Crystal structure of the DNA repair enzyme ultraviolet damage endonuclease

Biophysical Structural Chemistr

Optimal phase for coronary interpretations and correlation of ejection fraction using late-diastole and end-diastole imaging in cardiac computed tomography angiography: implications for prospective triggering

A typical acquisition protocol for multi-row detector computed tomography (MDCT) angiography is to obtain all phases of the cardiac cycle, allowing calculation of ejection fraction (EF) simultaneously with plaque burden. New MDCT protocols scanner, designed to reduce radiation, use prospectively acquired ECG gated image acquisition to obtain images at certain specific phases of the cardiac cycle with least coronary artery motion. These protocols do not we allow acquisition of functional data which involves measurement of ejection fraction requiring end-systolic and end-diastolic phases. We aimed to quantitatively identify the cardiac cycle phase that produced the optimal images as well as aimed to evaluate, if obtaining only 35% (end-systole) and 75% (as a surrogate for end-diastole) would be similar to obtaining the full cardiac cycle and calculating end diastolic volumes (EDV) and EF from the 35th and 95th percentile images. 1,085 patients with no history of coronary artery disease were included; 10 images separated by 10% of R–R interval were retrospectively constructed. Images with motion in the mid portion of RCA were graded from 1 to 3; with ‘1’ being no motion, ‘2’ if 0 to <1 mm motion, and ‘3’ if there is >1 mm motion and/or non-interpretable study. In a subgroup of 216 patients with EF > 50%, we measured left ventricular (LV) volumes in the 10 phases, and used those obtained during 25, 35, 75 and 95% phase to calculate the EF for each patient. The average heart rate (HR) for our patient group was 56.5 ± 8.4 (range 33–140). The distribution of image quality at all heart rates was 958 (88.3%) in Grade 1, 113 (10.42%) in Grade 2 and 14 (1.29%) in Grade 3 images. The area under the curve for optimum image quality (Grade 1 or 2) in patients with HR > 60 bpm for phase 75% was 0.77 ± 0.04 [95% CI: 0.61–0.87], while for similar heart rates the area under the curve for phases 75 + 65 + 55 + 45% combined was 0.92 ± 0.02. LV volume at 75% phase was strongly correlated with EDV (LV volume at 95% phase) (r = 0.970, P < 0.001). There was also a strong correlation between LVEF (75_35) and LVEF (95_35) (r = 0.93, P < 0.001). Subsequently, we developed a formula to correct for the decrement in LVEF using 35–75% phase: LVEF (95_35) = 0.783 × LVEF (75_35) + 20.68; adjusted R2 = 0.874, P < 0.001. Using 64 MDCT scanners, in order to acquire >90% interpretable studies, if HR < 60 bpm 75% phase of RR interval provides optimal images; while for HR > 60 analysis of images in 4 phases (75, 35, 45 and 55%) is needed. Our data demonstrates that LVEF can be predicted with reasonable accuracy by using data acquired in phases 35 and 75% of the R–R interval. Future prospective acquisition that obtains two phases (35 and 75%) will allow for motion free images of the coronary arteries and EF estimates in over 90% of patients

Overview of the CCP4 suite and current developments.

The CCP4 (Collaborative Computational Project, Number 4) software suite is a collection of programs and associated data and software libraries which can be used for macromolecular structure determination by X-ray crystallography. The suite is designed to be flexible, allowing users a number of methods of achieving their aims. The programs are from a wide variety of sources but are connected by a common infrastructure provided by standard file formats, data objects and graphical interfaces. Structure solution by macromolecular crystallography is becoming increasingly automated and the CCP4 suite includes several automation pipelines. After giving a brief description of the evolution of CCP4 over the last 30 years, an overview of the current suite is given. While detailed descriptions are given in the accompanying articles, here it is shown how the individual programs contribute to a complete software package

Recurrent Chromosome 16p13.1 Duplications Are a Risk Factor for Aortic Dissections

Chromosomal deletions or reciprocal duplications of the 16p13.1 region have been implicated in a variety of neuropsychiatric disorders such as autism, schizophrenia, epilepsies, and attention-deficit hyperactivity disorder (ADHD). In this study, we investigated the association of recurrent genomic copy number variants (CNVs) with thoracic aortic aneurysms and dissections (TAAD). By using SNP arrays to screen and comparative genomic hybridization microarrays to validate, we identified 16p13.1 duplications in 8 out of 765 patients of European descent with adult-onset TAAD compared with 4 of 4,569 controls matched for ethnicity (P = 5.0×10−5, OR = 12.2). The findings were replicated in an independent cohort of 467 patients of European descent with TAAD (P = 0.005, OR = 14.7). Patients with 16p13.1 duplications were more likely to harbor a second rare CNV (P = 0.012) and to present with aortic dissections (P = 0.010) than patients without duplications. Duplications of 16p13.1 were identified in 2 of 130 patients with familial TAAD, but the duplications did not segregate with TAAD in the families. MYH11, a gene known to predispose to TAAD, lies in the duplicated region of 16p13.1, and increased MYH11 expression was found in aortic tissues from TAAD patients with 16p13.1 duplications compared with control aortas. These data suggest chromosome 16p13.1 duplications confer a risk for TAAD in addition to the established risk for neuropsychiatric disorders. It also indicates that recurrent CNVs may predispose to disorders involving more than one organ system, an observation critical to the understanding of the role of recurrent CNVs in human disease and a finding that may be common to other recurrent CNVs involving multiple genes

Acute kidney disease and renal recovery : consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of > 90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD

Vitamin D status is inversely associated with markers of risk for type 2 diabetes: A population based study in Victoria, Australia

A growing body of evidence suggests a protective role of Vitamin D on the risk of type 2 diabetes mellitus (T2DM). We investigated this relationship in a population sample from one Australian state. The data of 3,393 Australian adults aged 18±75 years who participated in the 2009±2010 Victorian Health Monitor survey was analyzed. Socio-demographic information, biomedical variables, and dietary intakes were collected and fasting blood samples were analyzed for 25, hydroxycholecalciferol (25OHD), HbA1c, fasting plasma glucose (FPG), and lipid profiles. Logistic regression analyses were used to evaluate the association between tertiles of serum 25OHD and categories of FPG (&lt;5.6 mmol/L vs. 5.6±6.9 mmol/L), and HbA1c (&lt;5.7% vs. 5.7±6.4%). After adjusting for social, dietary, biomedical and metabolic syndrome (MetS) components (waist circumference, HDL cholesterol, triglycerides, and blood pressure), every 10 nmol/L increment in serum 25OHD significantly reduced the adjusted odds ratio (AOR) of a higher FPG [AOR 0.91, (0.86, 0.97); p = 0.002] and a higher HbA1c [AOR 0.94, (0.90, 0.98); p = 0.009]. Analysis by tertiles of 25OHD indicated that after adjustment for socio-demographic and dietary variables, those with high 25OHD (65±204 nmol/L) had reduced odds of a higher FPG [AOR 0.60, (0.43, 0.83); p = 0.008] as well as higher HbA1c [AOR 0.67, (0.53, 0.85); p = 0.005] compared to the lowest 25OHD (10±44 nmol/L) tertile. On final adjustment for other components of MetS, those in the highest tertile of 25OHD had significantly reduced odds of higher FPG [AOR 0.61, (0.44, 0.84); p = 0.011] and of higher HbA1c [AOR 0.74, (0.58, 0.93); p = 0.041] vs. low 25OHD tertile. Overall, the data support a direct, protective effect of higher 25OHD on FPG and HbA1c; two criteria for assessment of risk of T2DM

An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm

Thoracic aortic aneurysm (TAA) has been associated with mutations affecting members of the TGF-β signaling pathway, or components and regulators of the vascular smooth muscle cell (VSMC) actomyosin cytoskeleton. Although both clinical groups present similar phenotypes, the existence of potential common mechanisms of pathogenesis remain obscure. Here we show that mutations affecting TGF-β signaling and VSMC cytoskeleton both lead to the formation of a ternary complex comprising the histone deacetylase HDAC9, the chromatin-remodeling enzyme BRG1, and the long noncoding RNA MALAT1. The HDAC9–MALAT1–BRG1 complex binds chromatin and represses contractile protein gene expression in association with gain of histone H3-lysine 27 trimethylation modifications. Disruption of Malat1 or Hdac9 restores contractile protein expression, improves aortic mural architecture, and inhibits experimental aneurysm growth. Thus, we highlight a shared epigenetic pathway responsible for VSMC dysfunction in both forms of TAA, with potential therapeutic implication for other known HDAC9-associated vascular diseases