174 research outputs found
HEAVY METALS IN URBAN PARK SOILS FROM ATHENS, GREECE
Η αστική γεωχημεία είναιένας επιστημονικός κλάδος ο οποίος αναπτύσσεταιτα τελευταία χρόνια κυρίως λόγω των περιβαλλοντικών επιπτώσεων που προκύπτουν από την αστικοποίηση. Η παρούσα εργασία έχει ως στόχο τον προσδιορισμό των συγκεντρώσεων δυνητικά επιβλαβών στοιχείων (PHEs) των επιφανειακών (0-10 cm) εδαφών προερχόμενων από αλσύλια της Αθήνας. Η δειγματοληψία υπαίθρου πραγματοποιήθηκε σε 20 αλσύλια της Αττικής και κάλυψε συνολική έκταση περίπου 200km2 . Αναλύθηκαν 20 εδαφικά δείγματα κοκκομετρίας Mn >Ni≈ Cu≈ Zn> Cr. Τα δεδομένα της έρευνας υποδεικνύουν ότι το έδαφος των αλσυλίων μπορεί να είναι ένας σημαντικός ταμιευτήρας των ανθρωπογενών στοιχείων στο αστικό έδαφοςUrban geochemistry is a scientific discipline which is growing in the recent years mainly because of the environmental impact caused by urbanization. The present study aims to determine the concentrations of potentially harmful elements (PHEs) on surface soils (0-10cm) in Athens parks. Soil sampling was carried out in public park areas within the Athens urban area. Twenty surface soil (0-10cm) samples were collected and the Mn >Ni≈ Cu≈ Zn> Cr. The data indicate that park areas seem to be important sinks of anthropogenic elements in urban soils
Design methodology for ultra low-power analog circuits using next generation BSIM6 MOSFET compact model
The recently proposed BSIM6 bulk MOSFET compact model is set to replace the hitherto widely used BSIM3 and BSIM4 models as the de-facto industrial standard. Unlike its predecessors which were threshold voltage based, the BSIM6 core is charge based and thus physically continuous at all levels of inversion from linear operation to saturation. Hence, it lends itself conveniently for the use of a design methodology suited for low-power analog circuit design based on the inversion coefficient (IC) that has been extensively used in conjugation with the EIN model and allows to make simple calculations of, for example, transconductance efficiency, gain bandwidth product, etc. This methodology helps to make a near-optimal selection of transistor dimensions and operating points even in moderate and weak inversion regions. This paper will discuss the IC based design methodology and its application to the next generation BSIM6 compact MOSFET model. (C) 2013 Elsevier Ltd. All rights reserved
The one‐carbon metabolic enzyme MTHFD2 promotes resection and homologous recombination after ionizing radiation
The one-carbon metabolism enzyme bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2) is among the most overexpressed proteins across tumors and is widely recognized as a promising anticancer target. While MTHFD2 is mainly described as a mitochondrial protein, a new nuclear function is emerging. Here, we observe that nuclear MTHFD2 protein levels and association with chromatin increase following ionizing radiation (IR) in an ataxia telangiectasia mutated (ATM)- and DNA-dependent protein kinase (DNA-PK)-dependent manner. Furthermore, repair of IR-induced DNA double-strand breaks (DSBs) is delayed upon MTHFD2 knockdown, suggesting a role for MTHFD2 in DSB repair. In support of this, we observe impaired recruitment of replication protein A (RPA), reduced resection, decreased IR-induced DNA repair protein RAD51 homolog 1 (RAD51) levels and impaired homologous recombination (HR) activity in MTHFD2-depleted cells following IR. In conclusion, we identify a key role for MTHFD2 in HR repair and describe an interdependency between MTHFD2 and HR proficiency that could potentially be exploited for cancer therapy
Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators
A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu[superscript 230], located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.Glenn Foundation for Medical ResearchEllison Medical FoundationJuvenile Diabetes Research Foundation InternationalUnited Mitochondrial Disease FoundationNational Institutes of Health (U.S.)National Institute of Allergy and Infectious Diseases (U.S.
Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells
Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.In this study, Green, Marttila, Kiweler et al. characterize one-carbon metabolism rewiring in response to a dual MTHFD1 and MTHFD2 inhibitor. This work provides insight into one-carbon fluxes, and reveals a previously uncharacterized vulnerability in cancer cells created by folate trapping
The role of resveratrol on skeletal muscle cell differentiation and myotube hypertrophy during glucose restriction
Glucose restriction (GR) impairs muscle cell differentiation and evokes myotube atrophy. Resveratrol treatment in skeletal
muscle cells improves inflammatory-induced reductions in skeletal muscle cell differentiation. We therefore hypothesised
that resveratrol treatment would improve muscle cell differentiation and myotube hypertrophy in differentiating C2C12
myoblasts and mature myotubes during GR. Glucose restriction at 0.6 g/L (3.3 mM) blocked differentiation and myotube
hypertrophy versus high-glucose (4.5 g/L or 25 mM) differentiation media (DM) conditions universally used for myoblast
culture. Resveratrol (10 μM) treatment increased SIRT1 phosphorylation in DM conditions, yet did not improve differentiation
when administered to differentiating myoblasts in GR conditions. Resveratrol did evoke increases in hypertrophy of mature
myotubes under DM conditions with corresponding elevated Igf-I and Myhc7 gene expression, coding for the ‘slow’ type I
MYHC protein isoform. Inhibition of SIRT1 via EX-527 administration (100 nM) also reduced myotube diameter and area
in DM conditions and resulted in lower gene expression of Myhc 1, 2 and 4 coding for ‘intermediate’ and ‘faster’ IIx, IIa
and IIb protein isoforms, respectively. Resveratrol treatment did not appear to modulate phosphorylation of energy-sensing
protein AMPK or protein translation initiator P70S6K. Importantly, in mature myotubes, resveratrol treatment was able to
ameliorate reduced myotube growth in GR conditions over an acute 24-h period, but not over 48–72 h. Overall, resveratrol
evoked myotube hypertrophy in DM conditions while favouring ‘slower’ Myhc gene expression and acutely ameliorated
impaired myotube growth observed during glucose restriction
High fat diet-induced inflammation and oxidative stress are attenuated by N-acetylneuraminic acid in rats
Prox1 Regulates the Notch1-Mediated Inhibition of Neurogenesis
During development of the spinal cord, Prox1 controls the balance between proliferation and differentiation of neural progenitor cells via suppression of Notch1 gene expression
Specific Syndecan-1 Domains Regulate Mesenchymal Tumor Cell Adhesion, Motility and Migration
Malignant mesothelioma is an asbestos induced cancer that is difficult to diagnose.
Several studies have combined biomarkers to improve mesothelioma diagnosis, but
with moderate success, and there is a need for new mesothelioma biomarkers. The
tumour is often resistant to treatment and most patients will survive less than a year.
An indicator of patient survival is the tumours growth pattern, which in turn is
influenced by expressed proteoglycans.
In this thesis work, we aim to improve the possibilities to diagnose malignant
mesothelioma by combining biomarkers and by identifying new ones. We also
investigate tumour driving mechanisms with focus on one of these suggested
biomarkers, the cell-bound proteoglycan syndecan-1.
We were able to construct a diagnostic two-step model based on biomarkers in patient
material. By implementing a cut-off level and thereafter focusing on unresolved patients
we combined hyaluronan and N-ERC/mesothelin (paper I), which significantly increased
the diagnostic accuracy for malignant mesothelioma. To further improve diagnosis, we
used mass spectrometry to find new biomarkers. We identified and validated galectin-1,
which was excellent in discriminating mesotheliomas from adenocarcinomas (paper II).
In the same study, we were also the first to describe aldo-keto reductase 1B10 as a
novel prognostic mesothelioma biomarker.
Syndecan-1 has been indicated as a marker for carcinomas. In paper I we describe how
higher levels of syndecan-1 indicate the presence of a carcinoma over a mesothelioma.
This was verified in paper II when syndecan-1 was identified as downregulated in fluids
from mesothelioma patients compared to lung cancer patients. Paper III and paper IV
focus on this proteoglycan.
Malignant cell lines transfected with syndecan-1 and various truncated forms of
syndecan-1 affected adhesion and migration, which are key features of cancer invasion
(paper III). The results showed a domain- and cell type specific effect on the cells’
motility. Regulating syndecan-1 levels and analysing the global gene expression of
mesothelioma cells made it evident that this proteoglycan has a strong influence on
transforming growth factor β signalling and several growth factor pathways (paper IV).
Links to cell migration and proliferation were furthermore identified, along with
glycosaminoglycan modifying enzymes. These results can shed light on the complex role
of syndecan-1 in invasion and growth of malignant mesenchymal cells.
Taken together, this thesis work describes a complement to conventional mesothelioma
diagnosis and identifies novel biomarkers. Furthermore, the potential biomarker
syndecan-1 was shown to have an effect on cell motility and proliferation. These results
increase our understanding of this aggressive malignancy
Interstitial cell migration: integrin-dependent and alternative adhesion mechanisms
Adhesion and migration are integrated cell functions that build, maintain and remodel the multicellular organism. In migrating cells, integrins are the main transmembrane receptors that provide dynamic interactions between extracellular ligands and actin cytoskeleton and signalling machineries. In parallel to integrins, other adhesion systems mediate adhesion and cytoskeletal coupling to the extracellular matrix (ECM). These include multifunctional cell surface receptors (syndecans and CD44) and discoidin domain receptors, which together coordinate ligand binding with direct or indirect cytoskeletal coupling and intracellular signalling. We review the way that the different adhesion systems for ECM components impact cell migration in two- and three-dimensional migration models. We further discuss the hierarchy of these concurrent adhesion systems, their specific tasks in cell migration and their contribution to migration in three-dimensional multi-ligand tissue environments
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