265 research outputs found
The Importance of N186 in the Alpha-1-Antitrypsin Shutter Region Is Revealed by the Novel Bologna Deficiency Variant
Alpha-1-antitrypsin (AAT) deficiency causes pulmonary disease due to decreased levels of circulating AAT and consequently unbalanced protease activity in the lungs. Deposition of specific AAT variants, such as the common Z AAT, within hepatocytes may also result in liver disease. These deposits are comprised of ordered polymers of AAT formed by an inter-molecular domain swap. The discovery and characterization of rare variants of AAT and other serpins have historically played a crucial role in the dissection of the structural mechanisms leading to AAT polymer formation. Here, we report a severely deficient shutter region variant, Bologna AAT (N186Y), which was identified in five unrelated subjects with different geographical origins. We characterized the new variant by expression in cellular models in comparison with known polymerogenic AAT variants. Bologna AAT showed secretion deficiency and intracellular accumulation as detergent-insoluble polymers. Extracellular polymers were detected in both the culture media of cells expressing Bologna AAT and in the plasma of a patient homozygous for this variant. Structural modelling revealed that the mutation disrupts the hydrogen bonding network in the AAT shutter region. These data support a crucial coordinating role for asparagine 186 and the importance of this network in promoting formation of the native structure
Human iPSC-Derived 3D Hepatic Organoids in a Miniaturized Dynamic Culture System
The process of identifying and approving a new drug is a time-consuming and expensive procedure. One of the biggest issues to overcome is the risk of hepatotoxicity, which is one of the main reasons for drug withdrawal from the market. While animal models are the gold standard in preclinical drug testing, the translation of results into therapeutic intervention is often ambiguous due to interspecies differences in hepatic metabolism. The discovery of human induced pluripotent stem cells (hiPSCs) and their derivatives has opened new possibilities for drug testing. We used mesenchymal stem cells and hepatocytes both derived from hiPSCs, together with endothelial cells, to miniaturize the process of generating hepatic organoids. These organoids were then cultivated in vitro using both static and dynamic cultures. Additionally, we tested spheroids solely composed by induced hepatocytes. By miniaturizing the system, we demonstrated the possibility of maintaining the organoids, but not the spheroids, in culture for up to 1 week. This timeframe may be sufficient to carry out a hypothetical pharmacological test or screening. In conclusion, we propose that the hiPSCderived liver organoid model could complement or, in the near future, replace the pharmacological and toxicological tests conducted on animals
Gene flow at the leading range edge: the long-term consequences of isolation in European Beech (Fagus sylvatica L. Kuhn)
Aim Isolation is expected to lead to negative impacts on populations due to a reduction in effective population size and gene flow, exacerbating the effects of genetic drift, which might be stronger in peripheral and fragmented populations. Fagus sylvatica (European beech) in southern Sweden presents a gradient of isolation towards the leading range edge of the species. We sought to determine the impact of longâterm isolation on genetic diversity and population genetic structure within populations of this species. Location Samples were obtained from 14 sites towards the northern edge of the native range of beech in Sweden. Taxon Fagaceae. Methods Using historical sources, we obtained areaâ and distanceâbased measures of isolation. We measured genetic diversity and structure by using nuclear microsatellite marker data, and performed parentage analysis to estimate external pollenâmediated gene flow. We implemented a partial least squares regression to determine the effects of isolation on each of the genetic diversity estimators and the measures of external pollenâmediated gene flow. Results Longâterm isolation generally had a negative impact on genetic diversity, which is exacerbated over time, further affecting progeny and suggesting that isolated populations are subject to strong genetic drift, possibly due to the combination of founder events and persistent small population sizes. Bayesian cluster analysis revealed that isolation was also acting as a barrier to gene flow in the northâeastern distribution of beech. Main conclusions Isolation at the leading range edge of beech in Sweden has created gradients of contemporary gene flow within the species. The longâterm cumulative effects of isolation on this windâpollinated tree species and its negative impacts on genetic diversity and gene flow, could lead to inbreeding depression and higher extinction risk where populations remain small and isolated
Search for CP violation in D0 and D+ decays
A high statistics sample of photoproduced charm particles from the FOCUS
(E831) experiment at Fermilab has been used to search for CP violation in the
Cabibbo suppressed decay modes D+ to K-K+pi+, D0 to K-K+ and D0 to pi-pi+. We
have measured the following CP asymmetry parameters: A_CP(K-K+pi+) = +0.006 +/-
0.011 +/- 0.005, A_CP(K-K+) = -0.001 +/- 0.022 +/- 0.015 and A_CP(pi-pi+) =
+0.048 +/- 0.039 +/- 0.025 where the first error is statistical and the second
error is systematic. These asymmetries are consistent with zero with smaller
errors than previous measurements.Comment: 12 pages, 4 figure
Gender-based violence against women in contemporary France: domestic violence and forced marriage policy since the Istanbul Convention
ABSTRACT:
In 2014, France ratified the Council of Europeâs Convention on Preventing and Combating Violence against Women and Domestic Violence (the Istanbul Convention) and passed the Law for Equality between Women and Men to bring French law into line with it. The Law for Equality between Women and Men situates the fight against violence against women within a broader context of the need to address inequalities between women and men. This is not new at the international level, but it is new to France. When the structural, transformative understandings of violence against women found in international texts are translated into national laws, policy documents and implementation on the ground, they might challenge widespread ideas about gender relations, or they might be diluted in order to achieve consensus. To what extent has French violence against women policy moved into line with UN and Council of Europe initiatives which present violence against women as both a cause and a consequence of gendered power relations? Have internationally accepted concepts of gender and gender-based violence been incorporated into French policy debates and, if so, how? What implications, if any, does all this have for the continued struggle in France and elsewhere to eliminate violence a gainst women?
RĂSUMĂ:
En 2014, la France a ratifiĂ© la Convention du Conseil de lâEurope sur la prĂ©vention et la lutte contre la violence Ă lâĂ©gard des femmes et la violence domestique (dite Convention dâIstanbul) et a adoptĂ© dans la foulĂ©e la loi pour lâĂ©galitĂ© rĂ©elle entre les femmes et les hommes afin de mettre en conformitĂ© la lĂ©gislation française. Cette loi place la lutte contre la violence Ă lâĂ©gard des femmes dans un contexte de lutte contre les inĂ©galitĂ©s de genre. Si cela est loin dâĂȘtre une nouveautĂ© Ă lâĂ©chelle internationale, cela lâest en France. Lorsque les conceptions structurelles et transformatrices de la violence Ă lâĂ©gard des femmes prĂ©sentes dans les textes internationaux sont traduites Ă lâĂ©chelle nationale en lois, documents dâorientation et mesures de mise en Ćuvre sur le terrain, elles peuvent alors remettre en question des idĂ©es largement rĂ©pandues sur les rapports de genre, ou au contraire ĂȘtre Ă©dulcorĂ©es afin dâaboutir Ă un consensus. Dans quelle mesure la politique de la France relative Ă la violence Ă lâĂ©gard des femmes sâest-elle alignĂ©e sur les initiatives de lâONU et du Conseil de lâEurope qui prĂ©sentent ce type de violence comme Ă©tant Ă la fois une cause et une consĂ©quence des rapports de force liĂ©s au genre? Le genre et la violence fondĂ©e sur le genre, qui sont des concepts internationalement reconnus, ont-ils Ă©tĂ© intĂ©grĂ©s dans les dĂ©bats politiques français, et si oui, de quelle maniĂšre? Quelles en sont les implications le cas Ă©chĂ©ant sur la poursuite, en France et ailleurs, de la lutte pour Ă©liminer la violence Ă lâĂ©gard des femmes
Not Quite Right: Representations of Eastern Europeans in ECJ Discourse
Although the increasing responsiveness of the Court of Justice of the European Union (the âECJâ) jurisprudence to western Member Statesâ concerns regarding Central and Eastern European (âCEEâ) nationalsâ mobility has garnered academic attention, ECJ discourse has not been scrutinised for how it approaches the CEE region or CEE movers. Applying postcolonial theory, this article seeks to fill this gap and to explore whether there are any indications that ECJ discourse is in line with the historical western-centric inferiorisation of the CEE region. A critical discourse analysis of a set of ECJ judgments and corresponding Advocate General opinions pertaining to CEE nationals illustrates not only how the ECJ adopts numerous discursive strategies to maintain its authority, but also how it tends to prioritise values of the western Member States, while overlooking interests of CEE movers. Its one-sided approach is further reinforced by referring to irrelevant facts and negative assumptions to create an image of CEE nationals as socially and economically inferior to westerners, as not belonging to the proper EU polity and as not quite deserving of EU lawâs protections. By silencing CEE nationalsâ voices, while disregarding the background of east/west socio-economic and political power differentials and precariousness experienced by many CEE workers in the west, such racialising discourse normalises ethnicity- and class-based stereotypes. These findings also help to contextualise both EU and western policies targeting CEE movers and evidence of their unequal outcomes in the west, and are in line with todayâs nuanced expressions of racisms. By illustrating the ECJâs role in addressing values pertinent to mobile CEE individuals, this study facilitates a fuller appreciation of the ECJâs power in shaping and reflecting western-centric EU identity and policies. Engaging with such issues will not only allow us to better appreciateâand questionâthe ECJâs legitimacy, but might also facilitate a better understanding of power dynamics within the EU. This study also makes significant theoretical and methodological contributions. It expands (and complicates) the application of postcolonial theory to contemporary intra-EU processes, while illustrating the usefulness of applying critical discourse analysis to exploring differentiation, exclusion, subordination and power within legal language
Genes encoding α-amylase inhibitors are located in the short arms of chromosomes 3B, 3D and 6D of wheat (Triticum aestivum L.)
Three -amylase inhibitors, designated Inh. I, II and III have been purified from the 70% ethanol extract of hexaploid wheat (Triticum aestivum L.) and characterized by amino acid analysis, N-terminal amino acid sequencing and enzyme inhibition tests. Inhibitors I and III have identical N-terminal sequences and inhibitory properties to those of the previously described 0.19/0.53 group of dimeric inhibitors. Inhibitor II has an N-terminal sequence which is identical to that of the previously described 0.28 monomeric inhibitor, but differs from it in that in addition to being active against -amylase from Tenebrio molitor, it is also active against mammalian salivary and pancreatic -amylases. Compensating nulli-tetrasomic and ditelosomic lines of wheat cv. Chinese Spring have been analysed by two-dimensional electrophoresis, under conditions in which there is no overlap of the inhibitors with other proteins, and the chromosomal locations of the genes encoding these inhibitors have been established: genes for Inh. I and Inh. III are in the short arms of chromosomes 3B and 3D, respectively, and that for Inh. II in the short arm of chromosome 6D
Phase I/II trial of doxorubicin and fixed dose-rate infusion gemcitabine in advanced soft tissue sarcomas: a GEIS study
The aim of the study was to determine the dose-limiting toxicity and maximum tolerated dose of a first-line combination of doxorubicin and gemcitabine in adult patients with advanced soft tissue sarcomas and to explore its activity and toxicity, and the presence of possible interactions between these agents. Patients with measurable disease were initially treated with doxorubicin 60âmgâmâ2 by i.v. bolus on day 1 followed by gemcitabine at 800âmgâmâ2 over 80âmin on days 1 and 8, every 21 days. Concentrations of gemcitabine and 2âČ,2âČ-difluorodeoxyuridine in plasma, and gemcitabine triphosphate levels in peripheral blood mononuclear cells were determined during 8âh after the start of gemcitabine infusion. Myelosuppression and stomatitis were limiting toxicities, and the initial dose level was applied for the Phase II trial, where grade 3â4 granulocytopenia occurred in 70% of patients, grade 3 stomatitis in 46% and febrile neutropenia in 20%. Objective activity in 36 patients was 22% (95% CI: 9â35%), and a 50% remission rate was noted in leiomyosarcomas. Administration of doxorubicin preceding gemcitabine significantly reduced the synthesis of gemcitabine triphosphate. Clinical activity, similar to that of single-agent doxorubicin, and the toxicity encountered do not justify further studies with this schedule of administration
Social preferences and network structure in a population of reef manta rays
Understanding how individual behavior shapes the structure and ecology ofpopulations is key to species conservation and management. Like manyelasmobranchs, manta rays are highly mobile and wide ranging species threatened byanthropogenic impacts. In shallow-water environments these pelagic rays often formgroups, and perform several apparently socially-mediated behaviors. Group structuresmay result from active choices of individual rays to interact, or passive processes.Social behavior is known to affect spatial ecology in other elasmobranchs, but this isthe first study providing quantitative evidence for structured social relationships inmanta rays. To construct social networks, we collected data from more than 500groups of reef manta rays over five years, in the Raja Ampat Regency of West Papua.We used generalized affiliation indices to isolate social preferences from non-socialassociations, the first study on elasmobranchs to use this method. Longer lastingsocial preferences were detected mostly between female rays. We detectedassortment of social relations by phenotype and variation in social strategies, with theoverall social network divided into two main communities. Overall network structurewas characteristic of a dynamic fission-fusion society, with differentiated relationshipslinked to strong fidelity to cleaning station sites. Our results suggest that fine-scaleconservation measures will be useful in protecting social groups of M. alfredi in theirnatural habitats, and that a more complete understanding of the social nature of mantarays will help predict population response
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