Symptom burden, coagulopathy and heart disease after acute SARS-CoV-2 infection in primary practice.

SETANTA (Study of HEarT DiseAse and ImmuNiTy After COVID-19 in Ireland) study aimed to investigate symptom burden and incidence of cardiac abnormalities after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/COVID-19 and to correlate these results with biomarkers of immunological response and coagulation. SETANTA was a prospective, single-arm observational cross-sectional study condcuted in a primary practice setting, and prospectively registered with ClinicalTrials.gov (identifier: NCT04823182).

Anomalous origin of the left circumflex coronary artery: is surgery required? A case report.

Background: Deviations from usual coronary artery anatomy are well documented. The left circumflex artery (LCx) arising from the pulmonary artery is an example of one such deviation which is rarely seen. We present the case of a 26-year-old male with this coronary artery distribution presenting with an episode of ventricular flutter with late gadolinium enhancement and pluri-morphological ventricular arrhythmias.

Factors associated with SARS-CoV-2 infection in patients attending an acute hospital ambulatory assessment unit.

To describe the factors associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in mild-to-moderate patients attending for assessment. This observational study was conducted in a Model 4 tertiary referral center in Ireland. All patients referred for SARS-CoV-2 assessment over a 4-week period were included.

Plasma proteomic signatures predict dementia and cognitive impairment.

Introduction: Biomarker discovery of dementia and cognitive impairment is important to gather insight into mechanisms underlying the pathogenesis of these conditions.

Methods: In 997 adults from the InCHIANTI study, we assessed the association of 1301 plasma proteins with dementia and cognitive impairment. Validation was conducted in two Alzheimer's disease (AD) case-control studies as well as endophenotypes of AD including cognitive decline, brain amyloid burden, and brain volume.

The static and dynamic structural heterogeneities of B-DNA: extending Calladine-Dickerson rules.

We present a multi-laboratory effort to describe the structural and dynamical properties of duplex B-DNA under physiological conditions. By processing a large amount of atomistic molecular dynamics simulations, we determine the sequence-dependent structural properties of DNA as expressed in the equilibrium distribution of its stochastic dynamics. Our analysis includes a study of first and second moments of the equilibrium distribution, which can be accurately captured by a harmonic model, but with nonlocal sequence-dependence.

Internal Coordinate Normal Mode Analysis: A Strategy To Predict Protein Conformational Transitions.

We analyze the capacity of normal mode analysis in internal coordinates' space to generate large-amplitude structural deformations that can describe the conformational changes occurring upon the binding of proteins to other species. We also analyze how many modes need to be studied to capture a given transition and whether a combination of two modes is better than using a single mode. The technique is tested on known unbound-to-bound structural transitions for a set of single- or multidomain proteins.

Peptidyl arginine deiminase 2 (Padi2) is expressed in Sertoli cells in a specific manner and regulated by SOX9 during testicular development.

Peptidyl arginine deiminases (PADIs) are enzymes that change the charge of proteins through citrullination. We recently found Padi2 was expressed exclusively in fetal Sertoli cells. In this study, we analyzed the transcriptional regulation of Padi2 and the role of PADI2 in testicular development.

A molecular dynamics study of adenylyl cyclase: The impact of ATP and G-protein binding.

Adenylyl cyclases (ACs) catalyze the biosynthesis of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP) and play an important role in many signal transduction pathways. The enzymatic activity of ACs is carefully controlled by a variety of molecules, including G-protein subunits that can both stimulate and inhibit cAMP production. Using homology models developed from existing structural data, we have carried out all-atom, microsecond-scale molecular dynamics simulations on the AC5 isoform of adenylyl cyclase and on its complexes with ATP and with the stimulatory G-protein subunit Gsα.

Age adjusted D-dimer in the Belfast Health and Social Care Trust: A retrospective study.

D-dimers combined with clinical pre-test probability (PTP) scores are used to determine the likelihood of a venous thromboembolic event (VTE). It is recognised that with advancing age, d-dimer values increase, leading to a cohort of patients with a d-dimer above the standard cut-off of 500g/L. A recent systemic review, examined the accuracy of an age-adjusted D-dimer in those aged > 50 years with a low clinical risk of a VTE.

Does the Start of Dialysis Initiate a Period of Increased Risk of Ulceration or Amputation?

Background: Dialysis therapy is associated with an increased incidence of lower-extremity wounds and amputations. We compared the incidence of foot ulcers and amputations before and after the start of dialysis.

Methods: We evaluated 150 consecutive diabetic patients receiving dialysis and compared the incidence of foot complications 30 months before and after initiation of hemodialysis.

Sequence-dependent response of DNA to torsional stress: a potential biological regulation mechanism.

Torsional restraints on DNA change in time and space during the life of the cell and are an integral part of processes such as gene expression, DNA repair and packaging. The mechanical behavior of DNA under torsional stress has been studied on a mesoscopic scale, but little is known concerning its response at the level of individual base pairs and the effects of base pair composition. To answer this question, we have developed a geometrical restraint that can accurately control the total twist of a DNA segment during all-atom molecular dynamics simulations.

Decomposing protein-DNA binding and recognition using simplified protein models.

We analyze the role of different physicochemical factors in protein/DNA binding and recognition by comparing the results from all-atom molecular dynamics simulations with simulations using simplified protein models. These models enable us to separate the role of specific amino acid side chains, formal amino acid charges and hydrogen bonding from the effects of the low-dielectric volume occupied by the protein. Comparisons are made on the basis of the conformation of DNA after protein binding, the ionic distribution around the complex and the sequence specificity.

Structure and Dynamics of a 197 bp Nucleosome in Complex with Linker Histone H1.

Linker histones associate with nucleosomes to promote the formation of higher-order chromatin structure, but the underlying molecular details are unclear. We investigated the structure of a 197 bp nucleosome bearing symmetric 25 bp linker DNA arms in complex with vertebrate linker histone H1. We determined electron cryo-microscopy (cryo-EM) and crystal structures of unbound and H1-bound nucleosomes and validated these structures by site-directed protein cross-linking and hydroxyl radical footprinting experiments.

In mammalian foetal testes, SOX9 regulates expression of its target genes by binding to genomic regions with conserved signatures.

In mammalian embryonic gonads, SOX9 is required for the determination of Sertoli cells that orchestrate testis morphogenesis. To identify genetic networks directly regulated by SOX9, we combined analysis of SOX9-bound chromatin regions from murine and bovine foetal testes with sequencing of RNA samples from mouse testes lacking Sox9. We found that SOX9 controls a conserved genetic programme that involves most of the sex-determining genes.

Analyzing DNA curvature and its impact on the ionic environment: application to molecular dynamics simulations of minicircles.

We propose a method for analyzing the magnitude and direction of curvature within nucleic acids, based on the curvilinear helical axis calculated by Curves+. The method is applied to analyzing curvature within minicircles constructed with varying degrees of over- or under-twisting. Using the molecular dynamics trajectories of three different minicircles, we are able to quantify how curvature varies locally both in space and in time.

The Role of Unconventional Hydrogen Bonds in Determining BII Propensities in B-DNA.

An accurate understanding of DNA backbone transitions is likely to be the key for elucidating the puzzle of the intricate sequence-dependent mechanical properties that govern most of the biologically relevant functions of the double helix. One factor believed to be important in indirect recognition within protein-DNA complexes is the combined effect of two DNA backbone torsions (ε and ζ) which give rise to the well-known BI/BII conformational equilibrium. In this work we explain the sequence-dependent BII propensity observed in RpY steps (R = purine; Y = pyrimidine) at the tetranucleotide level with the help of a previously undetected C-H···O contact between atoms belonging to adjacent bases.

Extra views on structure and dynamics of DNA loops on nucleosomes studied with molecular simulations.

It has been shown experimentally that the action of the RSC chromatin remodeler leads to the formation of an irregular, partially remodeled nucleosome, termed a remosome. The remosome contains an extra 30-40 base pairs of DNA compared to a canonical nucleosome. Large-scale molecular simulations have provided information on the probable structure of remosomes and have explained why they remain stable in the absence of RSC.

Protein-DNA interfaces: a molecular dynamics analysis of time-dependent recognition processes for three transcription factors.

We have studied the dynamics of three transcription factor-DNA complexes using all-atom, microsecond-scale MD simulations. In each case, the salt bridges and hydrogen bond interactions formed at the protein-DNA interface are found to be dynamic, with lifetimes typically in the range of tens to hundreds of picoseconds, although some interactions, notably those involving specific binding to DNA bases, can be a hundred times longer lived. Depending on the complex studied, this dynamics may or may not lead to the existence of distinct conformational substates.

SOX9 regulates expression of the male fertility gene Ets variant factor 5 (ETV5) during mammalian sex development.

In humans, dysregulation of the sex determining gene SRY-box 9 (SOX9) leads to disorders of sex development (DSD). In mice, knock-out of Sox9 prior to sex determination leads to XY sex reversal, while Sox9 inactivation after sex determination leads to spermatogenesis defects. SOX9 specifies the differentiation and function of Sertoli cells from somatic cell precursors, which then orchestrate the development and maintenance of other testicular cell types, largely through unknown mechanisms.

Severe dysphagia requiring gastrostomy following cervical spine fracture fixation.

Background: The incidence of severe dysphagia requiring gastrostomy tube (GT) placement following operative fixation of traumatic cervical spine fractures is unknown. Risk factors for severe dysphagia are not well identified and GT placement is often delayed due to the belief that it will resolve quickly. We hypothesized that patient and clinical factors could be used to predict severe dysphagia requiring GT placement in this population.

Structure and dynamics of DNA loops on nucleosomes studied with atomistic, microsecond-scale molecular dynamics.

DNA loop formation on nucleosomes is strongly implicated in chromatin remodeling and occurs spontaneously in nucleosomes subjected to superhelical stress. The nature of such loops depends crucially on the balance between DNA deformation and DNA interaction with the nucleosome core. Currently, no high-resolution structural data on these loops exist.