Cardiac pathological outcome of metabolic remodeling is difficult to model using cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) due to low metabolic maturation.
hiPSC-CM ...spheres were treated with AMP-activated protein kinase (AMPK) activators and examined for hiPSC-CM maturation features, molecular changes and the response to pathological stimuli.
Treatment of hiPSC-CMs with AMPK activators increased ATP content, mitochondrial membrane potential and content, mitochondrial DNA, mitochondrial function and fatty acid uptake, indicating increased metabolic maturation. Conversely, the knockdown of AMPK inhibited mitochondrial maturation of hiPSC-CMs. In addition, AMPK activator-treated hiPSC-CMs had improved structural development and functional features-including enhanced Ca
transient kinetics and increased contraction. Transcriptomic, proteomic and metabolomic profiling identified differential levels of expression of genes, proteins and metabolites associated with a molecular signature of mature cardiomyocytes in AMPK activator-treated hiPSC-CMs. In response to pathological stimuli, AMPK activator-treated hiPSC-CMs had increased glycolysis, and other pathological outcomes compared to untreated cells.
AMPK activator-treated cardiac spheres could serve as a valuable model to gain novel insights into cardiac diseases.
The proliferation of RTAs is a recognized feature of our time. While such agreements are permitted under Article XXIV of the GATT, this has not been without controversy and one aspect which remains ...unclear concerns the role decisions rendered by RTA dispute settlement bodies play in WTO cases. Are RTA dispute settlement systems in competition with and possibly even in contradiction to the WTO DSU or are they complementary? Can they co-exist or are they cast in eternal opposition? Are they equal or are they inherently subordinate to the WTO DSU? The article considers the WTO's treatment of RTAs in GATT and WTO case law, and weighs arguments for and against the consideration of RTA decisions by the DSB. The article submits that the DSB should not be blind to the equities of a situation where two states have reached an agreement in an RTA selecting dispute settlement under that body. This is more than a theoretical argument, it has happened, and the increasingly complex co-existence of the WTO with some 400 RTAs suggests that similar problems can arise in the future. Furthermore, these issues deserve a much more open and careful analysis than they have had to date.
Cerebrospinal fluid (CSF) biomarkers are valuable tools for the diagnosis of neurological diseases. We aimed to investigate within a retrospective multicentric study the final diagnosis associated ...with very high CSF Tau levels and to identify patterns of biomarkers that would differentiate them in clinical practice, to help clinical biologists into physicians' counseling.
Within the national multicentric network ePLM, we included 1743 patients from January 1, 2008, to December 31, 2013, with CSF biomarkers assayed by the same Innotest assays (protein Tau, phospho-Tau pTau, and Aβ 1-42). We identified 205 patients with protein Tau concentration higher than 1200 pg/mL and final diagnosis.
Among those patients, 105 (51.2%) were suffering from Alzheimer's disease, 37 (18%) from sporadic Creuztfeldt-Jakob disease, and 63 (30.7%) from other neurological diseases including paraneoplastic/ central nervous system tumor, frontotemporal dementia, other diagnoses, amyloid angiopathy, Lewy body dementia, and infections of the central nervous system. Phospho-Tau, Aβ1-42 and Aβ1-42/pTau values differed significantly between the three groups of patients (p < .001). An Aβ1-42/pTau ratio between 4.7 and 9.7 was suggestive of other neurological diseases (threshold in AD: 8.3). CSF 14-3-3 was useful to discriminate Alzheimer's disease from Creuztfeldt-Jakob disease in case of Aβ1-42 concentrations <550 pg/mL or pTau>60 pg/mL.
This work emphasizes the interest of a well-thought-out interpretation of CSF biomarkers in neurological diseases, particularly in the case of high Tau protein concentrations in the CSF.
•Few patients (<10%) suspected of neurodegenerative diseases exhibit a CSF protein Tau concentration higher than 1200 pg/mL.•These patients mainly have Alzheimer disease, then Creutzfeld-Jakob disease, and for few other neurodegenerative and neurological diseases.•Current CSF biomarkers, including Amyloid beta 1-42, phosphoTau and the 14-3-3 are useful to differentiate those patients.
In this paper, the influence of deposition current density on microstructure and purity of nickel coatings was studied. Complementary characterization methods (SEM, TEM, XRD, EBSD, GDOES and SIMS) ...were used to investigate different scales of the microstructure and to understand the metallurgical states of the coatings. As deposition current density decreases, grain refinement and texture modifications are observed which are linked with the grain boundary character (disorientation angle and Coincidence Site Lattice). Moreover, in sulphamate bath without additive, the contamination by light elements and metallic impurities strongly depends on deposition parameters and must be taken into account to discuss the microstructure changes.
► Nickel sulphamate bath without additive is used to limit sulphur incorporation. ► A multi-scale approach is necessary to describe the microstructure of deposits. ► Several metallurgical parameters are modified when grain size is decreased. ► Grain refinement and texture modifications are linked with the GB character.
Abstract
Canada’s trade relations with the UK have been governed by the CETA since the signature of that agreement with the EU in October 2016. Subsequent to the decision of the UK electorate to ...leave the EU, it became necessary to envisage the creation of a new trade agreement directly between the UK and Canada. Initially, the Government of Canada indicated a willingness to negotiate a new trade agreement with the UK as quickly as possible. But, as the future relationship of the UK to the EU became increasingly uncertain, the Government of Canada decided to hold back until greater clarity could be obtained. As of July 2020, Canada was still waiting. The future trade agreement will reflect the desire of both countries to maintain their long-standing and close relationship. Both have strong interests in trade and investment with the other and both will seek to reinforce these interests. The particular concerns of both countries are outlined in this paper and the outlines of a future trade agreement are set out. In conclusion, the author suggests that it would be in the interests of the UK, rather than seeking simply a bilateral agreement, to seek to negotiate an Atlantic Free Trade Agreement, thereby clarifying its relations not simply with Canada but with all of Europe and North America.
"In recent years, the world has witnessed the coming of age of international investment law. The numbers are telling with over 2600 bilateral investment treaties, over 462 free trade, customs unions ...and other economic partnership agreements notified to the WTO, with 276 being in force, an increasing number of which include investment chapters, and over 350 known investor-State treaty-based arbitrations. This phenomenon has not left many untouched as over 175 States have signed international investment agreements (IIAs) and at least 81 governments have faced investment treaty arbitrations. The regime, however, has not been without criticisms. The main criticisms being: that IIAs do not fulfil their great bargain the promotion of investment, while they effectively protect powerful economic interests; that IIAs protect investor's rights over the public interest of the host country; that the dispute settlement system put in place by IIAs lacks legitimacy due to the fundamentally ad hoc nature of investor-State arbitration; and that the complexity and cost of the system are out of control.This book takes stock of developments in international investment law and analyzes potential solutions to some of these criticisms from the perspective of international public policy, in negotiations, substantive obligations and dispute resolution. The book is prepared by a group of scholars and practitioners from Canada and Europe. It takes a multidisciplinary approach to the subject, with analysis from the legal, political and economic perspectives. The first part of the book traces the evolution in IIA treaty-making and provides an evaluation from a political economy and economics perspective. The other three parts are organised around the concepts of efficiency, legitimacy and sustainability. Each contributor analyzes one or more issues of treaty negotiation, substance or dispute resolution, with the ultimate aim of improving IIA treaty-making in these respects."--
Alcohol use in pregnancy increases the risk of abnormal cardiac development, and excessive alcohol consumption in adults can induce cardiomyopathy, contractile dysfunction, and arrhythmias. ...Understanding molecular mechanisms underlying alcohol-induced cardiac toxicity could provide guidance in the development of therapeutic strategies.
We have performed proteomic and bioinformatic analysis to examine protein alterations globally and quantitatively in cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) treated with ethanol (EtOH). Proteins in both cell lysates and extracellular culture media were systematically quantitated.
Treatment with EtOH caused severe detrimental effects on hiPSC-CMs as indicated by significant cell death and deranged Ca
handling. Treatment of hiPSC-CMs with EtOH significantly affected proteins responsible for stress response (e.g., GPX1 and HSPs), ion channel-related proteins (e.g. ATP1A2), myofibril structure proteins (e.g., MYL2/3), and those involved in focal adhesion and extracellular matrix (e.g., ILK and PXN). Proteins involved in the TNF receptor-associated factor 2 signaling (e.g., CPNE1 and TNIK) were also affected by EtOH treatment.
The observed changes in protein expression highlight the involvement of oxidative stress and dysregulation of Ca
handling and contraction while also implicating potential novel targets in alcohol-induced cardiotoxicity. These findings facilitate further exploration of potential mechanisms, discovery of novel biomarkers, and development of targeted therapeutics against EtOH-induced cardiotoxicity.
L’analyse semi-quantitative de la TEP aux marqueurs de la plaque amyloïde est utile en complément à l’analyse visuelle standard, mais elle nécessite classiquement de disposer des images d’IRM ...cérébrale des patients pour la normalisation spatiale des images TEP. Dans cette étude, les images de correction d’atténuation du scanner ont été utilisées pour la normalisation spatiale des images TEP et l’analyse semi-quantitative ainsi obtenue a été comparée à l’analyse visuelle standard chez des patients ayant bénéficié d’une TEP aux marqueurs de la plaque amyloïde.
Trente-quatre patients (73±9 ans, 16 femmes) ont bénéficié d’une TEP au 18F-Florbetaben avec un scanner cérébral de correction d’atténuation couplé. Une analyse semi-quantitative, utilisant les images de correction d’atténuation du scanner pour la normalisation spatiale des images TEP et des ratios de SUV pour la définition des TEP pathologiques (SUVr>1,478), a été comparée à une analyse visuelle consensuelle réalisée par 2 médecins nucléaires expérimentés et utilisant un score de brain amyloid plaque load (BAPL) supérieur à 1 comme critère de positivité.
Une très bonne concordance a été observée entre les 2 analyses avec un coefficient kappa de 0,77 (p<0,001), et 31 (91 %) examens classés de manière identique par les 2 analyses (7 examens positifs et 24 examens négatifs). Les 3 cas de discordance se situaient à la limite des seuils visuel et quantitatif, avec un examen classé négatif quantitativement et positif visuellement mais avec un score BAPL de seulement 2, et avec 2 examens classés négatifs visuellement et positifs quantitativement mais avec des seuils de SUVr à seulement 1,523 et 1,629.
l’analyse semi-quantitative après normalisation spatiale sur le scanner de correction d’atténuation des images de TEP aux marqueurs de la plaque amyloïde est très bien corrélée à l’analyse visuelle et pourrait être implémentée facilement en routine clinique et en recherche pour conforter ses résultats.
Au cours des dernières années, l’importance fonctionnelle des astrocytes au sein du système nerveux central est devenue de plus en plus évidente. Grâce à son équipement enzymatique, ce type ...cellulaire est particulièrement actif dans le métabolisme cérébral et dans la défense du système nerveux central.
Les astrocytes expriment notamment plusieurs cytochromes P450. Ces enzymes interviennent dans l’oxydation de nombreuses substances endogènes ou exogènes et leur régulation peut avoir des conséquences pharmacologiques ou toxicologiques. Les cytochromes P450 astrocytaires participent également à la neurostéroïdongénèse ainsi qu’à la transformation de l’acide arachidonique en métabolites vasoactifs et, par conséquent, à la régulation du flux sanguin cérébral.
Cette revue souligne l’importance de ces fonctions métaboliques. L’étude des mécanismes moléculaires impliqués dans la régulation des cytochromes P450 astrocytaires pourrait permettre d’ouvrir de nouvelles perspectives thérapeutiques et d’améliorer les connaissances en neuroprotection.
Astrocytes are involved in multiple brain functions in physiological conditions. Cytochromes P450 are expressed in astrocytes and play a role in brain metabolism and in neuroprotection.
Although the levels of various cytochromes P450 in brain regions are low, these enzymes were reported to be expressed at relatively high level in astroglial cells and may play a critical role in the biotransformation of endogenous or exogenous compounds. Astroglial cytochromes P450 expression suggests a putative capacity to metabolize psychoactive or lipophilic xenobiotics
in situ, associated with pharmacological and/or toxicological consequences. Astrocytes appear to be the most active steroidogenic cells in the brain, expressing neurosteroïdogenic cytochromes P450 and producing various neurosteroids. Cytochrome P450 epoxygenase enzymes, which catalyze the formation of vasoactive compounds are also present in astrocytes, contributing to the regulation of the cerebral blood flow.
This review underlines the crucial roles of astroglial cytochromes P450 in brain functions. Identification of the molecular mechanisms involved in the regulation of these enzymes could open therapeutic perspectives and improve our understanding in neuroprotection.
Background
Alcohol use in pregnancy increases the risk of abnormal cardiac development, and excessive alcohol consumption in adults can induce cardiomyopathy, contractile dysfunction, and ...arrhythmias. Understanding molecular mechanisms underlying alcohol‐induced cardiac toxicity could provide guidance in the development of therapeutic strategies.
Methods
We have performed proteomic and bioinformatic analysis to examine protein alterations globally and quantitatively in cardiomyocytes derived from human‐induced pluripotent stem cells (hiPSC‐CMs) treated with ethanol (EtOH). Proteins in both cell lysates and extracellular culture media were systematically quantitated.
Results
Treatment with EtOH caused severe detrimental effects on hiPSC‐CMs as indicated by significant cell death and deranged Ca2+ handling. Treatment of hiPSC‐CMs with EtOH significantly affected proteins responsible for stress response (e.g., GPX1 and HSPs), ion channel‐related proteins (e.g. ATP1A2), myofibril structure proteins (e.g., MYL2/3), and those involved in focal adhesion and extracellular matrix (e.g., ILK and PXN). Proteins involved in the TNF receptor‐associated factor 2 signaling (e.g., CPNE1 and TNIK) were also affected by EtOH treatment.
Conclusions
The observed changes in protein expression highlight the involvement of oxidative stress and dysregulation of Ca2+ handling and contraction while also implicating potential novel targets in alcohol‐induced cardiotoxicity. These findings facilitate further exploration of potential mechanisms, discovery of novel biomarkers, and development of targeted therapeutics against EtOH‐induced cardiotoxicity.
Treatment of human stem cell‐derived cardiomyocytes with ethanol results in cell death and abnormal Ca2+ handling. Proteomic profiling and bioinformatic analysis reveal that ethanol treatment affects the expression of proteins involved in oxidative stress, ion channels, myofibril structure, focal adhesion, extracellular matrix and TRAF2 signaling.
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