An integrated machine-learning model to predict nucleosome architecture.

We demonstrate that nucleosomes placed in the gene body can be accurately located from signal decay theory assuming two emitters located at the beginning and at the end of genes. These generated wave signals can be in phase (leading to well defined nucleosome arrays) or in antiphase (leading to fuzzy nucleosome architectures). We found that the first (+1) and the last (-last) nucleosomes are contiguous to regions signaled by transcription factor binding sites and unusual DNA physical properties that hinder nucleosome wrapping.

A commentary on the ABC consortium and its impact on the development of mesoscopic models of DNA.

In this commentary, it is presented how the Ascona B-DNA (ABC) consortium analyses of the DNA structure and deformability had a great influence in the development of mesoscopic models of DNA. The generation of databases using molecular dynamics ensembles to describe the DNA flexibility, allowed mesoscopic models to improve and become more accurate with a quality similar to that of all-atom MD simulations. All this will be translated in the future in the development of mesoscopic methods that could study and reproduce large biological systems such as chromatin structure, nucleosome arrangements, and protein recognition.

Association of circulating biomarkers with illness severity measures differentiates myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 condition: a prospective pilot cohort study.

Background: Accumulating evidence suggests that autonomic dysfunction and persistent systemic inflammation are common clinical features in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID. However, there is limited knowledge regarding their potential association with circulating biomarkers and illness severity in these conditions.

Methods: This single-site, prospective, cross-sectional, pilot cohort study aimed to distinguish between the two patient populations by using self-reported outcome measures and circulating biomarkers of endothelial function and systemic inflammation status.

The pseudotorsional space of RNA.

The characterization of the conformational landscape of the RNA backbone is rather complex due to the ability of RNA to assume a large variety of conformations. These backbone conformations can be depicted by pseudotorsional angles linking RNA backbone atoms, from which Ramachandran-like plots can be built. We explore here different definitions of these pseudotorsional angles, finding that the most accurate ones are the traditional (eta) and (theta) angles, which represent the relative position of RNA backbone atoms P and C4'.

Sequence-Dependent Properties of the RNA Duplex.

Sequence-dependent properties of the DNA duplex have been accurately described using extensive molecular dynamics simulations. The RNA duplex meanwhile─which is typically represented as a sequence-averaged rigid rod─does not benefit from having equivalent molecular dynamics simulations. In this paper, we present a massive simulation effort using a set of ABC-optimized duplexes from which we derived tetramer-resolution properties of the RNA duplex and a simple mesoscopic model that can represent elastic properties of long RNA duplexes.

Molecular dynamics modelling of the interaction of a synthetic zinc-finger miniprotein with DNA.

We report the modelling of the DNA complex of an artificial miniprotein composed of two zinc finger modules and an AT-hook linking peptide. The computational study provides for the first time a structural view of these types of complexes, dissecting interactions that are key to modulate their stability. The relevance of these interactions was validated experimentally.

Correlated motions in DNA: beyond base-pair step models of DNA flexibility.

Traditional mesoscopic models of DNA flexibility use a reductionist-local approach, which assumes that the flexibility of DNA can be expressed as local harmonic movements (at the base-pair step level) in the helical space, ignoring multimodality and correlations in DNA movements, which have in reality a large impact in modulating DNA movements. We present a new multimodal-harmonic correlated model, which takes both contributions into account, providing, with a small computational cost, results of an unprecedented local and global quality. The accuracy of this method and its computational efficiency make it an alternative to explore the dynamics of long segments of DNA, approaching the chromatin range.

DNA double-strand break-derived RNA drives TIRR/53BP1 complex dissociation.

Tudor-interacting repair regulator (TIRR) is an RNA-binding protein and a negative regulator of the DNA-repair factor p53-binding protein 1 (53BP1). In non-damage conditions, TIRR is bound to 53BP1. After DNA damage, TIRR and 53BP1 dissociate, and 53BP1 binds the chromatin at the double-strand break (DSB) to promote non-homologous end joining (NHEJ)-mediated repair.

DNAffinity: a machine-learning approach to predict DNA binding affinities of transcription factors.

We present a physics-based machine learning approach to predict in vitro transcription factor binding affinities from structural and mechanical DNA properties directly derived from atomistic molecular dynamics simulations. The method is able to predict affinities obtained with techniques as different as uPBM, gcPBM and HT-SELEX with an excellent performance, much better than existing algorithms. Due to its nature, the method can be extended to epigenetic variants, mismatches, mutations, or any non-coding nucleobases.

Sequence-dependent structural properties of B-DNA: what have we learned in 40 years?

The structure of B-DNA, the physiological form of the DNA molecule, has been a central topic in biology, chemistry and physics. Far from uniform and rigid, the double helix was revealed as a flexible and structurally polymorphic molecule. Conformational changes that lead to local and global changes in the helix geometry are mediated by a complex choreography of base and backbone rearrangements affecting the ability of the B-DNA to recognize ligands and consequently on its functionality.

Molecular basis of Arginine and Lysine DNA sequence-dependent thermo-stability modulation.

We have used a variety of theoretical and experimental techniques to study the role of four basic amino acids-Arginine, Lysine, Ornithine and L-2,4-Diaminobutyric acid-on the structure, flexibility and sequence-dependent stability of DNA. We found that the presence of organic ions stabilizes the duplexes and significantly reduces the difference in stability between AT- and GC-rich duplexes with respect to the control conditions. This suggests that these amino acids, ingredients of the primordial soup during abiogenesis, could have helped to equalize the stability of AT- and GC-rich DNA oligomers, facilitating a general non-catalysed self-replication of DNA.

Clinical course and risk factors for severe COVID-19 among Italian patients with cystic fibrosis: a study within the Italian Cystic Fibrosis Society.

Purpose: To describe the clinical course of COVID-19 in patients with cystic fibrosis (CF) and to identify risk factors for severe COVID-19.

Methods: We conducted a prospective study within the Italian CF Society. CF centers collected baseline and follow-up data of patients with virologically confirmed SARS-CoV-2 infection between March 2020 and June 2021.

The Impact of the HydroxyMethylCytosine epigenetic signature on DNA structure and function.

We present a comprehensive, experimental and theoretical study of the impact of 5-hydroxymethylation of DNA cytosine. Using molecular dynamics, biophysical experiments and NMR spectroscopy, we found that Ten-Eleven translocation (TET) dioxygenases generate an epigenetic variant with structural and physical properties similar to those of 5-methylcytosine. Experiments and simulations demonstrate that 5-methylcytosine (mC) and 5-hydroxymethylcytosine (hmC) generally lead to stiffer DNA than normal cytosine, with poorer circularization efficiencies and lower ability to form nucleosomes.

Ion concentrations in nasal airway surface liquid: a prediction model for the identification of cystic fibrosis carriers.

Background: Cystic fibrosis (CF) carriers seem to have a higher risk to develop chronic rhino-sinusitis (CRS), although the full underlying mechanisms are unknown. Ion concentrations in nasal airway surface liquid (ASL) may be influenced by the heterozygosity for CF gene mutation, with possible impacts on the development of CRS.

Methods: A cheap and feasible standardized technique was designed to measure the ion levels in nasal ASL.

Colibactin DNA-damage signature indicates mutational impact in colorectal cancer.

The mucosal epithelium is a common target of damage by chronic bacterial infections and the accompanying toxins, and most cancers originate from this tissue. We investigated whether colibactin, a potent genotoxin associated with certain strains of Escherichia coli, creates a specific DNA-damage signature in infected human colorectal cells. Notably, the genomic contexts of colibactin-induced DNA double-strand breaks were enriched for an AT-rich hexameric sequence motif, associated with distinct DNA-shape characteristics.

Multiscale Modeling of Thiol Overoxidation in Peroxiredoxins by Hydrogen Peroxide.

In this work, we employ a multiscale quantum-classical mechanics (QM/MM) scheme to investigate the chemical reactivity of sulfenic acids toward hydrogen peroxide, both in aqueous solution and in the protein environment of the peroxiredoxin alkyl hydroperoxide reductase E from (AhpE). The reaction of oxidation of cysteine with hydrogen peroxides, catalyzed by peroxiredoxins, is usually accelerated several orders of magnitude in comparison with the analogous reaction in solution. The resulting cysteine sulfenic acid is then reduced in other steps of the catalytic cycle, recovering the original thiol.

Nucleosome Dynamics: a new tool for the dynamic analysis of nucleosome positioning.

We present Nucleosome Dynamics, a suite of programs integrated into a virtual research environment and created to define nucleosome architecture and dynamics from noisy experimental data. The package allows both the definition of nucleosome architectures and the detection of changes in nucleosomal organization due to changes in cellular conditions. Results are displayed in the context of genomic information thanks to different visualizers and browsers, allowing the user a holistic, multidimensional view of the genome/transcriptome.

How B-DNA Dynamics Decipher Sequence-Selective Protein Recognition.

The rules governing sequence-specific DNA-protein recognition are under a long-standing debate regarding the prevalence of base versus shape readout mechanisms to explain sequence specificity and of the conformational selection versus induced fit binding paradigms to explain binding-related conformational changes in DNA. Using a combination of atomistic simulations on a subset of representative sequences and mesoscopic simulations at the protein-DNA interactome level, we demonstrate the prevalence of the shape readout model in determining sequence-specificity and of the conformational selection paradigm in defining the general mechanism for binding-related conformational changes in DNA. Our results suggest that the DNA uses a double mechanism to adapt its structure to the protein: it moves along the easiest deformation modes to approach the bioactive conformation, while final adjustments require localized rearrangements at the base-pair step and backbone level.

DNA specificities modulate the binding of human transcription factor A to mitochondrial DNA control region.

Human mitochondrial DNA (h-mtDNA) codes for 13 subunits of the oxidative phosphorylation pathway, the essential route that produces ATP. H-mtDNA transcription and replication depends on the transcription factor TFAM, which also maintains and compacts this genome. It is well-established that TFAM activates the mtDNA promoters LSP and HSP1 at the mtDNA control region where DNA regulatory elements cluster.

A multifunctional toolkit for target-directed cancer therapy.

Here we present 2shRNA, a shRNA-based nanobinder, which can simultaneously attack two therapeutic targets involved in drug resistance pathways and can additionally bind accessory molecules such as cell targeting peptides or fluorophores. We create 2shRNAs designed to specifically kill HER2+ breast cancer cells in the absence of a transfecting agent.

Protein Flexibility and Synergy of HMG Domains Underlie U-Turn Bending of DNA by TFAM in Solution.

Human mitochondrial transcription factor A (TFAM) distorts DNA into a U-turn, as shown by crystallographic studies. The relevance of this U-turn is associated with transcription initiation at the mitochondrial light strand promoter (LSP). However, it has not been yet discerned whether a tight U-turn or an alternative conformation, such as a V-shape, is formed in solution.

Urinary excretion of ciprofloxacin after administration of extended release tablets in healthy volunteers. Swellable drug-polyelectrolyte matrix versus bilayer tablets.

This paper builds on a previous paper in which new ciprofloxacin extended-release tablets were developed based on a ciprofloxacin-based swellable drug polyelectrolyte matrix (SDPM-CIP). The matrix contains a molecular dispersion of ciprofloxacin ionically bonded to the acidic groups of carbomer, forming the polyelectrolyte-drug complex CB-CIP. This formulation showed that the release profile of the ciprofloxacin bilayer tablets currently commercialised can be achieved with a simpler strategy.

Repair of UV-Induced DNA Damage Independent of Nucleotide Excision Repair Is Masked by MUTYH.

DNA lesions caused by UV damage are thought to be repaired solely by the nucleotide excision repair (NER) pathway in human cells. Patients carrying mutations within genes functioning in this pathway display a range of pathologies, including an increased susceptibility to cancer, premature aging, and neurological defects. There are currently no curative therapies available.

The role of hyaluronan as a drug carrier to enhance the bioavailability of extended release ophthalmic formulations. Hyaluronan-timolol ionic complexes as a model case.

The aim of this work was to obtain information concerning the properties of ophthalmic formulations based on hyaluronic-drug ionic complexes, to identify the factors that determine the onset, intensity and duration of the pharmacotherapeutic effect. Dispersions of a complex of 0.5% w/v of sodium hyaluronate (HyNa) loaded with 0.