Models of Fractal River Basins

Two distinct models for self-similar and self-affine river basins are numerically investigated. They yield fractal aggregation patterns following non-trivial power laws in experimentally relevant distributions. Previous numerical estimates on the critical exponents, when existing, are confirmed and superseded. A physical motivation for both models in the present framework is also discussed.Comment: 16 pages, latex, 9 figures included using uufiles command (for any problem: [email protected]), to be publishes in J. Stat. Phys. (1998

Extra-hepatic metabolism of 7-ketocholesterol occurs by esterification to fatty acids via cPLA2α and SOAT1 followed by selective efflux to HDL

AbstractAccumulation of 7-ketocholesterol (7KCh) in tissues has been previously associated with various chronic aging diseases. Orally ingested 7KCh is readily metabolized by the liver and does not pose a toxicity threat. However, 7KCh formed in situ, usually associated with lipoprotein deposits, can adversely affect surrounding tissues by causing inflammation and cytotoxicity. In this study we have investigated various mechanisms for extra-hepatic metabolism of 7KCh (e.g. hydroxylation, sulfation) and found only esterification to fatty acids. The esterification of 7KCh to fatty acids involves the combined action of cytosolic phospholipase A2 alpha (cPLA2α) and sterol O-acyltransferase (SOAT1). Inhibition of either one of these enzymes ablates 7KCh-fatty acid ester (7KFAE) formation. The 7KFAEs are not toxic and do not induce inflammatory responses. However, they can be unstable and re-release 7KCh. The higher the degree of unsaturation, the more unstable the 7KFAE (e.g. 18:0>18:1>18:2>18:3≫20:4). Biochemical inhibition and siRNA knockdown of SOAT1 and cPLA2α ablated the 7KFAE synthesis in cultured ARPE19 cells, but had little effect on the 7KCh-induced inflammatory response. Overexpression of SOAT1 reduced the 7KCh-induced inflammatory response and provided some protection from cell death. This effect is likely due to the increased conversion of 7KCh to 7KFAEs, which reduced the intracellular 7KCh levels. Addition of HDL selectively increased the efflux of 7KFAEs and enhanced the effect of SOAT1 overexpression. Our data suggests an additional function for HDL in aiding extra-hepatic tissues to eliminate 7KCh by returning 7KFAEs to the liver for bile acid formation

Dielectric branes in non-trivial backgrounds

We present a procedure to evaluate the action for dielectric branes in non-trivial backgrounds. These backgrounds must be capable to be taken into a Kaluza-Klein form, with some non-zero wrapping factor. We derive the way this wrapping factor is gauged away. Examples of this are AdS_5xS^5 and AdS_3xS^3xT^4, where we perform the construction of different stable systems, which stability relies in its dielectric character.Comment: 14 pages, published versio

Relationship between handgrip strength and endogenous hormones in postmenopausal women

Objectives :This study aimed to evaluate the endogenous hormonal factors related to dominant handgrip strength (HGS) in postmenopausal women. Methods : A cross-sectional study was performed on 402 postmenopausal women aged 47 to 83 years. The following variables were recorded: age, age at menopause, smoking status, adiposity, HGS, and physical activity. Hormonal parameters (follicle-stimulating hormone, estradiol, testosterone, cortisol, dehydroepiandrosterone sulfate, ∆4 androstenedione, insulin-like growth factor-1 [IGF-1], vitamin D, and parathormone levels) were measured and results reported as odds ratios (ORs), β coefficients and 95% confidence interval (95% CI). A directed acyclic graph was used to identify potential confounding variables and was adjusted in the regression model to assess associations between endogenous hormones and HGS. Results :The mean dominant HGS was 22.8 ± 3.7 kg, and 25.6% of women had dynapenia. There were significant differences in plasma levels of follicle-stimulating hormone (OR, 0.99; 95% CI, 0.98-1.00), cortisol (OR, 1.07; 95% CI, 1.02-1.12), and dehydroepiandrosterone sulfate (OR, 0.99; 95% CI, 0.98-1.00) between women with normal HGS and those who presented with dynapenia. After adjusting for confounding variables, no significant association was found between endogenous hormones and HGS. Conclusions: Our results showed that studied ovarian steroids, adrenal hormones, IGF-1, parathormone, and vitamin D were not associated with HGS

Association of Endogenous Hormones and Bone Mineral Density in Postmenopausal Women

Aim: The aim of this study was to examine the association between endogenous hormones and bone mineral density (BMD) in postmenopausal women. Materials and Methods: This was a cross-sectional study of 798 postmenopausal women aged 47-85 years. Data were collected on age, age at menopause, years since menopause, smoking status, body mass index, adiposity, BMD, physical activity, and Vitamin D supplementation. Measured hormonal parameters were: follicle-stimulating hormone (FSH), estradiol, testosterone, dehydroepiandrosterone sulfate, 4-androstenedione, cortisol, insulin-like growth factor-1, 25-hydroxyvitamin D, and parathormone (PTH) levels. BMD was measured at the lumbar spine, femoral neck, and total hip using dual-energy X-ray absorptiometry. A directed acyclic graph was used to select potential confounding variables. Results: Multivariable analysis showed significant associations between cortisol and femoral neck BMD (β: -0.02, 95% confidence interval [CI]: -0.03 - 0.00), and PTH with femoral neck BMD (β: -0.01, 95% CI: -0.02 - 0.01) and total hip BMD (β: -0.01, 95% CI: -0.01 - 0.00). Hormonal factors more likely associated with a higher risk of low BMD (osteopenia or osteoporosis) were FSH (odds ratio [OR]: 1.02, 95% CI: 1.01-1.03) and PTH (OR: 1.02, 95% CI: 1.01-1.04). Conclusions: Higher cortisol and PTH levels were inversely associated with BMD. Postmenopausal women with higher FSH or PTH levels were likely to have low BMD. © 2023 Journal of Mid-life Health

7-Ketocholesterol increases retinal microglial migration, activation, and angiogenicity: a potential pathogenic mechanism underlying age-related macular degeneration.

Age-related macular degeneration (AMD) has been associated with both accumulation of lipid and lipid oxidative products, as well as increased neuroinflammatory changes and microglial activation in the outer retina. However, the relationships between these factors are incompletely understood. 7-Ketocholesterol (7KCh) is a cholesterol oxidation product localized to the outer retina with prominent pro-inflammatory effects. To explore the potential relationship between 7KCh and microglial activation, we localized 7KCh and microglia to the outer retina of aged mice and investigated 7KCh effects on retinal microglia in both in vitro and in vivo systems. We found that retinal microglia demonstrated a prominent chemotropism to 7KCh and readily internalized 7KCh. Sublethal concentrations of 7KCh resulted in microglial activation and polarization to a pro-inflammatory M1 state via NLRP3 inflammasome activation. Microglia exposed to 7KCh reduced expression of neurotrophic growth factors but increased expression of angiogenic factors, transitioning to a more neurotoxic and pro-angiogenic phenotype. Finally, subretinal transplantation of 7KCh-exposed microglia promoted choroidal neovascularization (CNV) relative to control microglia in a Matrigel-CNV model. The interaction of retinal microglia with 7KCh in the aged retina may thus underlie how outer retinal lipid accumulation in intermediate AMD results in neuroinflammation that ultimately drives progression towards advanced AMD

Mechanical properties of geopolymer concretes reinforced with waste steel fibers

The article presents the research that try to determinate the possibilities of utilization the waste came from used tires to create the composites based on geopolymer matrix. The tire is multicomponent construction. It mainly consists of elastomer (rubber), metal and textile fibres such called textile cord. A lot of components causes difficulties in the tire recycling process. The main aim of the research was determinate the possibilities of recycling the waste steel from used tires in geopolymer composites and develop the eco-friendly material for construction industry. The matrix based on fly ash from power station located in city named Skawina (Poland) and fine sand at a ratio of 1:1. The process of activation was made by 10M sodium hydroxide solution combined with the sodium silicate solution. In order to manufacture these composites the addition of 2% and 3.5% of waste steel fibres by mass was applied. Also specimen without steel fiber reinforcement were made to get reference specimens. The waste steel fibres came from recycling company from Argentina - 'Regomax'. The specimens were prepared according to the methodology described in the standard EN 12390-1. The research methods used were: microstructure research, tensile strength and compressive strength tests as well as analysis of breakthroughs.Fil: Gailitis, R. Riga Technical University; LetoniaFil: Korniejenko, K. Cracow University Of Technology; PoloniaFil: Lach, M. Riga Technical University; LetoniaFil: Sliseris, J. Riga Technical University; LetoniaFil: Moran, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; ArgentinaFil: Rodriguez, Exequiel Santos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; ArgentinaFil: Mikula, J. Cracow University Of Technology; Poloni

Combining chemotherapy and targeted therapies in metastatic colorectal cancer

Colorectal cancer remains one of the major causes of cancer death worldwide. During the past years, the development of new effective treatment options has led to a considerable improvement in the outcome of this disease. The advent of agents such as capecitabine, irinotecan, oxaliplatin, cetuximab and bevacizumab has translated into median survival times in the range of 2 years. Intense efforts have focused on identifying novel agents targeting specific growth factor receptors, critical signal transduction pathways or mediators of angiogenesis. In addition, several clinical trials have suggested that some of these molecularly targeted drugs can be safely and effectively used in combination with conventional chemotherapy. In this article we review various treatment options combining cytotoxic and targeted therapies currently available for patients with metastatic colorectal cancer

New compound sets identified from high throughput phenotypic screening against three kinetoplastid parasites:an open resource

Using whole-cell phenotypic assays, the GlaxoSmithKline high-throughput screening (HTS) diversity set of 1.8 million compounds was screened against the three kinetoplastids most relevant to human disease, i.e. Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei. Secondary confirmatory and orthogonal intracellular anti-parasiticidal assays were conducted, and the potential for non-specific cytotoxicity determined. Hit compounds were chemically clustered and triaged for desirable physicochemical properties. The hypothetical biological target space covered by these diversity sets was investigated through bioinformatics methodologies. Consequently, three anti-kinetoplastid chemical boxes of ~200 compounds each were assembled. Functional analyses of these compounds suggest a wide array of potential modes of action against kinetoplastid kinases, proteases and cytochromes as well as potential host–pathogen targets. This is the first published parallel high throughput screening of a pharma compound collection against kinetoplastids. The compound sets are provided as an open resource for future lead discovery programs, and to address important research questions.The support and funding of Tres Cantos Open Lab Foundation is gratefully acknowledgedPeer reviewe

ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA

Circulating tumour DNA; Pancreatic cancer; Tumour evolutionADN tumoral circulant; Càncer de pàncrees; Evolució tumoralADN tumoral circulante; Cáncer de páncreas; Evolución tumoralBackground Liquid biopsies and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, identifying and tracking dynamic changes in somatic copy number alterations (SCNAs), which have been associated with poor outcome and metastasis, using ctDNA is challenging. Pancreatic adenocarcinoma is a disease which has been considered to harbour early punctuated events in its evolution, leading to an early fitness peak, with minimal further subclonal evolution. Methods To interrogate the role of SCNAs in pancreatic adenocarcinoma cancer evolution, we applied whole-exome sequencing of 55 longitudinal cell-free DNA (cfDNA) samples taken from 24 patients (including 8 from whom a patient-derived xenograft (PDX) was derived) with metastatic disease prospectively recruited into a clinical trial. We developed a method, Aneuploidy in Circulating Tumour DNA (ACT-Discover), that leverages haplotype phasing of paired tumour biopsies or PDXs to identify SCNAs in cfDNA with greater sensitivity. Results SCNAs were observed within 28 of 47 evaluable cfDNA samples. Of these events, 30% could only be identified by harnessing the haplotype-aware approach leveraged in ACT-Discover. The exceptional purity of PDX tumours enabled near-complete phasing of genomic regions in allelic imbalance, highlighting an important auxiliary function of PDXs. Finally, although the classical model of pancreatic cancer evolution emphasises the importance of early, homogenous somatic events as a key requirement for cancer development, ACT-Discover identified substantial heterogeneity of SCNAs, including parallel focal and arm-level events, affecting different parental alleles within individual tumours. Indeed, ongoing acquisition of SCNAs was identified within tumours throughout the disease course, including within an untreated metastatic tumour. Conclusions This work demonstrates the power of haplotype phasing to study genomic variation in cfDNA samples and reveals undiscovered intra-tumour heterogeneity with important scientific and clinical implications. Implementation of ACT-Discover could lead to important insights from existing cohorts or underpin future prospective studies seeking to characterise the landscape of tumour evolution through liquid biopsy.This work was supported by the European Research Council (ERC) no. 670582 (Call: ERC-2014-ADG) to Dr. Hidalgo. R.A.T is supported by the Miguel Servet-II Research Award and the 2021 call for Proyectos de generación de conocimiento by the Institute of Health Carlos III (ISCIII) of the Ministry of Economy [CP17/00199], the Olga Torres Foundation Award to emerging researchers [2017, to R.A.T, 2601], and received research grants from Novartis, Astrazeneca, and Beigene pharmaceuticals, not related to this study. N.M is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (Grant Number 211179/Z/18/Z), and also receives funding from Cancer Research UK Lung Cancer Centre of Excellence, Rosetrees, and the NIHR BRC at University College London Hospitals