Cardiac hypertrophy and dilatation can result from stimulation of signal transduction pathways mediated by heterotrimeric G proteins, especially G q , whose ␣ subunit activates phospholipase C␤ (PLC␤). We now report that transient, modest expression of a hemagglutinin (HA) epitope-tagged, constitutively active mutant of the G q ␣ subunit (HA␣* q ) in hearts of transgenic mice is sufficient to induce cardiac hypertrophy and dilatation that continue to progress after the initiating stimulus becomes undetectable. At 2 weeks, HA␣ * q protein is expressed at less than 50% of endogenous ␣ q͞11 , and the transgenic hearts are essentially normal morphologically. Although HA␣ * q protein declines at 4 weeks and is undetectable by 10 weeks, the animals develop cardiac hypertrophy and dilatation and die between 8 and 30 weeks in heart failure. As the pathology develops, endogenous ␣ q͞11 rises (2.9-fold in atria; 1.8-fold in ventricles). At 2 weeks, basal PLC activity is increased 9-to 10-fold in atria but not ventricles. By 10 weeks, it is elevated in both, presumably because of the rise in endogenous ␣ q͞11 . We conclude that the pathological changes initiated by early, transient HA␣ * q expression are maintained in part by compensatory changes in signal transduction and other pathways.

Background: Diabetes increases the risk of hypertension and orthostatic hypotension and raises the risk of cardiovascular death during heat waves and high pollution episodes.Objective: We examined whether short-term exposures to air pollution (fine particles, ozone) and heat resulted in perturbation of arterial blood pressure (BP) in persons with type 2 diabetes mellitus (T2DM).Methods: We conducted a panel study in 70 subjects with T2DM, measuring BP by automated oscillometric sphygmomanometer and pulse wave analysis every 2 weeks on up to five occasions (355 repeated measures). Hourly central site measurements of fine particles, ozone, and meteorology were conducted. We applied linear mixed models with random participant intercepts to investigate the association of fine particles, ozone, and ambient temperature with systolic, diastolic, and mean arterial BP in a multipollutant model, controlling for season, meteorological variables, and subject characteristics.Results: An interquartile increase in ambient fine particle mass [particulate matter (PM) with an aerodynamic diameter of ≤ 2.5 μm (PM2.5)] and in the traffic component black carbon in the previous 5 days (3.54 and 0.25 μg/m3, respectively) predicted increases of 1.4 mmHg [95% confidence interval (CI): 0.0, 2.9 mmHg] and 2.2 mmHg (95% CI: 0.4, 4.0 mmHg) in systolic BP (SBP) at the population geometric mean, respectively. In contrast, an interquartile increase in the 5-day mean of ozone (13.3 ppb) was associated with a 5.2 mmHg (95% CI: –8.6, –1.8 mmHg) decrease in SBP. Higher temperatures were associated with a marginal decrease in BP.Conclusions: In subjects with T2DM, PM was associated with increased BP, and ozone was associated with decreased BP. These effects may be clinically important in patients with already compromised autoregulatory function.

Red blood cells (RBCs) undergo numerous changes during storage; however, the clinical relevance of these storage "lesions" is unclear. We hypothesized that the duration of storage of transfused RBCs is associated with mortality after repeat sternotomy for cardiac surgery, because these patients are at high risk for both RBC transfusion and adverse outcome. We retrospectively analyzed 434 patients who underwent repeat median sternotomy for coronary artery bypass graft or valve surgery and who received allogeneic RBCs. Three-hundred-twenty-one (74%) patients met the criteria for eligibility. After adjusting for the effects of confounders and the total number of RBC transfusions, the duration of storage of the oldest RBC unit transfused was found to be associated with both in-hospital mortality (Cox proportional hazard ratio (HR) = 1.151; P < 0.0001) and out-of-hospital mortality (HR = 1.116; P < 0.0001). The mean duration of storage of transfused RBCs was also an independent predictor of in-hospital mortality (HR = 1.036; P < 0.0001). Independent associations between the duration of storage of transfused RBCs and acute renal dysfunction and intensive care unit and hospital length of stay were also observed. The duration of storage of RBCs is associated with adverse outcome after repeat sternotomy for cardiac surgery. The clinical significance of this finding should be investigated in a large, randomized, blinded clinical trial.

The small single-stranded DNA (ssDNA) bacteriophages of the subfamily Gokushovirinae were traditionally perceived as narrowly targeted, niche-specific viruses infecting obligate parasitic bacteria, such as Chlamydia. The advent of metagenomics revealed gokushoviruses to be widespread in global environmental samples. This study expands knowledge of gokushovirus diversity in the environment by developing a degenerate PCR assay to amplify a portion of the major capsid protein (MCP) gene of gokushoviruses. Over 500 amplicons were sequenced from 10 environmental samples (sediments, sewage, seawater and freshwater), revealing the ubiquity and high diversity of this understudied phage group. Residue-level conservation data generated from multiple alignments was combined with a predicted 3D structure, revealing a tendency for structurally internal residues to be more highly conserved than surface-presenting protein–protein or viral–host interaction domains. Aggregating this data set into a phylogenetic framework, many gokushovirus MCP clades contained samples from multiple environments, although distinct clades dominated the different samples. Antarctic sediment samples contained the most diverse gokushovirus communities, whereas freshwater springs from Florida were the least diverse. Whether the observed diversity is being driven by environmental factors or host-binding interactions remains an open question. The high environmental diversity of this previously overlooked ssDNA viral group necessitates further research elucidating their natural hosts and exploring their ecological roles.

Telomeric regions contain prominent sites of heterochromatin, which is associated with unique histone modification profiles such as the methylation of histone H3 at Lys9 (H3K9me). In fission yeast, the conserved telomeric shelterin complex recruits the histone H3K9 methyltransferase complex CLRC to establish subtelomeric heterochromatin. Although many shelterin mutations affect subtelomeric heterochromatin assembly, the mechanism remains elusive due to the diverse functions of shelterin. Through affinity purification, we found that shelterin directly associates with CLRC through the Ccq1 subunit. Surprisingly, mutations that disrupt interactions between shelterin subunits compromise subtelomeric heterochromatin without affecting CLRC interaction with shelterin component Pot1, located at chromosome ends. We further discovered that telomeric repeats are refractory to heterochromatin spreading and that artificial restoration of shelterin connections or increased heterochromatin spreading rescued heterochromatin defects in these shelterin mutants. Thus, subtelomeric heterochromatin assembly requires both the recruitment of CLRC by shelterin to chromosome ends and the proper connection of shelterin components, which allows CLRC to skip telomeric repeats to internal regions.

Chromatin is generally classified as euchromatin or heterochromatin, each with distinct histone modifications, compaction levels, and gene expression patterns. Although the proper formation of heterochromatin is essential for maintaining genome integrity and regulating gene expression, heterochromatin can also spread into neighboring regions in a sequence-independent manner, leading to the inactivation of genes. Because the distance of heterochromatin spreading is stochastic, the formation of boundaries, which block the spreading of heterochromatin, is critical for maintaining stable gene expression patterns. Here we review the current understanding of the mechanisms underlying heterochromatin spreading and boundary formation.

It appears likely that early and aggressive treatment with multiple drug combinations will become more common in the management of T2DM. The new treatment modalities discussed here offer hope for improved outcomes and for meeting the considerable public health challenges posed by this complex condition. However, long-term studies are needed to determine durability of treatment effects, as well as the ultimate role of these new agents in the management of patients with T2DM.

Objective:To assess whether glycemic control, soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF) were associated with the development of preeclampsia (PE) or gestational hypertension (GHTN) in women with preexisting diabetes.Methods:Maternal circulating angiogenic factors (sFlt1 and PlGF) measured on automated platform were studied at four time points during pregnancy in women with diabetes (N = 159) and reported as multiples of the median (MOM) of sFlt1/PlGF ratio (median, 25th–75th percentile) noted in non-diabetic non-hypertensive control pregnant population (N = 139). Diagnosis of PE or GHTN was determined by review of de-identified clinical data.Results:PE developed in 12% (N = 19) and GHTN developed in 23% (N = 37) of the women with diabetes. Among diabetic women without PE or GHTN, median sFlt1/PlGF levels at 35–40 weeks was threefold higher than in non-diabetic controls [MOM 3.21(1.19–7.24), p = 0.0001]. Diabetic women who subsequently developed PE had even greater alterations in sFlt1/PlGF ratio during the third trimester [MOM for PE at 27–34 weeks 15.18 (2.37–26.86), at 35–40 weeks 8.61(1.20–18.27), p ≤ 0.01 for both windows compared to non-diabetic controls]. Women with diabetes who subsequently developed GHTN also had significant alterations in angiogenic factors during third trimester; however, these findings were less striking. Among women with diabetes, glycosylated hemoglobin (HbA1c) during the first trimester was higher in subjects who subsequently developed PE (7.7 vs 6.7%, p = 0.0001 for diabetic PE vs diabetic non-PE).Conclusions:Women with diabetes had a markedly altered anti-angiogenic state late in pregnancy that was further exacerbated in subjects who developed PE. Altered angiogenic factors may be one mechanism for the increased risk of PE in this population. Increased HbA1c in the first trimester of pregnancies in women with diabetes was strongly associated with subsequent PE.