Non-severe aortic regurgitation increases short-term mortality in acute heart failure with preserved ejection fraction.

Mild or moderate aortic regurgitation (AR) has only little effect on cardiovascular outcome in people with normal left ventricular ejection fraction (EF); therefore, it is not perceived as a major clinical problem. This study investigates whether mild or moderate AR is associated with increased short-term mortality in patients hospitalized for treatment of acute heart failure (AHF) and whether mild or moderate AR impacts differently on short-term mortality in AHF patients with reduced EF (AHFrEF), mid-range EF (AHFmrEF), or preserved EF (AHFpEF). This mono-centric study included 505 consecutive adult patients hospitalized for de novo or worsening chronic HF not related to acute ischaemia or severe valvular pathology in the echocardiogram at index hospitalization. Cox regression analysis studied the impact of AR on all-cause mortality (ACM) over the 150 days' study period. Mild or moderate AR was associated with increased ACM (HR 1.75 [95% CI: 1.1-2.7]; P = 0.009). The prevalence of mild or moderate AR in the study population was 42% and not significantly different between AHFpEF (n = 227), AHFmrEF (n = 86), and AHFrEF (n = 192) study participants (37.9% vs. 50.0% vs. 42.7%; P = 0.144). In AHFpEF patients, the age-adjusted hazard for ACM was increased in patients with AR compared with patients without AR (HR 2.17 [95% CI: 1.1-4.2]; P = 0.002). The age-adjusted hazard for ACM was increased by a trend in AHFmrEF with AR (HR 7.11, [95% CI: 0.9-57.8]; P = 0.067) and not different between the AHFrEF groups (HR 0.95 [95% CI: 0.5-1.8]; P = 0.875). Mild or moderate AR increased ACM only in AHFpEF patients, highlighting a distinct clinical relevance

Already low drug dose antagonism of the renin-angiotensin aldosterone system decreases 1-year mortality and rehospitalization in old heart failure patients

Hospitalization for heart failure treatment (HHF) is an incisive event in the course of HF. Today, the large majority of HHF patients is ≥ 65 years and discharge HF drugs are most often not applied at dose levels acknowledged to provide prognostic benefit. This study therefore aims to investigate the treatment effect size of discharge HF drugs in old HHF patients. Drugs are analyzed according to pharmacological class. Individual discharge HF drug dose is reported as percentage of guidelines-recommended target dose. Primary endpoint was 1-year all-cause mortality (ACM) after discharge; the secondary endpoint combined 1-year ACM and first cardiovascular hospitalization within 1 year after discharge. Comparison between 65-80 years and > 80 years old study participants tested the relative treatment effect size as a function of respective age group. The 875 consecutive HHF patients had a median age of 82 years [76-87 years]; 48.6 % were females. Betablocker and diuretic treatment did not change the incidence of endpoints. Inhibition of the renin-angiotensin system (RASi), when compared to no treatment, decreased the incidence of endpoints both at the 1-25 % and the > 25 % target dose level. Antagonists of the mineralocorticoid receptor (MRA), when compared to no treatment, decreased the secondary endpoint at the 1-25 % target dose level but not at the > 25 % target dose level. The relative treatment effect size of RASi or MRA corresponded between the age strata for both endpoints. Low-dose RASi and MRA had beneficial effects in these old HHF patients

Decongestion improving right heart function ameliorates prognosis after an acute heart failure episode.

The prognostic role of decongestion-related change of cardiac morphology and in particular right heart function has not been investigated comprehensively in AHF patients. This prospective observational single-centre study included consecutive patients hospitalized for treatment of AHF with reduced, mildly-reduced or preserved left ventricular ejection fraction (LVEF). Comprehensive transthoracic echocardiography at admission and discharge assessed decongestion-related change of cardiac function and morphology. The combined endpoint of 1 year all-cause mortality and cardiovascular rehospitalization explored the prognostic importance of decongestion-related change. The 176 study participants were 83 years old [74-87] and 54% were men. Fifty one (29%) had rLVEF, 65 (37%) mrLVEF, and 60 (34%) pLVEF. The proportion of de novo or worsening chronic HF was not different between LVEF groups. HF aetiology and cardiovascular risk factors were equally distributed across all groups except for a higher BMI in the pLVEF group. Decongestion equally reduced body weight, heart rate, systolic and diastolic blood pressure, tricuspid regurgitation gradient, and inferior vena cava diameter across all groups (P < 0.004 for all). Decongestion-related increase in TAPSE independent of the LVEF was associated with improvement of right-ventricular-pulmonary artery coupling and a lower incidence of the combined outcome in the Cox proportional hazard risk analysis (unadjusted HR 0.50 95% CI 0.33-0.78, P = 0.002; adjusted HR 0.46 95% CI: 0.33-0.78, P = 0.001). Decongestion-related increase in TAPSE and recovery of RV/pulmonary artery coupling was observed across all LVEF groups and associated with a risk reduction for the combined endpoint highlighting the important prognostic role of right heart recovery after an AHF episode

DNA topoisomerases participate in fragility of the oncogene RET

Fragile site breakage was previously shown to result in rearrangement of the RET oncogene, resembling the rearrangements found in thyroid cancer. Common fragile sites are specific regions of the genome with a high susceptibility to DNA breakage under conditions that partially inhibit DNA replication, and often coincide with genes deleted, amplified, or rearranged in cancer. While a substantial amount of work has been performed investigating DNA repair and cell cycle checkpoint proteins vital for maintaining stability at fragile sites, little is known about the initial events leading to DNA breakage at these sites. The purpose of this study was to investigate these initial events through the detection of aphidicolin (APH)-induced DNA breakage within the RET oncogene, in which 144 APHinduced DNA breakpoints were mapped on the nucleotide level in human thyroid cells within intron 11 of RET, the breakpoint cluster region found in patients. These breakpoints were located at or near DNA topoisomerase I and/or II predicted cleavage sites, as well as at DNA secondary structural features recognized and preferentially cleaved by DNA topoisomerases I and II. Co-treatment of thyroid cells with APH and the topoisomerase catalytic inhibitors, betulinic acid and merbarone, significantly decreased APH-induced fragile site breakage within RET intron 11 and within the common fragile site FRA3B. These data demonstrate that DNA topoisomerases I and II are involved in initiating APH-induced common fragile site breakage at RET, and may engage the recognition of DNA secondary structures formed during perturbed DNA replication

Interaction of the Retinoblastoma Protein with Orc1 and Its Recruitment to Human Origins of DNA Replication

Background: The retinoblastoma protein (Rb) is a crucial regulator of cell cycle progression by binding with E2F transcription factor and repressing the expression of a variety of genes required for the G1-S phase transition. Methodology/Principal Findings: Here we show that Rb and E2F1 directly participate in the control of initiation of DNA replication in human HeLa, U2OS and T98G cells by specifically binding to origins of DNA replication in a cell cycle regulated manner. We show that, both in vitro and inside the cells, the largest subunit of the origin recognition complex (Orc1) specifically binds hypo-phosphorylated Rb and that this interaction is competitive with the binding of Rb to E2F1. The displacement of Rb-bound Orc1 by E2F1 at origins of DNA replication marks the progression of the G1 phase of the cell cycle toward the G1-S border. Conclusions/Significance: The participation of Rb and E2F1 in the formation of the multiprotein complex that binds origins of DNA replication in mammalian cells appears to represent an effective mechanism to couple the expression of gene

Preferential Localization of Human Origins of DNA Replication at the 5′-Ends of Expressed Genes and at Evolutionarily Conserved DNA Sequences

Replication of mammalian genomes requires the activation of thousands of origins which are both spatially and temporally regulated by as yet unknown mechanisms. At the most fundamental level, our knowledge about the distribution pattern of origins in each of the chromosomes, among different cell types, and whether the physiological state of the cells alters this distribution is at present very limited.We have used standard λ-exonuclease resistant nascent DNA preparations in the size range of 0.7–1.5 kb obtained from the breast cancer cell line MCF–7 hybridized to a custom tiling array containing 50–60 nt probes evenly distributed among genic and non-genic regions covering about 1% of the human genome. A similar DNA preparation was used for high-throughput DNA sequencing. Array experiments were also performed with DNA obtained from BT-474 and H520 cell lines. By determining the sites showing nascent DNA enrichment, we have localized several thousand origins of DNA replication. Our major findings are: (a) both array and DNA sequencing assay methods produced essentially the same origin distribution profile; (b) origin distribution is largely conserved (>70%) in all cell lines tested; (c) origins are enriched at the 5′ends of expressed genes and at evolutionarily conserved intergenic sequences; and (d) ChIP on chip experiments in MCF-7 showed an enrichment of H3K4Me3 and RNA Polymerase II chromatin binding sites at origins of DNA replication.Our results suggest that the program for origin activation is largely conserved among different cell types. Also, our work supports recent studies connecting transcription initiation with replication, and in addition suggests that evolutionarily conserved intergenic sequences have the potential to participate in origin selection. Overall, our observations suggest that replication origin selection is a stochastic process significantly dependent upon local accessibility to replication factors

DNA replication and the GINS complex: localization on extended chromatin fibers

<p>Abstract</p> <p>Background</p> <p>The GINS complex is thought to be essential for the processes of initiation and elongation of DNA replication. This complex contains four subunits, one of which (Psf1) is proposed to bind to both chromatin and DNA replication-associated proteins. To date there have been no microscopic analyses to evaluate the chromatin distribution of this complex. Here, we show the organization of GINS complexes on extended chromatin fibers in relation to sites of DNA replication and replication-associated proteins.</p> <p>Results</p> <p>Using immunofluorescence microscopy we were able to visualize ORC1, ORC2, PCNA, and GINS complex proteins Psf1 and Psf2 bound to extended chromatin fibers. We were also able to detect these proteins concurrently with the visualization of tracks of recently replicated DNA where EdU, a thymidine analog, was incorporated. This allowed us to assess the chromatin association of proteins of interest in relation to the process of DNA replication. ORC and GINS proteins were found on chromatin fibers before replication could be detected. These proteins were also associated with newly replicated DNA in bead-like structures. Additionally, GINS proteins co-localized with PCNA at sites of active replication.</p> <p>Conclusion</p> <p>In agreement with its proposed role in the initiation of DNA replication, GINS proteins associated with chromatin near sites of ORC binding that were devoid of EdU (absence of DNA replication). The association of GINS proteins with PCNA was consistent with a role in the process of elongation. Additionally, the large size of our chromatin fibers (up to approximately 7 Mb) allowed for a more expansive analysis of the distance between active replicons than previously reported.</p

Imaging and Modeling Data from the Hydrogen Epoch of Reionization Array

We analyze data from the Hydrogen Epoch of Reionization Array. This is the third in a series of papers on the closure phase delay-spectrum technique designed to detect the HI 21cm emission from cosmic reionization. We present the details of the data and models employed in the power spectral analysis, and discuss limitations to the process. We compare images and visibility spectra made with HERA data, to parallel quantities generated from sky models based on the GLEAM survey, incorporating the HERA telescope model. We find reasonable agreement between images made from HERA data, with those generated from the models, down to the confusion level. For the visibility spectra, there is broad agreement between model and data across the full band of $\sim 80$MHz. However, models with only GLEAM sources do not reproduce a roughly sinusoidal spectral structure at the tens of percent level seen in the observed visibility spectra on scales $\sim 10$ MHz on 29 m baselines. We find that this structure is likely due to diffuse Galactic emission, predominantly the Galactic plane, filling the far sidelobes of the antenna primary beam. We show that our current knowledge of the frequency dependence of the diffuse sky radio emission, and the primary beam at large zenith angles, is inadequate to provide an accurate reproduction of the diffuse structure in the models. We discuss implications due to this missing structure in the models, including calibration, and in the search for the HI 21cm signal, as well as possible mitigation techniques

Validation of the HERA Phase i Epoch of Reionization 21 cm Power Spectrum Software Pipeline

We describe the validation of the HERA Phase I software pipeline by a series of modular tests, building up to an end-to-end simulation. The philosophy of this approach is to validate the software and algorithms used in the Phase I upper-limit analysis on wholly synthetic data satisfying the assumptions of that analysis, not addressing whether the actual data meet these assumptions. We discuss the organization of this validation approach, the specific modular tests performed, and the construction of the end-to-end simulations. We explicitly discuss the limitations in scope of the current simulation effort. With mock visibility data generated from a known analytic power spectrum and a wide range of realistic instrumental effects and foregrounds, we demonstrate that the current pipeline produces power spectrum estimates that are consistent with known analytic inputs to within thermal noise levels (at the 2σ level) for k &gt; 0.2h Mpc-1 for both bands and fields considered. Our input spectrum is intentionally amplified to enable a strong "detection"at k ∼ 0.2 h Mpc-1 - at the level of ∼25σ - with foregrounds dominating on larger scales and thermal noise dominating at smaller scales. Our pipeline is able to detect this amplified input signal after suppressing foregrounds with a dynamic range (foreground to noise ratio) of ⪆107. Our validation test suite uncovered several sources of scale-independent signal loss throughout the pipeline, whose amplitude is well-characterized and accounted for in the final estimates. We conclude with a discussion of the steps required for the next round of data analysis