hole was 0.15 mm, the surface roughness of the inner wall of the hole was 0.487 μm. The data shows that this combination of processing parameters meets the production requirements of the product. The data shows that this combination of machining parameters meets the production requirements of the product. The COMSOL simulation method significantly shortens the research cycle and saves research costs. [ABSTRACT FROM AUTHOR]

The biophysical and biomechanical properties of the extracellular matrix (ECM) are crucial in the processes of cell differentiation and proliferation. However, it is unclear to what extent tumor cells are influenced by biomechanical and biophysical changes of the surrounding microenvironment and how this response varies between different tumor forms, and over the course of tumor progression. The entire ensemble of genes encoding the ECM associated proteins is called matrisome. In cancer, the ECM evolves to become highly dysregulated, rigid, and fibrotic, serving both pro-tumorigenic and antitumorigenic roles. Tumor desmoplasia is characterized by a dramatic increase of α-smooth muscle actin expressing fibroblast and the deposition of hard ECM containing collagen, fibronectin, proteoglycans, and hyaluronic acid and is common in many solid tumors. In this review, we described the role of inflammation and inflammatory cytokines, in desmoplastic matrix remodeling, tumor state transition driven by microenvironment forces and the signaling pathways in mechanotransduction as potential targeted therapies, focusing on the impact of qualitative and quantitative variations of the ECM on the regulation of tumor development, hypothesizing the presence of matrisome drivers, acting alongside the cell-intrinsic oncogenic drivers, in some stages of neoplastic progression and in some tumor contexts, such as pancreatic carcinoma, breast cancer, lung cancer and mesothelioma. [ABSTRACT FROM AUTHOR]

The mammalian neocortex is formed by sequential radial migration of newborn excitatory neurons. Migrating neurons undergo a multipolar-to-bipolar transition at the subplate (SP) layer, where extracellular matrix (ECM) components are abundantly expressed. Here, we investigate the role of the ECM at the SP layer. We show that TGF-β signaling-related ECM proteins, and their downstream effector, p-smad2/3, are selectively expressed in the SP layer. We also find that migrating neurons express a disintegrin and metalloproteinase with thrombospondin motif 2 (ADAMTS2), an ECM metalloproteinase, just below the SP layer. Knockdown and knockout of Adamts2 suppresses the multipolar-to-bipolar transition of migrating neurons and disturbs radial migration. Time-lapse luminescence imaging of TGF-β signaling indicates that ADAMTS2 activates this signaling pathway in migrating neurons during the multipolar-to-bipolar transition at the SP layer. Overexpression of TGF-β2 in migrating neurons partially rescues migration defects in ADAMTS2 knockout mice. Our data suggest that ADAMTS2 secreted by the migrating multipolar neurons activates TGF-β signaling by ECM remodeling of the SP layer, which might drive the multipolar to bipolar transition. Synopsis: ADAMTS2 is secreted by migratory neurons during the formation of the mammalian neocortex. ADAMTS2 promotes neuronal migration by activating TGF-β signaling in migrating neurons during the multipolar-to-bipolar transition at the SP layer. ECM proteins are abundant in the subplate layer of the neocortex. Admts2 is upregulated during the migration of newborn neurons in the developing cortex. ADAMTS2 activates TGF-β signaling perhaps by ECM remodeling of the SP layer, which might facilitate the multipolar to bipolar transition. ADAMTS2 is secreted by migratory neurons during the formation of the mammalian neocortex. ADAMTS2 promotes neuronal migration by activating TGF-β signaling in migrating neurons during the multipolar-to-bipolar transition at the SP layer. [ABSTRACT FROM AUTHOR]