Bile acid retention and activation of endogenous hepatic farnesoid-X-receptor in the pathogenesis of fatty liver disease in ob/ob-mice

The nuclear bile acid receptor FXR (farnesoid-X-receptor) has recently been implicated in the pathophysiology of non-alcoholic fatty liver disease because selective FXR-agonists improve glucose and lipid metabolism in rodent models of obesity. However, the regulation of FXR and other relevant nuclear receptors as well as their lipogenic target genes in fatty liver is still not revealed in detail. Livers were harvested from 14-week-old male ob/ob mice and wild-type controls. Serum bile acids were quantified by radioimmunoassay. mRNA and protein expression of transporters and nuclear receptors was analyzed by reverse transcriptase-polymerase chain reaction and Western blotting, whereas DNA binding to the IR-1 element was examined by electrophoretic mobility shift assay. In this study we show: (i) bile acid retention in ob/ob mice, (ii) a resulting FXR upregulation and binding to the IR-1 element in ob/ob animals and (iii) concomitant activation of the fatty acid synthase as a potential lipogenic FXR target gene in vivo. The present study suggests a potential role of hepatic bile acid retention and FXR activation in the induction of lipogenic target genes. Differences between intestinal and hepatic FXR could explain apparent contradictory information regarding its effects on fatty liver diseas

Practices of knowledge intensive process management: quantitative insights

Purpose – In contemporary businesses, the importance of knowledge workers and the knowledge intensive business processes (KIBPs) is ever increasing, yet they seem very hard to control and manage. The purpose of this paper is to grasp the specific characteristics of KIBPs and how they differ from non‐knowledge intensive business processes (non‐KIBP), also to question how organizations are using business process management (BPM) to manage and improve KIBPs. The differences in maturity and effectiveness of both types of processes are also evaluated. Design/methodology/approach – Data for this research were collected through an online survey. The survey was designed based on a previously conducted exploratory study with semi‐structured interviews as well as the literature. The target group was BPM practitioners and the final sample included 98 respondents. Due to non‐normality, the analyses were conducted with non‐parametric tests. The research questions were analysed using Mann‐Whitney U test and Spearman's correlations. Findings – It was found that KIBP and non‐KIBP have clearly different characteristics, such as the level of complexity, repeatability and creativity required. Also it was found that these processes are not managed or improved differently than non‐KIBPs, and suggest that organizations need to take these differences into consideration while managing and improving these processes. Furthermore, the results suggest that applying methodologies that aim to provide operational improvements may not necessarily produce the best results for KIBPs. Originality/value – The paper answers a call for further development of the body of knowledge on knowledge‐intensive business processes, a rapidly emerging field of interest for BPM practitioners, where a clear gap in literature exists

Проект планировки и межевания территории квартала в производственно-деловой зоне г. Томска

Подготовка проекта межевания осуществляется применительно к территории, расположенной в границах элемента планировочной структуры – нежилого квартала, ограниченного проспектом Кирова, улицами Киевская, Усова, Артёма. Границы квартала определены генеральным планом города Томска, а также правилами землепользования и застройки города Томска. Проект межевания квартала подготавливается на основе проекта планировки данной территории в целях установления границ земельных участков и содержит графическую и текстовую части. Основанием для подготовки проекта межевания является постановление администрации Города Томска от 27.03.2017 г. №275-з.The boundary-setting plan is developed to the Tomsk’s non-residental quarter. An element of planning structure has its borders submitted by Kirova avenue, Kievskaya, Usova and Artyoma streets. Borders of quarter are defined by the city master plan and rules of land use and building of the city of Tomsk. The boundary-setting plan of quarter is prepared on the basis of the draft area plan of this territory for the purpose of land parcels borders establishment. The project consists of a graphic part and the text explanation. The basis for preparation of the project is the resolution of city administration of Tomsk

False Hopes, Missed Opportunities: How Economic Models Affect the IPCC Proposals in Special Report 15 “Global Warming of 1.5 °C” (2018). An Analysis From the Scientific Advisory Board of BUND

The 2018 IPCC Special Report SR15 developed four scenarios how temperature increases could either be limited to 1.5°, or, in the case of overshoot, could be brought back to that level by 2100. However, the Carbon Dioxide Removal options discussed to achieve “negative emissions” will affect not only the climate system, but also biodiversity and the ecosystem services it provides. Unfortunately, the Integrated Assessment Models, and in particular the economic models incorporated in them were capable of integrating only a selective fraction of these effects, and ignore potential tipping points triggering irreversible processes, policies beyond economic instruments and consumption changes to happen over the next 80 years. Our analysis is based on an interdisciplinary expert elicitation, analysing the options suggested by the IPCC one by one. We find that most of them are associated with biodiversity loss, hazardous chemicals dispersion, enhanced energy consumption and/or other severe other damages. We suggest which measures can be applied sustainably, which should be dropped, and which additional ones have been omitted by the report

Intramolecular Structural Heterogeneity altered by Long-range Contacts in an Intrinsically Disordered Protein

Short-range interactions and long-range contacts drive the 3D folding of structured proteins. The proteins' structure has a direct impact on their biological function. However, nearly 40% of the eukaryotes proteome is composed of intrinsically disordered proteins (IDPs) and protein regions that fluctuate between ensembles of numerous conformations. Therefore, to understand their biological function, it is critical to depict how the structural ensemble statistics correlate to the IDPs' amino acid sequence. Here, using small-angle x-ray scattering (SAXS) and time-resolved F\"orster resonance energy transfer (trFRET), we study the intra-molecular structural heterogeneity of the neurofilament low intrinsically disordered tail domain (NFLt). Using theoretical results of polymer physics, we find that the Flory scaling exponent of NFLt sub-segments correlates linearly with their net charge, ranging from statistics of ideal to self-avoiding chains. Surprisingly, measuring the same segments in the context of the whole NFLt protein, we find that regardless of the peptide sequence, the segments' structural statistics are more expanded than when measured independently. Our findings show that while polymer physics can, to some level, relate the IDP's sequence to its ensemble conformations, long-range contacts between distant amino acids play a crucial role in determining intra-molecular structures. This emphasizes the necessity of advanced polymer theories to fully describe IDPs ensembles with the hope it will allow us to model their biological function

Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion

Nephrocalcinosis, acute calcium oxalate (CaOx) nephropathy, and renal stone disease can lead to inflammation and subsequent renal failure, but the underlying pathological mechanisms remain elusive. Other crystallopathies, such as gout, atherosclerosis, and asbestosis, trigger inflammation and tissue remodeling by inducing IL-1β secretion, leading us to hypothesize that CaOx crystals may induce inflammation in a similar manner. In mice, intrarenal CaOx deposition induced tubular damage, cytokine expression, neutrophil recruitment, and renal failure. We found that CaOx crystals activated murine renal DCs to secrete IL-1β through a pathway that included NLRP3, ASC, and caspase-1. Despite a similar amount of crystal deposits, intrarenal inflammation, tubular damage, and renal dysfunction were abrogated in mice deficient in MyD88; NLRP3, ASC, and caspase-1; IL-1R; or IL-18. Nephropathy was attenuated by DC depletion, ATP depletion, or therapeutic IL-1 antagonism. These data demonstrated that CaOx crystals trigger IL-1β–dependent innate immunity via the NLRP3/ASC/caspase-1 axis in intrarenal mononuclear phagocytes and directly damage tubular cells, leading to the release of the NLRP3 agonist ATP. Furthermore, these results suggest that IL-1β blockade may prevent renal damage in nephrocalcinosis

Extreme ultraviolet detection using AlGaN-on-Si inverted Schottky photodiodes

We report on the fabrication of aluminum gallium nitride (AlGaN) Schottky diodes for extreme ultraviolet (EUV) detection. AlGaN layers were grown on silicon wafers by molecular beam epitaxy with the conventional and inverted Schottky structure, where the undoped, active layer was grown before or after the n-doped layer, respectively. Different current mechanisms were observed in the two structures. The inverted Schottky diode was designed for the optimized backside sensitivity in the hybrid imagers. A cut-off wavelength of 280 nm was observed with three orders of magnitude intrinsic rejection ratio of the visible radiation. Furthermore, the inverted structure was characterized using a EUV source based on helium discharge and an open electrode design was used to improve the sensitivity. The characteristic He I and He II emission lines were observed at the wavelengths of 58.4 nm and 30.4 nm, respectively, proving the feasibility of using the inverted layer stack for EUV detectio

A new pedigree with thrombomodulin-associated coagulopathy in which delayed fibrinolysis is partially attenuated by co-inherited TAFI deficiency

ACKNOWLEDGEMENTS We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health Research and NHS Blood and Transplant. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. S.K.W. was supported during this work by the Medical Research Council (MR/K023489/1) and is now funded through an NIHR-funded Academic Clinical Lectureship. K.D. is supported as a HSST trainee by NHS Health Education England. N.J.M. and C.S.W. are supported by the British Heart Foundation (PG/15/82/31721). J.C.M. is a fellow of the Research Foundation Flanders (FWO Vlaanderen; 1137717N). A.D.M. is supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol National Health Service Foundation Trust and the University of Bristol. We thank Prof Paul Declerck and Prof Ann Gils, University Leuven, Belgium for the kind gift of the MA-T12D11 antibody. We acknowledge technical assistance from Dorien Leenaerts, University of Antwerp, Belgium and Michela Donnarumma, University of Aberdeen, UK.Peer reviewedPublisher PD