Background-HMGCR (3-Hydroxy-3-methylglutaryl coenzyme A reductase), the direct target of statin inhibition, undergoes alternative splicing of exon 13, which encodes part of the statin-binding domain of the enzyme. We hypothesized that HMGCR alternative splicing might be related to the interindividual variation in plasma low-density lipoprotein cholesterol response to statin treatment. Methods and Results-We measured mRNA expression of both the full-length and the alternatively spliced HMGCR transcript lacking exon 13 (HMGCRv_1) in 170 simvastatin-incubated immortalized lymphocyte cell lines derived from participants in the Cholesterol and Pharmacogenetics (CAP) study who were treated with simvastatin 40 mg/d for 6 weeks. Greater upregulation of HMGCRv_1 in vitro was significantly correlated (PՅ0.0001) with smaller in vivo reductions of plasma total cholesterol, low-density lipoprotein cholesterol, apoprotein B, and triglycerides and explained 6% to 15% of the variation in their response to treatment. In contrast, no significant relationship was found between expression of the full-length HMGCR transcript and in vivo response. By siRNA knockdown of the full-length transcript, we found that HMGCR enzyme activity measured in cells enriched in HMGCRv_1 was relatively resistant to statin inhibition, consistent with the association of increased alternative splicing with reduced statin response in the CAP study. In addition, we found that a common HMGCR single-nucleotide polymorphism (rs3846662) located within intron 13 was associated with variation in the proportion of HMGCR mRNA that is alternatively spliced. Conclusions-Variation in the production of an HMGCR isoform with reduced statin sensitivity is a determinant of interindividual differences in low-density lipoprotein cholesterol, apolipoprotein B, and triglyceride response to statin treatment. (Circulation. 2008;118:355-362.)

No abstract

Diurnal variations in the formation and development of convective storms over contiguous North China during the warm season were studied using reflectivity from six China Next Generation Weather Radars between 2008 and 2011. Our results, including temporal and spatial analysis of hourly storm frequency through the warm season, and inter‐month comparisons during June, July and August, indicate that most storms initiate over the northwestern mountains in the afternoon as a result of solar heating, with the highest frequency in June, and the lowest in August. Storms propagate from the mountains to the southeastern foothills and plains, with the highest rates occurring in June, and the lowest in August. In the late afternoon, there is a remarkably high storm frequency over the foothills and plains, which indicates a significant topographic control on the southeastward propagation and intensification of storms during the warm season. Storm activity occurs mainly on the plains through the night, with the highest frequency in July and the lowest in June, as a result of a favorable nocturnal convection mechanism. The region‐averaged hourly storm frequencies for the warm season, and also for each month in JJA, are all bimodally distributed, with peak frequencies occurring in late afternoon and during the night, with the highest frequency recorded in the late afternoon during June and July, but at night in August. In general, the mean storm frequency is highest during the day and night in July, and lowest from afternoon to evening in August, but from nighttime to the next morning in June.

Genes involved in cholesterol biosynthesis and uptake are transcriptionally regulated in response to cellular sterol content in a coordinated manner. A number of these genes, including 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and LDL receptor (LDLR), undergo alternative splicing, resulting in reductions of enzyme or protein activity. Here we demonstrate that cellular sterol depletion suppresses, and sterol loading induces, alternative splicing of multiple genes involved in the maintenance of cholesterol homeostasis including HMGCR and LDLR, the key regulators of cellular cholesterol biosynthesis and uptake, respectively. These changes were observed in both in vitro studies of the HepG2 human hepatoma derived cell line, as well as in vivo studies of St. Kitts vervets, also known as African green monkeys, a commonly used primate model for investigating cholesterol metabolism. These effects are mediated in part by sterol regulation of polypyrimidine tract binding protein 1 (PTBP1), since knock-down of PTBP1 eliminates sterol induced changes in alternative splicing of several of these genes. Single nucleotide polymorphisms (SNPs) that influence HMGCR and LDLR alternative splicing (rs3846662 and rs688, respectively), have been associated with variation in plasma LDL-cholesterol levels. Sterol-induced changes in alternative splicing are blunted in carriers of the minor alleles for each of these SNPs, indicating an interaction between genetic and non-genetic regulation of this process. Our results implicate alternative splicing as a novel mechanism of enhancing the robust transcriptional response to conditions of cellular cholesterol depletion or accumulation. Thus coordinated regulation of alternative splicing may contribute to cellular cholesterol homeostasis as well as plasma LDL levels.

Because of natural decadal climate variability-Atlantic multi-decadal variability (AMV) and Pacific decadal variability (PDV)-the increase of global mean surface air temperature (GMSAT) has not been monotonic although atmospheric greenhouse-gas (GHG) concentrations have been increasing continuously. It has always been a challenge regarding how to separate the effects of these two factors on GMSAT. Here, we find a physically based quasi-linear relationship between transient GMSAT and well-mixed GHG changes for both observations and model simulations. With AMV and PDV defined as the combination of variability over both the Atlantic and Pacific basins after the GHG-related trend is removed, we show that the observed GMSAT changes from 1880 to 2017 on multi-decadal or longer timescales receive contributions of about 70% from GHGs, while AMV and PDV together account for roughly 30%. Moreover, AMV contributes more to time-evolving GMSAT on multi-decadal and longer timescales, but PDV leads AMV on decadal timescales with comparable contributions to GMSAT trends.