Three-dimensional tissue engineered skeletal muscle modelling facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by sporadic misexpression of the transcription factor double homeobox 4 (DUX4) in skeletal muscles. So far, monolayer cultures and animal models have been used to study the FSHD disease mechanism and for FSHD therapy development, but these models do not fully recapitulate the disease and there is a lack of knowledge on how DUX4 misexpression leads to skeletal muscle dysfunction. To overcome these barriers, we have developed a three-dimensional tissue engineered skeletal muscle (3D-TESM) model by generating genetically matched myogenic progenitors (MPs) from human induced pluripotent stem cells of three mosaic FSHD patients.

Impact of Phosphorylation on the Physiological Form of Human alpha-Synuclein in Aqueous Solution.

Serine 129 can be phosphorylated in pathological inclusions formed by the intrinsically disordered protein human α-synuclein (AS), a key player in Parkinson's disease and other synucleinopathies. Here, molecular simulations provide insight into the structural ensemble of phosphorylated AS. The simulations allow us to suggest that phosphorylation significantly impacts the structural content of the physiological AS conformational ensemble in aqueous solution, as the phosphate group is mostly solvated.

Liver-targeted Angptl4 silencing by antisense oligonucleotide treatment attenuates hyperlipidaemia and atherosclerosis development in APOE*3-Leiden.CETP mice.

Aims: Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase to regulate tissue fatty acid (FA) uptake from triglyceride (TG)-rich lipoproteins such as very low density lipoproteins (VLDL). While pharmacological inhibition of ANGPTL3 is being evaluated as a lipid-lowering strategy, systemic ANGPTL4 inhibition is not pursued due to adverse effects. This study aims to compare the therapeutic potential of liver-specific Angptl3 and Angptl4 silencing to attenuate hyperlipidemia and atherosclerosis development in APOE*3-Leiden.

Absolute electron impact ionization cross-sections for CF4: Three dimensional recoil-ion imaging combined with the relative flow technique.

Here we present measurements of dissociative and non-dissociative cross-sections for the electron impact of the CF4 molecule. The present experiments are based on a Recoil Ion Momentum Spectrometer (RIMS), a standard gas mixing setup for CF4, and a reference gas. The measurements were carried out at several electron energies up to 1 keV, covering the energy range of previous experiments.

Tracking Cation Exchange in Individual Nanowires Transistor Characterization.

Cation exchange is a versatile method for modifying the material composition and properties of nanostructures. However, control of the degree of exchange and material properties is difficult at the single-particle level. Successive cation exchange from CdSe to AgSe has been utilized here on the same individual nanowires to monitor the change of electronic properties in field-effect transistor devices.

Pediatric central nervous system (CNS) neuroblastoma: A case report.

Background: Neuroblastomas are rare tumors activated by the gene commonly found in pediatric patients. Due to the novelty of these tumors, there is no standard diagnostic profile. However, they have been found to express , and synaptophysin, and they can be identified with magnetic resonance imaging (MRI).

Revealing the Role of N Heteroatoms in Noncovalent Aromatic Interactions by Ultrafast Intermolecular Coulombic Decay.

Despite the widely recognized importance of noncovalent interactions involving aromatic rings in many fields, our understanding of the underlying forces and structural patterns, especially the impact of heteroaromaticity, is still incomplete. Here, we investigate the relaxation processes that follow inner-valence ionization in a range of molecular dimers involving various combinations of benzene, pyridine, and pyrimidine, which initiate an ultrafast intermolecular Coulombic decay process. Multiparticle coincidence momentum spectroscopy, combined with calculations, enables us to explore the principal orientations of these fundamental dimers and, thus, to elucidate the influence of N heteroatoms on the relative preference of the aromatic π-stacking, H-bonding, and CH-π interactions and their dependence on the number of nitrogen atoms in the rings.

Deficiency of both classical and alternative end-joining pathways leads to a synergistic defect in double-strand break repair but not to an increase in homology-dependent gene targeting in Arabidopsis.

In eukaryotes, double-strand breaks (DSBs) are either repaired by homologous recombination (HR) or non-homologous end-joining (NHEJ). In somatic plant cells, HR is very inefficient. Therefore, the vast majority of DSBs are repaired by two different pathways of NHEJ.

Sex differences in response to obesity and caloric restriction on cognition and hippocampal measures of autophagic-lysosomal transcripts and signaling pathways.

Background: Obesity rates in the U.S. continue to increase, with nearly 50% of the population being either obese or morbidly obese.

Low and High Ankle-Brachial Index Are Both Associated with Mortality in German Nursing Home Residents-The Five-Year Follow-Up of the "Allo-Study" Cohort.

Peripheral arterial disease (PAD) is associated with high cardiovascular morbidity and mortality. We aimed to examine this relation in a population that tends to be under-represented in research on the topic. In a prospective observational cohort study, residents of 45 nursing homes in Germany were screened for pathological ankle-brachial index (ABI) and observed for five years.

Intermolecular Charge Transfer Induced Fragmentation of Formic Acid Dimers.

We investigate the intermolecular nonradiative charge transfer process in a double hydrogen-bonded formic acid (FA) dimer, initiated by electron-collision induced double ionization of one FA molecule. Through fragment ions and electron coincident momentum measurements and ab initio calculations, we obtain direct evidence that electron transfer from the neighboring FA molecule to fill one of the two vacancies occurs by a potential energy curve crossing of FA^{++}+FA with FA^{+}+FA^{+*} curves, forming an electronic excited state of dicationic dimers. This process causes the breaking of two hydrogen bonds and subsequently the cleavage of C─H and C─O covalent bonds in the dimers, which is expected to be a general phenomenon occurring in molecular complexes and can have important implications for radiation damage to biological matter.

TRAX-CHEMxt: Towards the Homogeneous Chemical Stage of Radiation Damage.

The indirect effect of radiation plays an important role in radio-induced biological damages. Monte Carlo codes have been widely used in recent years to study the chemical evolution of particle tracks. However, due to the large computational efforts required, their applicability is typically limited to simulations in pure water targets and to temporal scales up to the µs.

SPEADI: Accelerated Analysis of IDP-Ion Interactions from MD-Trajectories.

The disordered nature of Intrinsically Disordered Proteins (IDPs) makes their structural ensembles particularly susceptible to changes in chemical environmental conditions, often leading to an alteration of their normal functions. A Radial Distribution Function (RDF) is considered a standard method for characterizing the chemical environment surrounding particles during atomistic simulations, commonly averaged over an entire or part of a trajectory. Given their high structural variability, such averaged information might not be reliable for IDPs.

A multiplex inhalation platform to model like aerosol delivery in a breathing lung-on-chip.

Prolonged exposure to environmental respirable toxicants can lead to the development and worsening of severe respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and fibrosis. The limited number of FDA-approved inhaled drugs for these serious lung conditions has led to a shift from towards the use of alternative human-relevant models to better predict the toxicity of inhaled particles in preclinical research. While there are several inhalation exposure models for the upper airways, the fragile and dynamic nature of the alveolar microenvironment has limited the development of reproducible exposure models for the distal lung.

SMC5/6 complex-mediated SUMOylation stimulates DNA-protein cross-link repair in Arabidopsis.

DNA-protein cross-links (DPCs) are highly toxic DNA lesions consisting of proteins covalently attached to chromosomal DNA. Unrepaired DPCs physically block DNA replication and transcription. Three DPC repair pathways have been identified in Arabidopsis (Arabidopsis thaliana) to date: the endonucleolytic cleavage of DNA by the structure-specific endonuclease MUS81; proteolytic degradation of the crosslinked protein by the metalloprotease WSS1A; and cleavage of the cross-link phosphodiester bonds by the tyrosyl phosphodiesterases TDP1 and TDP2.

Analysis of assembly tolerance compensation in microscope objectives with a free-form element at the aperture stop.

We analyze the feasibility of using refractive free-form phase plates at the aperture stop of microscope objectives as an alternative to active alignment to compensate for assembly tolerances. The method involves the determination of misalignment-induced aberrations at the exit pupil, and transferring them to the aperture stop while taking pupil aberrations into consideration. We demonstrate that despite being able to correct only for field-independent aberrations, this method can restore near-diffraction-limited imaging performance of passively aligned systems with practical tolerances, given that the as-designed system is highly corrected.

Injection Molding of Magnesium Aluminate Spinel Nanocomposites for High-Throughput Manufacturing of Transparent Ceramics.

Transparent ceramics like magnesium aluminate spinel (MAS) are considered the next step in material evolution showing unmatched mechanical, chemical and physical resistance combined with high optical transparency. Unfortunately, transparent ceramics are notoriously difficult to shape, especially on the microscale. Therefore, a thermoplastic MAS nanocomposite is developed that can be shaped by polymer injection molding at high speed and precision.

Concerted Double Hydrogen-Bond Breaking by Intermolecular Coulombic Decay in the Formic Acid Dimer.

Hydrogen bonds are ubiquitous in nature and of fundamental importance to the chemical and physical properties of molecular systems in the condensed phase. Nevertheless, our understanding of the structural and dynamical properties of hydrogen-bonded complexes in particular in electronic excited states remains very incomplete. Here, by using formic acid (FA) dimer as a prototype of DNA base pair, we investigate the ultrafast decay process initiated by removal of an electron from the inner-valence shell of the molecule upon electron-beam irradiation.

Inhibition of Cdk5 increases osteoblast differentiation and bone mass and improves fracture healing.

Identification of regulators of osteoblastogenesis that can be pharmacologically targeted is a major goal in combating osteoporosis, a common disease of the elderly population. Here, unbiased kinome RNAi screening in primary murine osteoblasts identified cyclin-dependent kinase 5 (Cdk5) as a suppressor of osteoblast differentiation in both murine and human preosteoblastic cells. Cdk5 knockdown by siRNA, genetic deletion using the Cre-loxP system, or inhibition with the small molecule roscovitine enhanced osteoblastogenesis in vitro.

α-Synuclein phosphorylation at serine 129 occurs after initial protein deposition and inhibits seeded fibril formation and toxicity.

α-Synuclein (α-syn) phosphorylation at serine 129 (pS129–α-syn) is substantially increased in Lewy body disease, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). However, the pathogenic relevance of pS129–α-syn remains controversial, so we sought to identify when pS129 modification occurs during α-syn aggregation and its role in initiation, progression and cellular toxicity of disease. Using diverse aggregation assays, including real-time quaking-induced conversion (RT-QuIC) on brain homogenates from PD and DLB cases, we demonstrated that pS129–α-syn inhibits α-syn fibril formation and seeded aggregation.