A genetic deficiency of the solute carrier monocarboxylate transporter 8 (MCT8), termed Allan-Herndon-Dudley syndrome, is an important cause of X-linked intellectual and motor disability. MCT8 ...transports thyroid hormones across cell membranes. While thyroid hormone analogues improve peripheral changes of MCT8 deficiency, no treatment of the neurological symptoms is available so far. Therefore, we tested a gene replacement therapy in Mct8- and Oatp1c1-deficient mice as a well-established model of the disease. Here, we report that targeting brain endothelial cells for Mct8 expression by intravenously injecting the vector AAV-BR1-Mct8 increased tri-iodothyronine (T3) levels in the brain and ameliorated morphological and functional parameters associated with the disease. Importantly, the therapy resulted in a long-lasting improvement in motor coordination. Thus, the data support the concept that MCT8 mediates the transport of thyroid hormones into the brain and indicate that a readily accessible vascular target can help overcome the consequences of the severe disability associated with MCT8 deficiency.
Glycosylphosphatidylinositol (GPI)-anchored proteins (APs) are anchored at the outer leaflet of the plasma membrane (PM) bilayer by covalent linkage to a typical glycolipid and expressed in all ...eukaryotic organisms so far studied. Lipolytic release from PMs into extracellular compartments and intercellular transfer are regarded as the main (patho)physiological roles exerted by GPI-APs. The intercellular transfer of GPI-APs relies on the complete GPI anchor and is mediated by extracellular vesicles such as microvesicles and exosomes and lipid-free homo- or heteromeric aggregates, and lipoprotein-like particles such as prostasomes and surfactant-like particles, or lipid-containing micelle-like complexes. In mammalian organisms, non-vesicular transfer is controlled by the distance between donor and acceptor cells/tissues; intrinsic conditions such as age, metabolic state, and stress; extrinsic factors such as GPI-binding proteins; hormones such as insulin; and drugs such as anti-diabetic sulfonylureas. It proceeds either "directly" upon close neighborhood or contact of donor and acceptor cells or "indirectly" as a consequence of the induced lipolytic release of GPI-APs from PMs. Those displace from the serum GPI-binding proteins GPI-APs, which have retained the complete anchor, and become assembled in aggregates or micelle-like complexes. Importantly, intercellular transfer of GPI-APs has been shown to induce specific phenotypes such as stimulation of lipid and glycogen synthesis, in cultured human adipocytes, blood cells, and induced pluripotent stem cells. As a consequence, intercellular transfer of GPI-APs should be regarded as non-genetic inheritance of (acquired) features between somatic cells which is based on the biogenesis and transmission of matter such as GPI-APs and "membrane landscapes", rather than the replication and transmission of information such as DNA. Its operation in mammalian organisms remains to be clarified.
This study presents results from the Community Climate System Model 3 (CCSM3) forced with early to middle Miocene (∼20–14 Ma) vegetation, topography, bathymetry, and modern CO₂. A decrease in the ...meridional temperature gradient of 6.5°C and an increase in global mean temperature of 1.5°C are modeled in comparison with a control simulation forced with modern boundary conditions. Seasonal poleward displacements of the subtropical jet streams and storm tracks compared to the control simulation are associated with changes in Hadley circulation and significant cooling of the polar stratosphere, consistent with previously predicted effects of global warming. Energy budget calculations indicate that reduced albedo and topography were responsible for Miocene warmth in the high-latitude Northern Hemisphere while a combination of increased ocean heat transport and reduced albedo was responsible for relative warmth in the high-latitude Southern Hemisphere, compared to the present. Model–data analysis suggests Miocene climate was significantly warmer and wetter than simulated here, consistent with previous uncoupled Miocene models and supports recent reconstructions of Miocene CO₂ substantially higher than present.
Aim
To assess the lipid‐lowering efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in people with hypercholesterolaemia and prediabetes at baseline ...vs people with normoglycaemia at baseline in a pooled analysis of 10 ODYSSEY phase III trials.
Methods
People classified as having prediabetes had baseline HbA1c ≥39 mmol/mol (5.7%) and <48 mmol/mol (6.5%), or two baseline fasting plasma glucose values ≥5.6 mmol/l (100 mg/dl) but no more than one fasting plasma glucose value ≥7.0 mmol/l (126 mg/dl), or had specific terms reported in their medical history; people diagnosed with diabetes at baseline were excluded, and the remainder were classified as having normoglycaemia. Participants received alirocumab or control (placebo/ezetimibe) for 24–104 weeks, with maximally tolerated statin in most cases. The primary efficacy endpoint was LDL cholesterol reductions from baseline to week 24 in the intention‐to‐treat population using the mixed‐effect model with a repeated measures approach.
Results
Reductions in LDL cholesterol from baseline to week 24 with alirocumab were 44.0–61.8% (prediabetes group) and 45.8–59.5% (normoglycaemia group). In both subgroups, LDL cholesterol reductions were generally similar in those with and without baseline triglycerides ≥1.7 mmol/l (150 mg/dl). Alirocumab was not associated with changes in HbA1c or fasting plasma glucose over time in either subgroup (up to 24 months' follow‐up). Adverse event rates were generally similar in those with and without prediabetes.
Conclusions
Over a mean follow‐up of 24–104 weeks, alirocumab treatment resulted in significant LDL cholesterol reductions from baseline that were similar in participants with prediabetes and those with normoglycaemia at baseline, with no effect on glycaemia and a safety profile similar to that of the control.
What's new?
With statins being associated with an increased risk of diabetes (especially in individuals with risk factors for diabetes) and recent studies linking PCSK9 to glucose homeostasis, there is much interest in whether PCSK9 inhibitors affect diabetes risk.
We assessed the efficacy/safety of alirocumab, a PCSK9 inhibitor, vs control over a mean follow‐up of 24–104 weeks in people with hypercholesterolaemia and prediabetes vs people with normoglycaemia at baseline from 10 ODYSSEY phase III trials.
Our findings show alirocumab is generally well tolerated and significantly reduced LDL cholesterol levels to similar extents in individuals with prediabetes and those with normoglycaemia without any changes in measures of glycaemic control.
Sandy soils can benefit greatly from the addition of biochar, but the benefits depend on the properties of both the soil and the biochar. This study investigated the role of biochar particle size in ...controlling pore size distribution, hydraulic conductivity and water retention after careful mixing with coarse sandy subsoil. Intact commercial pellets of straw biochar (SB; approx. 8 × 5 mm) and ground pellets separated into 6 size fractions (median diameter 15, 33, 44, 81, 135 and 205 μm) were investigated at two concentrations (1.50 and 3.00 wt%). The results were compared with effects obtained with another feedstock (wood; WB) and another soil. Light microscopy and water retention measurements showed that smaller biochar particles settled into large existing soil pores, creating smaller interstitial pores to a much greater extent than larger particles. Accordingly, small particles (≤44 μm) had large enhancing effects on water retention and hydraulic conductivity in the medium suction range (pF1.7‐pF3.0), which were not found to a similar extent after the addition of larger particles (>81 μm). It was not possible to systematically distinguish the effects obtained with the three smallest particle fractions (SB15, WB18 and SB33). All effects measured were greatest at the highest biochar concentration level. In one soil, amendment with 3.00 wt% of SB15 decreased the fractional volume of drainable pores with an equivalent diameter of ≥60 μm from 31.3 vol% in the control to 19.1 vol%, while increasing the volume of pores in the 0.2–60 μm range that could potentially retain plant‐available water from 8.7 vol% to 20.1 vol%. Hydraulic conductivity at pF1.7 was increased by a factor of 10 (from 2.3 to 22.5 cm/day) and at pF3.0 by a factor of 14 (from 0.1*10−3 to 1.4*10−3 cm/day). Similar effects were observed in the other soil but at slightly different levels. The PDI version of the bimodal van Genuchten model was successfully fitted to measured water retention and log‐transformed hydraulic conductivity data (RMSE values in the interval 0.0011–0.0029 and 0.024–0.215, respectively). Dynamic simulation under variable field conditions including the hydraulic properties of biochar‐amended soil layers could be a useful method to investigate the effects on crop water supply, water and fertilizer utilization and yields.
•Fluidized bed-fired Stirling engine as efficient micro-scale CHP solution.•In-bed heat exchanger avoids ash induced fouling and enhances heat transfer.•Biomass micro-scale BFB with horizontal ...cyclone enables low emission operation.•The electrical efficiency for biomass-fired Stirling engines reaches 13–15%.•Part-load operation enhances efficiencies at consistently low CO emissions.
Combined heat and power production in micro- to small-scale is one main part of the decentralization of energy production. Concepts using solid biogenic fuels to provide power and heat are manifold, but often focus on a nominal power output above 50kWel. Moreover, slagging or fouling issues in combustion processes provoke reduced electrical efficiencies and short maintenance intervals. This research paper presents an efficient and fuel-flexible micro-scale combined heat and power solution. The developed demo plant consists of a 45kWth fluidized bed combustion chamber and a 5kWel Stirling engine. Bringing the heat exchanger surfaces of the Stirling engine directly into the bubbling fluidized bed enables an efficient heat transfer, while a cooled combustion avoids exceeding low ash melting temperatures. This prevents the Stirling’s in-bed heat exchanger surfaces from fouling and slagging. The comprehensive lab experiments show carbon monoxide emissions below 100 ppm for full and part load operation, which emphasizes the flexibility of the micro-scale combustion. The integrated Stirling engine reached its nominal electrical power output of 5kWel. The evaluation of the electrical efficiency in a 72 h long-term lab test revealed 13–15% electrical efficiency, which is maximal in part-load operation and goes beyond known comparable approaches. The overall fuel utilization rate exceeded 85%.
Adipocyte-derived extracellular vesicles (AdEVs) are membranous nanoparticles that convey communication from adipose tissue to other organs. Here, to delineate their role as messengers with ...glucoregulatory nature, we paired fluorescence AdEV-tracing and SILAC-labeling with (phospho)proteomics, and revealed that AdEVs transfer functional insulinotropic protein cargo into pancreatic β-cells. Upon transfer, AdEV proteins were subjects for phosphorylation, augmented insulinotropic GPCR/cAMP/PKA signaling by increasing total protein abundances and phosphosite dynamics, and ultimately enhanced 1st-phase glucose-stimulated insulin secretion (GSIS) in murine islets. Notably, insulinotropic effects were restricted to AdEVs isolated from obese and insulin resistant, but not lean mice, which was consistent with differential protein loads and AdEV luminal morphologies. Likewise, in vivo pre-treatment with AdEVs from obese but not lean mice amplified insulin secretion and glucose tolerance in mice. This data suggests that secreted AdEVs can inform pancreatic β-cells about insulin resistance in adipose tissue in order to amplify GSIS in times of increased insulin demand.
The use of magnesium alloys as degradable metals for biomedical applications is a topic of ongoing research and the demand for multifunctional materials is increasing. Hence, binary Mg-Ag alloys were ...designed as implant materials to combine the favourable properties of magnesium with the well-known antibacterial property of silver. In this study, three Mg-Ag alloys, Mg2Ag, Mg4Ag and Mg6Ag that contain 1.87 %, 3.82 % and 6.00 % silver by weight, respectively, were cast and processed with solution (T4) and aging (T6) heat treatment. The metallurgical analysis and phase identification showed that all alloys contained Mg4Ag as the dominant β phase. After heat treatment, the mechanical properties of all Mg-Ag alloys were significantly improved and the corrosion rate was also significantly reduced, due to presence of silver. Mg(OH)₂ and MgO present the main magnesium corrosion products, while AgCl was found as the corresponding primary silver corrosion product. Immersion tests, under cell culture conditions, demonstrated that the silver content did not significantly shift the pH and magnesium ion release. In vitro tests, with both primary osteoblasts and cell lines (MG63, RAW 264.7), revealed that Mg-Ag alloys show negligible cytotoxicity and sound cytocompatibility. Antibacterial assays, performed in a dynamic bioreactor system, proved that the alloys reduce the viability of two common pathogenic bacteria, Staphylococcus aureus (DSMZ 20231) and Staphylococcus epidermidis (DSMZ 3269), and the results showed that the killing rate of the alloys against tested bacteria exceeded 90%. In summary, biodegradable Mg-Ag alloys are cytocompatible materials with adjustable mechanical and corrosion properties and show promising antibacterial activity, which indicates their potential as antibacterial biodegradable implant materials.
Abstract
As energy efficiency demands increase, buildings get smarter, and the amount of data to analyze grows, where each building device may generate multiple data streams. These extensive ...quantities of monitoring data serve as a great opportunity for detecting anomalies in building automation systems and for optimizing their control. However, each building usually uses a custom format for data labels, therefore requiring an individual data label analysis per building. This makes the conceptually manageable task of detecting energy systems from the raw data increasingly complex and error-prone, which is a further hurdle that any building operation optimizer must resolve. This paper presents a methodology for automatically categorizing and labeling raw monitoring data from building automation systems. Using statistical features of the data, the method checks which data streams follow which known building operation rules and patterns. Therefore, an initial labeling of the data streams takes place. Furthermore, examining the correlation between the data streams indicates possible related system components using the concept of conditional probability. As a use case for the methodology, unlabeled data from a real building automation system are examined. The results show that, using unlabeled time series, data types from certain sensors and actuators can be reliably identified. The proposed methodology could therefore simplify the implementation of energy applications such as operation optimization and fault detection of building automation systems
Arc42 by Example Starke, Gernot; Simons, Michael; Zörner, Stefan ...
2019
eBook
This book teaches everything you need to know to jumpstart your own software architecture documentation. Through several elaborate examples, you'll learn how to write useful documentation that ...clearly explains the architecture of your software.
PDF
