Cyclin-dependent kinase 13 is indispensable for normal mouse heart development.

Congenital heart disease (CHD) has an incidence of approximately 1%. Over the last decade, sequencing studies including large cohorts of individuals with CHD have begun to unravel the genetic mechanisms underpinning CHD. This includes the identification of variants in cyclin-dependent kinase 13 (CDK13), in individuals with syndromic CHD.

Spectroscopic and thermodynamic characterization of a cobalt-verdazyl valence tautomeric system. influence of crystal structure, solvent and counterion.

Crystallization of the verdazyl-based valence tautomeric ion [Co(dipyvd)] (where dipyvd is the radical ligand 1-isopropyl-3,5-di(2'-pyridyl)-6-oxoverdazyl) with a variety of different counterions results in materials that show varying degrees of valence tautomeric (VT) transition in the solid state. The X-ray structure of the SbF salt at 150 K reveals a localized structure for the = 1/2 tautomer, with a Co cation and distinct anionic and radical ligands. Comparison with the structure of the same material at 300 K reveals large structural changes in the ligand as a result of the valence tautomeric equilibrium.

Effect of deletion of the protein kinase PRKD1 on development of the mouse embryonic heart.

Congenital heart disease (CHD) is the most common congenital anomaly, with an overall incidence of approximately 1% in the United Kingdom. Exome sequencing in large CHD cohorts has been performed to provide insights into the genetic aetiology of CHD. This includes a study of 1891 probands by our group in collaboration with others, which identified three novel genes-CDK13, PRKD1, and CHD4, in patients with syndromic CHD.

Metal-ligand interactions in a redox active ligand system. Electrochemistry and spectroscopy of [M(dipyvd)] (M=Zn, Ni, =0, 1, 2).

Reaction of nickel and zinc triflates with the tridentate leucoverdazyl 1-isopropyl-3,5-di (2'-pyridyl)-6-oxo-2H-tetrazine (dipyvdH) and triethylamine resulted in the neutral coordination compounds M(dipyvd) (M = Ni,Zn). In acetonitrile, both compounds undergo two one electron oxidation processes, Zn (dipyvd) at -0.28 V and -0.

Modifications of Tanabe-Sugano Diagram Induced by Radical Ligand Field: Ab Initio Inspection of a Fe(II)-Verdazyl Molecular Complex.

Quantum entanglement between the spin states of a metal center and radical ligands is suggested in an iron(II) [Fe(dipyvd)] compound (dipyvd = 1-isopropyl-3,5-dipyridil-6-oxoverdazyl). Wave function (Difference Dedicated Configuration Interaction, DDCI) inspections were carried out to stress the versatility of local spin states. We named this phenomenon , in reference to our previous work (see Roseiro et al.

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease.

Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls.

Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot.

Purpose: Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear.

Methods: We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF.

Adolescent risk and protective factors predicting triple trajectories of substance use from adolescence into adulthood.

Objectives: Since the number of individuals who use substances in the United States has markedly increased every year, substance use is a significant public health concern. The current study examines the possible risk and protective factors associated with triple comorbid trajectories of longitudinal alcohol, tobacco, and cannabis use from age 14 to 36.

Methods: A community sample of 674 participants (53% African Americans and 47% Puerto Ricans; 60% females) were recruited from the Harlem Longitudinal Development Study.

Systems genetics analysis identifies calcium-signaling defects as novel cause of congenital heart disease.

Background: Congenital heart disease (CHD) occurs in almost 1% of newborn children and is considered a multifactorial disorder. CHD may segregate in families due to significant contribution of genetic factors in the disease etiology. The aim of the study was to identify pathophysiological mechanisms in families segregating CHD.

CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model.

Myotonic dystrophy type 1 (DM1) is an RNA-based disease with no current treatment. It is caused by a transcribed CTG repeat expansion within the 3' untranslated region of the dystrophia myotonica protein kinase () gene. Mutant repeat expansion transcripts remain in the nuclei of patients' cells, forming distinct microscopically detectable foci that contribute substantially to the pathophysiology of the condition.

Valence tautomerism in a cobalt-verdazyl coordination compound.

Coordination of 1-isopropyl-3,5-dipyridyl-6-oxoverdazyl to cobalt results in a dication best described in the solid state as a high spin cobalt(ii) ion coordinated to two radical ligands with an S = 3/2 ground state. On dissolution in acetonitrile, the cobalt(ii) form equilibrates with a cobalt(iii) valence tautomer with an S = 1/2 ground state.

HDAC4 and 5 repression of TBX5 is relieved by protein kinase D1.

TBX5 is a T-box family transcription factor that regulates heart and forelimb development in vertebrates and functional deficiencies in this protein result in Holt-Oram syndrome. Recently, we have shown that acetylation of TBX5 potentiates its activity and is important for heart and limb development. Here we report that class II histone deacetylases HDAC4 and HDAC5 associate with TBX5 and repress its role in cardiac gene transcription.

Long-range spin dependent delocalization promoted by the pseudo Jahn-Teller effect.

Strong spin-dependent delocalization (double exchange) was previously demonstrated for the complexes, NN-Bridge-SQ-Co(py)Cat-Bridge-NN (where NN = S = 12 nitronylnitroxide, Bridge = 1,4-phenylene and single bond, SQ = S = 12 orthobenzosemiquinone, Co = low-spin d cobalt 3+, and Cat = diamagnetic catecholate). The mixed-valent S = 12 SQ-Co-Cat triad results in ferromagnetic alignment of localized (pinned) NN spins which are ∼22 Å apart (Bridge = Ph). Herein, we report similar ferromagnetic coupling of localized verdazyl (Vdz) radical spins.

Global Increase in Circular RNA Levels in Myotonic Dystrophy.

Splicing aberrations induced as a consequence of the sequestration of muscleblind-like splicing factors on the dystrophia myotonica protein kinase transcript, which contains expanded CUG repeats, present a major pathomechanism of myotonic dystrophy type 1 (DM1). As muscleblind-like factors may also be important factors involved in the biogenesis of circular RNAs (circRNAs), we hypothesized that the level of circRNAs would be decreased in DM1. To test this hypothesis, we selected 20 well-validated circRNAs and analyzed their levels in several experimental systems (e.

Single and dual diagnoses of major depressive disorder and posttraumatic stress disorder predicted by triple comorbid trajectories of tobacco, alcohol, and marijuana use among urban adults.

The adverse consequences of major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) affect a significant portion of the US population every year (i.e., 15 million for MDD; 8 million for PTSD) and are of public health concern.

Developmental Trajectories of Religious Service Attendance: Predictors of Nicotine Dependence and Alcohol Dependence/Abuse in Early Midlife.

This longitudinal study assesses the associations between developmental trajectories of religious service attendance from mean age 14 to mean age 43 and nicotine dependence and alcohol dependence/abuse at mean age 43 (N = 548). Six trajectories of religious service attendance were identified. As compared with belonging to weekly stable trajectory group, a higher probability of belonging to the weekly/none decreasing, occasional stable, and non-attendance trajectory group was significantly associated with a higher likelihood of nicotine dependence.

Transcriptome alterations in myotonic dystrophy skeletal muscle and heart.

Myotonic dystrophy (dystrophia myotonica, DM) is a multi-systemic disease caused by expanded CTG or CCTG microsatellite repeats. Characterized by symptoms in muscle, heart and central nervous system, among others, it is one of the most variable diseases known. A major pathogenic event in DM is the sequestration of muscleblind-like proteins by CUG or CCUG repeat-containing RNAs transcribed from expanded repeats, and differences in the extent of MBNL sequestration dependent on repeat length and expression level may account for some portion of the variability.

Season of birth: A predictor of ADHD symptoms in early midlife.

Objective: In this longitudinal study, we applied linear regression analyses to examine season of birth as related to symptoms of attention deficit/hyperactivity disorder (ADHD) in early midlife.

Method: We gathered longitudinal data on a prospective cohort of community-dwelling men and women (N = 548) followed from adolescence to early midlife.

Findings: The findings indicate that, as compared with participants who were born in the summer, those who were born in the spring (Beta = 0.

Correction: An electron transfer driven magnetic switch: ferromagnetic exchange and spin delocalization in iron verdazyl complexes.

Correction for 'An electron transfer driven magnetic switch: ferromagnetic exchange and spin delocalization in iron verdazyl complexes' by David J. R. Brook et al.

Sexual risk behaviors in African American and Puerto Rican women: Impulsivity and self-control.

Millions of people are living with the human immunodeficiency virus (HIV). African American and Hispanic/Latino communities suffer the most severe burden of HIV in the US. The ultimate goal of this study was to better understand risk factors for this infection: Do impulsivity and self control operate independently or synergistically with respect to HIV sexual risk behaviors in women? An enhanced understanding of these risk factors may better inform future interventions.