Protein disulfide isomerase (PDI) catalyzes disulfide bond oxidation, reduction and isomerization during protein synthesis in the endoplasmic reticulum (ER). In addition to its critical role in the ...ER, in vitro and in vivo studies with blocking antibodies and conditional knockout mice have demonstrated that cell surface PDI is required for thrombosis, hemostasis and vascular inflammation in a manner dependent on its isomerase activity. This review will focus on our current understanding of the pathophysiologic role of PDI in regulating integrin-mediated platelet and neutrophil functions during vascular disease.
L-ascorbate (L-ascorbic acid, vitamin C) clearly has an inhibitory effect on cancer cells. However, the mechanism underlying differential sensitivity of cancer cells from same tissue to L-ascorbate ...is yet to be clarified. Here, we demonstrate that L-ascorbate has a selective killing effect, which is influenced by sodium-dependent vitamin C transporter 2 (SVCT-2) in human breast cancer cells. Treatment of human breast cancer cells with L-ascorbate differentially induced cell death, dependent on the SVCT-2 protein level. Moreover, knockdown of endogenous SVCT-2 via RNA interference in breast cancer cells expressing high levels of the protein induced resistance to L-ascorbate treatment, whereas transfection with SVCT-2 expression plasmids led to enhanced L-ascorbate chemosensitivity. Surprisingly, tumor regression by L-ascorbate administration in mice bearing tumor cell xenograft also corresponded to the SVCT-2 protein level. Interestingly, SVCT-2 expression was absent or weak in normal tissues, but strongly detected in tumor samples obtained from breast cancer patients. In addition, enhanced chemosensitivity to L-ascorbate occurred as a result of caspase-independent autophagy, which was mediated by beclin-1 and LC3 II. In addition, treatment with N-acetyl-L-cysteine, a reactive oxygen species (ROS) scavenger, suppressed the induction of beclin-1 and LC3 II, implying that the differential SVCT-2 protein-dependent L-ascorbate uptake was attributable to intracellular ROS induced by L-ascorbate, subsequently leading to autophagy. These results suggest that functional SVCT-2 sensitizes breast cancer cells to autophagic damage by increasing the L-ascorbate concentration and intracellular ROS production and furthermore, SVCT-2 in breast cancer may act as an indicator for commencing L-ascorbate treatment.
ABSTRACT
We perform an extensive study of numerical convergence for hot-Jupiter atmospheric flow solutions in simulations employing a setup commonly used in extrasolar planet studies – a resting ...state thermally forced to a prescribed temperature distribution on a short time-scale at high altitudes. Convergence is assessed rigorously with (i) a highly accurate pseudospectral model that has been explicitly verified to perform well under hot-Jupiter flow conditions and (ii) comparisons of the kinetic energy spectra, instantaneous (unaveraged) vorticity fields and temporal evolutions of the vorticity field from simulations that are numerically equatable. In the simulations, the (horizontal as well as vertical) resolution, dissipation operator order, and viscosity coefficient are varied with identical physical and initial setups. All of the simulations are compared against a fiducial reference simulation at high horizontal resolution and dissipation order (T682 and ∇ 16, respectively) – as well as against each other. Broadly, the reference solution features a dynamic, zonally (east–west) asymmetric jet with a copious amount of small-scale vortices and gravity waves. Here, we show that simulations converge to the reference simulation only at T341 resolution and with ∇ 16 dissipation order. Below this resolution and order, simulations either do not converge or converge to unphysical solutions. The general convergence behaviour is independent of the vertical range of the atmosphere modelled, from $\sim 2 \times 10^{-3}$MPa to $\sim 2 \times 10^1$ MPa. Ramifications for current extrasolar planet atmosphere modelling and observations are discussed.
Summary
Background
Oltipraz is a synthetic dithiolethione with an antisteatotic effect by inhibiting the activity of liver X receptor alpha (LXR‐α). Recent studies demonstrated the disruptive role of ...oltipraz on LXR‐α‐dependent lipogenesis in hepatocytes and a high‐fat diet mouse model.
Aim
To evaluate the efficacy and safety of oltipraz for reducing liver fat in subjects with non‐alcoholic fatty liver disease (NAFLD).
Methods
We performed a multicentre, double‐blind, placebo‐controlled, phase II study. Subjects with a liver fat >20% and hypertransaminasemia were randomised to the three groups: placebo (n = 22), 30 mg of oltipraz (n = 22) or 60 mg of oltipraz (n = 24) twice daily for 24 weeks. Changes in the liver fat from baseline to 24 weeks quantified using magnetic resonance spectroscopy were the primary outcome.
Results
Compared with the placebo group (−3.2 ± 11.1%), absolute changes in the liver fat content increased in a dose‐dependent manner: −7.7 ± 7.0% and −13.9 ± 10.7% for the low‐dose and high‐dose groups (P = 0.13 and P < 0.01). Per cent reduction in the liver fat content was also significantly greater in the high‐dose group than in the placebo group (−34.6 ± 29.4% vs. −0.6 ± 62.9%, P = 0.046). Body mass indices (−1.0 ± 0.9% vs. −0.5 ± 1.4%, P = 0.04) significantly decreased in the high‐dose group compared to the placebo group. However, absolute changes in insulin resistance, liver enzymes, lipids and cytokines were not significantly different among groups. The incidence of adverse events was comparable among groups.
Conclusions
Twenty‐four‐week oltipraz treatment significantly reduced the liver fat content in patients with NAFLD. Clinicaltrials.gov (NCT01373554).
Linked ContentThis article is linked to Ajmera and Loomba, Wang and Lin, and Kim and Kim papers. To view this article visit https://doi.org/10.1111/apt.14081, https://doi.org/10.1111/apt.14122 and https://doi.org/10.1111/apt.14146.
ABSTRACT
We investigate modons on tidally synchronized extrasolar planet atmospheres. Modons are dynamic, coherent flow structures composed of a pair of storms with opposite signs of vorticity. ...Modons are important because they can divert flows and lead to recognizable weather patterns. On synchronized planets, powered by the intense irradiation from the host star, large modons reach planetary-scale in size and exhibit quasi-periodic life-cycles – chaotically moving around the planet, breaking and reforming many times over long durations (e.g. thousands of planet days). Additionally, the modons transport and mix planetary-scale patches of hot and cold air around the planet, leading to high-amplitude and quasi-periodic signatures in the disc-averaged temperature flux. Hence, they induce variations of the ‘hotspot’ longitude to either side of the planet’s substellar point – consistent with observations at different epochs. The variability behaviour in our simulations broadly underscores the importance of accurately capturing vortex dynamics in extrasolar planet atmosphere modelling, particularly in understanding current observations.
In this article, we introduce an inertial projection and contraction algorithm by combining inertial type algorithms with the projection and contraction algorithm for solving a variational inequality ...in a Hilbert space
H
. In addition, we propose a modified version of our algorithm to find a common element of the set of solutions of a variational inequality and the set of fixed points of a nonexpansive mapping in
H
. We establish weak convergence theorems for both proposed algorithms. Finally, we give the numerical experiments to show the efficiency and advantage of the inertial projection and contraction algorithm.
Summary
Effects of anti-osteoporosis medications such as anti-resorptive and anabolic agents on healing of osteoporotic spinal fracture were retrospectively investigated. The use of anabolic agent ...significantly enhanced fracture healing, reduced progressive collapse, and presented good pain relief. These findings suggest that proper selection of medication could improve initial management of acute osteoporotic spinal fractures (OSFs).
Introduction
Although anti-osteoporosis medications have beneficial effects on prevention of osteoporotic spinal fractures (OSFs), few studies have compared effects of medications on fracture healing following OSFs. Therefore, the purpose of this study was to elucidate the effects of different anti-osteoporosis medications on radiological and clinical outcomes after acute OSFs.
Methods
A total of 132 patients diagnosed with acute OSFs were enrolled and allocated into three groups group I (
n
= 39, no anti-osteoporosis medication), group II (
n
= 66, bisphosphonate), and group III (
n
= 27, parathyroid hormone (PTH). Radiological parameters including magnetic resonance (MR) classification, occurrence of intravertebral cleft (IVC), and clinical outcomes such as numerical rating scale (NRS) and Oswestry disability index were assessed. Risk analyses for IVC and progressive collapse were done along the related factors and medication type.
Results
IVC sign was observed in 30 patients. The rate of IVC sign was lower in group III (7.4%) than that in group I (20.5%) or group II (30.3%), although the difference was not statistically significant. Moreover, the degree of NRS improvement was better in group III than that in group I or group II (5.7 vs. 3.1 vs. 3.5,
p
< 0.001). On multiple regression analysis, mid-portion type fracture in MR classification was a significant risk factor for progressive OSFs. The use of PTH showed significant lower incidences of occurrence of IVC (odds ratio (OR) = 0.160) and increase in height loss (OR = 0.325).
Conclusions
Different anti-osteoporosis medications presented different clinical and radiological results after acute OSFs. The use of anabolic agent significantly enhanced fracture healing, reduced progressive collapse, and presented better clinical outcomes. Proper selection of medication might improve initial management of acute OSFs.
Type 2 innate lymphoid cells (ILC2s) promote anti-helminth responses and contribute to allergies. Here, we report that Bcl11b, previously considered a T-cell-specific transcription factor, acted ...directly upstream of the key ILC2 transcription factor Gfi1 to maintain its expression in mature ILC2s. Consequently, Bcl11b−/− ILC2s downregulated Gata3 and downstream genes, including Il1rl1 (encoding IL-33 receptor), and upregulated Rorc and type 3 ILC (ILC3) genes. Additionally, independent of Gfi1, Bcl11b directly repressed expression of the gene encoding the ILC3 transcription factor Ahr, further contributing to silencing of ILC3 genes in ILC2s. Thus, Bcl11b−/− ILC2s lost their functions and gained ILC3 functions, and although they expanded in response to the protease allergen papain, they produced ILC3 but not ILC2 cytokines and caused increased airway infiltration of neutrophils instead of eosinophils. Our results demonstrate that Bcl11b is more than just a T-cell-only transcription factor and establish that Bcl11b sustains mature ILC2 genetic and functional programs and lineage fidelity.
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•Bcl11b is expressed in mature ILC2s, but not in precursors•Bcl11b maintains mILC2 genetic and functional programs through Gfi1, Gata3, and Rorα•Bcl11b suppresses the ILC3 genetic program in ILC2s by repressing Rorc and Ahr•Bcl11b−/− ILC2s expand in response to papain but cause ILC3-type airway inflammation
Regulation of mature innate lymphoid cell identity and function is poorly understood. Avram and colleagues demonstrate that Bcl11b, a transcription factor previously considered specific to T cells, sustains key ILC2 transcription factors and restricts essential ILC3 transcription factors in mature ILC2s, thus maintaining the genetic and functional programs of peripheral ILC2s.
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