398 research outputs found
FOXO transcription factors as mediators of stress adaptation
No full textThe forkhead box protein O (FOXO, consisting of FOXO1, FOXO3, FOXO4 and FOXO6) transcription factors are the mammalian orthologues of Caenorhabditis elegans DAF-16, which gained notoriety for its capability to double lifespan in the absence of daf-2 (the gene encoding the worm insulin receptor homologue). Since then, research has provided many mechanistic details on FOXO regulation and FOXO activity. Furthermore, conditional knockout experiments have provided a wealth of data as to how FOXOs control development and homeostasis at the organ and organism levels. The lifespan-extending capabilities of DAF-16/FOXO are highly correlated with their ability to induce stress response pathways. Exogenous and endogenous stress, such as cellular redox stress, are considered the main drivers of the functional decline that characterizes ageing. Functional decline often manifests as disease, and decrease in FOXO activity indeed negatively impacts on major age-related diseases such as cancer and diabetes. In this context, the main function of FOXOs is considered to preserve cellular and organismal homeostasis, through regulation of stress response pathways. Paradoxically, the same FOXO-mediated responses can also aid the survival of dysfunctional cells once these eventually emerge. This general property to control stress responses may underlie the complex and less-evident roles of FOXOs in human lifespan as opposed to model organisms such as C. elegans
Protocol to profile the bioenergetics of organoids using Seahorse
No full textAddressing bioenergetics is key to evaluate the impact of metabolism on the regulation of biological processes and its alteration in disease. Organoids are in vitro grown self-organizing structures derived from healthy and diseased tissue that recapitulate with high fidelity the tissue of origin. Bioenergetics is commonly analyzed by Seahorse XF analysis. However, its application to organoid studies is technically challenging. Here, we share our in-house optimized protocols to examine organoid bioenergetics in response to drugs, gene knockdown, or to characterize the metabolism of specific cell types. For complete details on the use and execution of this protocol, please refer to Ludikhuize et al. (2020)
A transitory regime : water supply in Conakry, Guinea
No full textBoth consumers and the government benefited from reform of the water system in Conakry, Guinea, whose deterioration since independence had become critical by the mid-1980s. Less than 40 percent of Conakry's population had access to piped water - low even by regional standards - and service was intermittent, at best, for the few who had connections. The public agency in charge of the sector was inefficient, overstaffed, and virtually insolvent. In several ways, the reform introduced to the sector in 1989 under a World Bank-led project was remarkable. It showed that even in a weak institutional environment, where contracts are hard to enforce and political interference is common, private sector participation can improve sector performance. The authors discuss the mechanismsthat made progress possible and identify factors that inhibit the positive effects of reform. Water has become very expensive, the number of connections has increased very slowly, and conflicts have developed between SEEG (the private operator) and SONEG (the state agency). Among the underlying problems: a) The lack of strong, stable institutions. b) The lack of an independent agency capable of restraining arbitrary government action, regulating the private operator, and enforcing contractual arrangements. c) The lack of adequate conflict resolution mechanisms for contract disputes. d) Weak administrative capacity.Environmental Economics&Policies,Water and Industry,Water Conservation,Decentralization,Water Supply and Systems,Town Water Supply and Sanitation,Water and Industry,Water Supply and Sanitation Governance and Institutions,Environmental Economics&Policies,Water Conservation
Measurement of the effective B_s^0 -> J/ψ K_S^0 lifetime
No full textThis paper reports the first measurement of the effective B_s^0 -> J/{\psi} K_S^0 lifetime and an updated measurement of its time-integrated branching fraction. Both measurements are performed with a data sample, corresponding to an integrated luminosity of 1.0 fb^{-1} of pp collisions, recorded by the LHCb experiment in 2011 at a centre-of-mass energy of 7 TeV. The results are: tau_J/{\psi}K_S^0 = 1.75 +/- 0.12 (stat) +/- 0.07 (syst) and BR(B_s^0 -> J/{\psi} K_S^0) = (1.97 +/- 0.23) X 10^{-5}.
For the latter measurement, the uncertainty includes both statistical and systematic sources
Measurements of the Lambda_b0 -> J/psi Lambda decay amplitudes and the Lambda_b0 polarisation in pp collisions at sqrt(s) = 7 TeV
No full textAn angular analysis of View the Λb0→J/ψΛ decays is performed using a data sample corresponding to 1.0 fb−11.0 fb−1 collected in pp collisions at s=7 TeV with the LHCb detector at the LHC. A parity violating asymmetry parameter characterising the View the Λb0→J/ψΛ decay of 0.05±0.17±0.070.05±0.17±0.07 and a View the Λb0 transverse production polarisation of 0.06±0.07±0.020.06±0.07±0.02 are measured, where the first uncertainty is statistical and the second systematic
Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis
No full textThe lack of registered drugs for nonalcoholic fatty liver disease (NAFLD) is partly due to the paucity of human-relevant models for target discovery and compound screening. Here we use human fetal hepatocyte organoids to model the first stage of NAFLD, steatosis, representing three different triggers: free fatty acid loading, interindividual genetic variability (PNPLA3 I148M) and monogenic lipid disorders (APOB and MTTP mutations). Screening of drug candidates revealed compounds effective at resolving steatosis. Mechanistic evaluation of effective drugs uncovered repression of de novo lipogenesis as the convergent molecular pathway. We present FatTracer, a CRISPR screening platform to identify steatosis modulators and putative targets using APOB−/− and MTTP−/− organoids. From a screen targeting 35 genes implicated in lipid metabolism and/or NAFLD risk, FADS2 (fatty acid desaturase 2) emerged as an important determinant of hepatic steatosis. Enhancement of FADS2 expression increases polyunsaturated fatty acid abundancy which, in turn, reduces de novo lipogenesis. These organoid models facilitate study of steatosis etiology and drug targets
NAC regulates metabolism and cell fate in intestinal stem cells
No full textIntestinal stem cells (ISCs) face the challenge of integrating metabolic demands with unique regenerative functions. Studies have shown an intricate interplay between metabolism and stem cell capacity; however, it is still not understood how this process is regulated. Combining ribosome profiling and CRISPR screening in intestinal organoids, we identify the nascent polypeptide-associated complex (NAC) as a key mediator of this process. Our findings suggest that NAC is responsible for relocalizing ribosomes to the mitochondria and regulating ISC metabolism. Upon NAC inhibition, intestinal cells show decreased import of mitochondrial proteins, which are needed for oxidative phosphorylation, and, consequently, enable the cell to maintain a stem cell identity. Furthermore, we show that overexpression of NACα is sufficient to drive mitochondrial respiration and promote ISC identity. Ultimately, our results reveal the pivotal role of NAC in regulating ribosome localization, mitochondrial metabolism, and ISC function, providing insights into the potential mechanism behind it
The practice of access pricing : telecommunications in the United Kingdom
No full textTelecommunications was the first network utility to be privatized in the United Kingdom. Drawing on 15 years'experience and discussion in the field, the author shows the economic principles of regulation in general and access pricing in particular that have been implemented. British Telecommunications (BT), formed as a public enterprise in 1980-81, was privatized in 1984. Since then the approaches to regulation have changed in three broad periods: the duoply, the transition to competition, and the recently introduced normalization phase. Dealing with each period, the author focuses on how the actual implementation of access charges are determined, at the same time providing background needed on regulatory intervention generally. Rather than follow the model of competition for a common infrastructure, Oftel [the Office of Telecommunications, the regulatory agency]has encouraged competition between alternative networks, which benefits customers but involves duplication of fixed costs. As a result of Oftel's approach, customers have seen their bills reduced 50 percent in real terms since privatization. It is difficult to know how much to attribute this remarkable result to technological progress (BT halved its workforce in the same period), to regulatory intervention (Oftel set string caps until 1997), or to competition (there are hundreds of players in the market). The author contends more weight should probably be given to the first two. Entrants have not achieved big market shares, if one considers the asymmetric regulation that has been in place for more than a decade. Indirectly, at least, competition benefited consumers by applying discipline to BT's behavior. Oftel's approach was interventionist until 1997, when it began trying to normalize the industry, as authority overseeing competition. The odds on complete deregulation are slight, and some controls on industry will remain. In the longer term, Oftel should especially monitor anticompetitive practices and collusive behavior among the bigger players (BT, CWC, and cellulator operators), The United Kingdom's interconnection experience demonstrates the complexity of the problem and its relationship to other topics, such as tariff rebalancing, access deficit, and universal service. Although a bit ad hoc, the recent incentive regulation, with a network cap based on proper accounting procedures and engineering models, may represent the best practice available today in the telecommunications industry, says the author.Public Sector Economics&Finance,Decentralization,Knowledge Economy,Economic Theory&Research,Payment Systems&Infrastructure,Public Sector Economics&Finance,Education for the Knowledge Economy,Knowledge Economy,Economic Theory&Research,ICT Policy and Strategies
Measurement of the cross-section ratio σ(χc2)/σ(χc1) for prompt χc production at √s=7 TeV
No full textThe prompt production of the charmonium χc1 and χc2 mesons has been studied in proton–proton collisions at the Large Hadron Collider at a centre-of-mass energy of . The χc mesons are identified through their decays χc→J/ψγ with J/ψ→μ+μ− using 36 pb−1 of data collected by the LHCb detector in 2010. The ratio of the prompt production cross-sections for the two χc spin states, σ(χc2)/σ(χc1), has been determined as a function of the J/ψ transverse momentum, , in the range from 2 to 15 GeV/c. The results are in agreement with the next-to-leading order non-relativistic QCD model at high and lie consistently above the pure leading-order colour-singlet prediction
Trim17, novel E3 ubiquitin-ligase, initiates neuronal apoptosis
No full textAccumulating data indicate that the ubiquitin-proteasome system controls apoptosis by regulating the level and the function of key regulatory proteins. In this study, we identified Trim17, a member of the TRIM/RBCC protein family, as one of the critical E3 ubiquitin ligases involved in the control of neuronal apoptosis upstream of mitochondria. We show that expression of Trim17 is increased both at the mRNA and protein level in several in vitro models of transcription-dependent neuronal apoptosis. Expression of Trim17 is controlled by the PI3K/Akt/GSK3 pathway in cerebellar granule neurons (CGN). Moreover, the Trim17 protein is expressed in vivo, in apoptotic neurons that naturally die during post-natal cerebellar development. Overexpression of active Trim17 in primary CGN was sufficient to induce the intrinsic pathway of apoptosis in survival conditions. This pro-apoptotic effect was abolished in Bax(-/-) neurons and depended on the E3 activity of Trim17 conferred by its RING domain. Furthermore, knock-down of endogenous Trim17 and overexpression of dominant-negative mutants of Trim17 blocked trophic factor withdrawal-induced apoptosis both in CGN and in sympathetic neurons. Collectively, our data are the first to assign a cellular function to Trim17 by showing that its E3 activity is both necessary and sufficient for the initiation of neuronal apoptosis. Cell Death and Differentiation (2010) 17, 1928-1941; doi: 10.1038/cdd.2010.73; published online 18 June 201
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