Aims: Empagliflozin is a selective sodium glucose cotransporter‐2 (SGLT‐2) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study assessed pharmacological ...properties of empagliflozin in vitro and pharmacokinetic properties in vivo and compared its potency and selectivity with other SGLT‐2 inhibitors.
Methods: 14C‐alpha‐methyl glucopyranoside (AMG) uptake experiments were performed with stable cell lines over‐expressing human (h) SGLT‐1, 2 and 4. Two new cell lines over‐expressing hSGLT‐5 and hSGLT‐6 were established and 14C‐mannose and 14C‐myo‐inositol uptake assays developed. Binding kinetics were analysed using a radioligand binding assay with 3H‐labelled empagliflozin and HEK293‐hSGLT‐2 cell membranes. Acute in vivo assessment of pharmacokinetics was performed with normoglycaemic beagle dogs and Zucker diabetic fatty (ZDF) rats.
Results: Empagliflozin has an IC50 of 3.1 nM for hSGLT‐2. Its binding to SGLT‐2 is competitive with glucose (half‐life approximately 1 h). Compared with other SGLT‐2 inhibitors, empagliflozin has a high degree of selectivity over SGLT‐1, 4, 5 and 6. Species differences in SGLT‐1 selectivity were identified. Empagliflozin pharmacokinetics in ZDF rats were characterised by moderate total plasma clearance (CL) and bioavailability (BA), while in beagle dogs CL was low and BA was high.
Conclusions: Empagliflozin is a potent and competitive SGLT‐2 inhibitor with an excellent selectivity profile and the highest selectivity window of the tested SGLT‐2 inhibitors over hSGLT‐1. Empagliflozin represents an innovative therapeutic approach to treat diabetes.
The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA‐B Genotype and Abacavir Dosing were originally published in April 2012. We reviewed recent literature and concluded ...that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplementary Material online and included additional resources for applying CPIC guidelines to the electronic health record. Up‐to‐date information can be found at PharmGKB (http://www.pharmgkb.org).
Clinical Pharmacology & Therapeutics (2014); 95 5, 499–500. doi:10.1038/clpt.2014.38
A previous study identified kartogenin (KGN) as a potent modulator of bone marrow mesenchymal stem/stromal cell (BMSC) chondrogenesis. This initial report did not contrast KGN directly against ...transforming growth factor-beta 1 (TGF-β1), the most common growth factor used in chondrogenic induction medium. Herein, we directly compared the in vitro chondrogenic potency of TGF-β1 and KGN using a high resolution micropellet model system. Micropellets were cultured for 7-14 days in medium supplemented with TGF-β1, KGN, or both TGF-β1 + KGN. Following 14 days of induction, micropellets exposed to TGF-β1 alone or TGF-β1 + KGN in combination were larger and produced more glycosominoglycan (GAG) than KGN-only cultures. When TGF-β1 + KGN was used, GAG quantities were similar or slightly greater than the TGF-β1-only cultures, depending on the BMSC donor. BMSC micropellet cultures supplemented with KGN alone contracted in size over the culture period and produced minimal GAG. Indicators of hypertrophy were not mitigated in TGF-β1 + KGN cultures, suggesting that KGN does not obstruct BMSC hypertrophy. KGN appears to have weak chondrogenic potency in human BMSC cultures relative to TGF-β1, does not obstruct hypertrophy, and may not be a viable alternative to growth factors in cartilage tissue engineering.
During the Late Cretaceous and early Cenozoic the Earth experienced prolonged climatic cooling most likely caused by decreasing volcanic activity and atmospheric CO
levels. However, the causes and ...mechanisms of subsequent major global warming culminating in the late Paleocene to Eocene greenhouse climate remain enigmatic. We present deep and intermediate water Nd-isotope records from the North and South Atlantic to decipher the control of the opening Atlantic Ocean on ocean circulation and its linkages to the evolution of global climate. The marked convergence of Nd-isotope signatures 59 million years ago indicates a major intensification of deep-water exchange between the North and South Atlantic, which coincided with the turning point of deep-water temperatures towards early Paleogene warming. We propose that this intensification of Atlantic overturning circulation in concert with increased atmospheric CO
from continental rifting marked a climatic tipping point contributing to a more efficient distribution of heat over the planet.
In vitro neuronal models are essential for studying neurological physiology, disease mechanisms and potential treatments. Most in vitro models lack controlled vasculature, despite its necessity in ...brain physiology and disease. Organ-on-chip models offer microfluidic culture systems with dedicated micro-compartments for neurons and vascular cells. Such multi-cell type organs-on-chips can emulate neurovascular unit (NVU) physiology, however there is a lack of systematic data on how individual cell types are affected by culturing on microfluidic systems versus conventional culture plates. This information can provide perspective on initial findings of studies using organs-on-chip models, and further optimizes these models in terms of cellular maturity and neurovascular physiology. Here, we analysed the transcriptomic profiles of co-cultures of human induced pluripotent stem cell (hiPSC)-derived neurons and rat astrocytes, as well as one-day monocultures of human endothelial cells, cultured on microfluidic chips. For each cell type, large gene expression changes were observed when cultured on microfluidic chips compared to conventional culture plates. Endothelial cells showed decreased cell division, neurons and astrocytes exhibited increased cell adhesion, and neurons showed increased maturity when cultured on a microfluidic chip. Our results demonstrate that culturing NVU cell types on microfluidic chips changes their gene expression profiles, presumably due to distinct surface-to-volume ratios and substrate materials. These findings inform further NVU organ-on-chip model optimization and support their future application in disease studies and drug testing.
In this paper, we discuss energy-efficiency improvements in core networks obtained as a result of work carried out by the GreenTouch consortium over a five-year period. A number of techniques that ...yield substantial energy savings in core networks were introduced, including (i) the use of improved network components with lower power consumption, (ii) putting idle components into sleep mode, (iii) optically bypassing intermediate routers, (iv) the use of mixed line rates, (v) placing resources for protection into a low power state when idle, (vi) optimization of the network physical topology, and (vii) the optimization of distributed clouds for content distribution and network equipment virtualization. These techniques are recommended as the main energy-efficiency improvement measures for 2020 core networks. A mixed integer linear programming optimization model combining all the aforementioned techniques was built to minimize energy consumption in the core network. We consider group 1 nations' traffic and place this traffic on a US continental network represented by the AT&T network topology. The projections of the 2020 equipment power consumption are based on two scenarios: a business as usual (BAU) scenario and a GreenTouch (GT) (i.e., BAU + GT) scenario. The results show that the 2020 BAU scenario improves the network energy efficiency by a factor of 4.23 x compared with the 2010 network as a result of the reduction in the network equipment power consumption. Considering the 2020 BAU + GT network, the network equipment improvements alone reduce network power by a factor of 20 x compared with the 2010 network. Including of all the BAU + GT energy-efficiency techniques yields a total energy efficiency improvement of 315×. We have also implemented an experimental demonstration that illustrates the feasibility of energy-efficient content distribution in IP/WDM networks.
We review observational, experimental, and model results on how plants respond to extreme climatic conditions induced by changing climatic variability. Distinguishing between impacts of changing mean ...climatic conditions and changing climatic variability on terrestrial ecosystems is generally underrated in current studies. The goals of our review are thus (1) to identify plant processes that are vulnerable to changes in the variability of climatic variables rather than to changes in their mean, and (2) to depict/evaluate available study designs to quantify responses of plants to changing climatic variability. We find that phenology is largely affected by changing mean climate but also that impacts of climatic variability are much less studied, although potentially damaging. We note that plant water relations seem to be very vulnerable to extremes driven by changes in temperature and precipitation and that heatwaves and flooding have stronger impacts on physiological processes than changing mean climate. Moreover, interacting phenological and physiological processes are likely to further complicate plant responses to changing climatic variability. Phenological and physiological processes and their interactions culminate in even more sophisticated responses to changing mean climate and climatic variability at the species and community level. Generally, observational studies are well suited to study plant responses to changing mean climate, but less suitable to gain a mechanistic understanding of plant responses to climatic variability. Experiments seem best suited to simulate extreme events. In models, temporal resolution and model structure are crucial to capture plant responses to changing climatic variability. We highlight that a combination of experimental, observational, and/or modeling studies have the potential to overcome important caveats of the respective individual approaches.
Data on changes in dietary intake and related blood parameters throughout pregnancy are scarce; moreover, few studies have examined their association with glucose homeostasis. Therefore, we monitored ...intake of folate, vitamin B6, vitamin B12, vitamin D and iron, their status markers, and diet quality from preconception to the second trimester of pregnancy, and we examined whether these dietary factors were associated with glucose homeostasis during pregnancy. We included 105 women aged 18⁻40 years with a desire to get pregnancy or who were already <24 weeks pregnant. Women at increased gestational diabetes (GDM) risk were oversampled. Measurements were scheduled at preconception (
= 67), and 12 (
=53) and 24 weeks of pregnancy (
=66), including a fasting venipuncture, 75-grams oral glucose tolerance test, and completion of a validated food frequency questionnaire. Changes in micronutrient intake and status, and associations between dietary factors and glucose homeostasis, were examined using adjusted repeated measures mixed models. Micronutrient intake of folate, vitamin B6 and vitamin D and related status markers significantly changed throughout pregnancy, which was predominantly due to changes in the intake of supplements. Micronutrient intake or status levels were not associated with glucose homeostasis, except for iron intake (FE µg/day) with fasting glucose (β = -0.069 mmol/L,
= 0.013) and HbA1c (β = -0.4843 mmol,
= 0.002). Diet quality was inversely associated with fasting glucose (β = -0.006 mmol/L for each DHD15-index point,
= 0.017). It was shown that micronutrient intakes and their status markers significantly changed during pregnancy. Only iron intake and diet quality were inversely associated with glucose homeostasis.
Numerical models that combine weather forecasting and atmospheric chemistry are here referred to as chemical weather forecasting models. Eighteen operational chemical weather forecasting models on ...regional and continental scales in Europe are described and compared in this article. Topics discussed in this article include how weather forecasting and atmospheric chemistry models are integrated into chemical weather forecasting systems, how physical processes are incorporated into the models through parameterization schemes, how the model architecture affects the predicted variables, and how air chemistry and aerosol processes are formulated. In addition, we discuss sensitivity analysis and evaluation of the models, user operational requirements, such as model availability and documentation, and output availability and dissemination. In this manner, this article allows for the evaluation of the relative strengths and weaknesses of the various modelling systems and modelling approaches. Finally, this article highlights the most prominent gaps of knowledge for chemical weather forecasting models and suggests potential priorities for future research directions, for the following selected focus areas: emission inventories, the integration of numerical weather prediction and atmospheric chemical transport models, boundary conditions and nesting of models, data assimilation of the various chemical species, improved understanding and parameterization of physical processes, better evaluation of models against data and the construction of model ensembles.
Many aspects of the supposed hyperthermal Toarcian Oceanic Anoxic Event (T-OAE, Early Jurassic, c. 182 Ma) are well understood but a lack of robust palaeotemperature data severely limits ...reconstruction of the processes that drove the T-OAE and associated environmental and biotic changes. New oxygen isotope data from calcite shells of the benthic fauna suggest that bottom water temperatures in the western Tethys were elevated by c. 3.5 °C through the entire T-OAE. Modelling supports the idea that widespread marine anoxia was induced by a greenhouse-driven weathering pulse, and is compatible with the OAE duration being extended by limitation of the global silicate weathering flux. In the western Tethys Ocean, the later part of the T-OAE is characterized by abundant occurrences of the brachiopod Soaresirhynchia, which exhibits characteristics of slow-growing, deep sea brachiopods. The unlikely success of Soaresirhynchia in a hyperthermal event is attributed here to low metabolic rate, which put it at an advantage over other species from shallow epicontinental environments with higher metabolic demand.
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