Revisiting Butafulvene Formation by Thermal Dimerization of Fluorene-Based Dialkynes - Effects of Aromatic Substituents.

Butafulvenes, together with pentafulvenes and [3]radialenes, form a series of constitutional benzene isomers in which aromaticity changes significantly and can be strongly substituent dependent. Butafulvene, as a member of this series, is frequently proposed to be antiaromatic. Based on butafulvenes Hopf, Zimmerman and coworkers first time described, derivatives thereof were synthesized and the effects of substituents on both the stability of the intermediate isobenzenes and on their optoelectronic and (anti)aromatic properties are discussed.

High-Yielding Nanobelt Formation by Chirality-Assisted Synthesis.

Shape-persistent conjugated nanobelts (CNBs) are fascinating synthetic targets. However, in most cases these are made in low overall yields by applying strategies of macrocyclization followed by (multiple) ring fusion reactions for nanobelt formation. Here, we describe the high yielding synthesis of enantiopure chiral nanobelts in 84 % yield by applying chirality-assisted synthesis (CAS).

A Negatively Curved Nanographene with Four Embedded Heptagons.

Negatively curved nanographenes are considered as cutouts of three-dimensional fully sp-hybridized carbon allotropes such as Schwarzites. Here we present the synthesis of a C cut-out of the Schwarzite 8-4-1-p proposed by Lenosky et al. and investigate its optical as well as electrochemical properties.

Substituent Effects in Scholl-Type Reactions of 1,2-Terphenyls to Triphenylenes.

A series of 3,3''- and 4,4''-dimethoxy terphenyls with different second substituents on their ortho-positions have been synthesized and investigated upon the possibility to be oxidatively cyclodehydrogenated to the corresponding triphenylenes under Scholl-type conditions. The experimentally obtained selectivities were supported and explained by quantum chemical calculations and conclusions on the involved mechanisms (acid catalyzed arenium-ion mechanism (AIM) vs radical cation mechanism) were drawn.

Probing entanglement in a 2D hard-core Bose-Hubbard lattice.

Entanglement and its propagation are central to understanding many physical properties of quantum systems. Notably, within closed quantum many-body systems, entanglement is believed to yield emergent thermodynamic behaviour. However, a universal understanding remains challenging owing to the non-integrability and computational intractability of most large-scale quantum systems.

Ofatumumab Desensitization Protocol: A Case of Refractory Immune Thrombocytopenic Purpura.

Chronic immune thrombocytopenic purpura (ITP) is an acquired hematologic condition that involves immune-mediated platelet destruction with resultant bleeding of variable severity. Refractory ITP occurs when patients fail to tolerate and/or respond to multiple treatment modalities. In this case, we examine the clinical course of a 39-year-old female with refractory ITP and discuss how we navigated a multitude of challenges by adapting an established desensitization protocol to meet our patient's needs.

Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3 in the Netherlands.

Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in the cardiac myosin binding protein-C (cMyBP-C) encoding gene MYBPC3. In the Netherlands, approximately 25% of patients carry the MYBPC3 founder mutation. Most patients are heterozygous (MYBPC3) and have highly variable phenotypic expression, whereas homozygous (MYBPC3) patients have severe HCM at a young age.

A masquerade of recurrent anaphylaxis.

We present a case of a 37 year old man with a history of human immunodeficiency virus, latent syphilis, anxiety, posttraumatic stress disorder. attention deficit/hyperactivity disorder, multiple drug intolerance syndrome who presented with concerns of recurrent episodes of rash and respiratory symptoms with questionable "anaphylaxis" episodes without clear etiology or known trigger. To evaluate some of the potential causes of recurrent anaphylaxis in our patient.

EGFR/IGF1R Signaling Modulates Relaxation in Hypertrophic Cardiomyopathy.

Background: Diastolic dysfunction is central to diseases such as heart failure with preserved ejection fraction and hypertrophic cardiomyopathy (HCM). However, therapies that improve cardiac relaxation are scarce, partly due to a limited understanding of modulators of cardiomyocyte relaxation. We hypothesized that cardiac relaxation is regulated by multiple unidentified proteins and that dysregulation of kinases contributes to impaired relaxation in patients with HCM.

Untargeted Metabolomics Identifies Potential Hypertrophic Cardiomyopathy Biomarkers in Carriers of Founder Variants.

Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by pathogenic variants, and a significant cause of sudden cardiac death. Severity is highly variable, with incomplete penetrance among genotype-positive family members. Previous studies demonstrated metabolic changes in HCM.

Slower Calcium Handling Balances Faster Cross-Bridge Cycling in Human HCM.

Background: The pathogenesis of -associated hypertrophic cardiomyopathy (HCM) is still unresolved. In our HCM patient cohort, a large and well-characterized population carrying the :c772G>A variant (p.Glu258Lys, E258K) provides the unique opportunity to study the basic mechanisms of -HCM with a comprehensive translational approach.

Effect of Stiffening the Printed Circuit Board in the Fatigue Life of the Solder Joint.

Predictive analysis of the life of an electronic package requires a sequence of processes involving: (i) development of a finite element (FE) model, (ii) correlation of the FE model using experimental data, and (iii) development of a local model using the correlated FE model. The life of the critical components is obtained from the local model and is usually compared to the experimental results. Although the specifics of such analyses are available in the literature, a comparison among them and against the same electronic package with different user printed circuit board (PCB) thicknesses does not exist.

miR449 Protects Airway Regeneration by Controlling AURKA/HDAC6-Mediated Ciliary Disassembly.

Airway mucociliary regeneration and function are key players for airway defense and are impaired in chronic obstructive pulmonary disease (COPD). Using transcriptome analysis in COPD-derived bronchial biopsies, we observed a positive correlation between cilia-related genes and microRNA-449 (. In vitro, was strongly increased during airway epithelial mucociliary differentiation.

Distinct Metabolomic Signatures in Preclinical and Obstructive Hypertrophic Cardiomyopathy.

Hypertrophic Cardiomyopathy (HCM) is a common inherited heart disease with poor risk prediction due to incomplete penetrance and a lack of clear genotype-phenotype correlations. Advanced imaging techniques have shown altered myocardial energetics already in preclinical gene variant carriers. To determine whether disturbed myocardial energetics with the potential to serve as biomarkers are also reflected in the serum metabolome, we analyzed the serum metabolome of asymptomatic carriers in comparison to healthy controls and obstructive HCM patients (HOCM).

Metabolomics in Severe Aortic Stenosis Reveals Intermediates of Nitric Oxide Synthesis as Most Distinctive Markers.

Background: Calcific aortic valve disease (CAVD) is a rapidly growing global health problem with an estimated 12.6 million cases globally in 2017 and a 112% increase of deaths since 1990 due to aging and population growth. CAVD may develop into aortic stenosis (AS) by progressive narrowing of the aortic valve.

Multi-omics integration identifies key upstream regulators of pathomechanisms in hypertrophic cardiomyopathy due to truncating MYBPC3 mutations.

Background: Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the cardiac muscle, frequently caused by mutations in MYBPC3. However, little is known about the upstream pathways and key regulators causing the disease. Therefore, we employed a multi-omics approach to study the pathomechanisms underlying HCM comparing patient hearts harboring MYBPC3 mutations to control hearts.

Sex-Related Differences in Protein Expression in Sarcomere Mutation-Positive Hypertrophic Cardiomyopathy.

Sex-differences in clinical presentation contribute to the phenotypic heterogeneity of hypertrophic cardiomyopathy (HCM) patients. While disease prevalence is higher in men, women present with more severe diastolic dysfunction and worse survival. Until today, little is known about the cellular differences underlying sex-differences in clinical presentation.

Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. While ≈50% of patients with HCM carry a sarcomere gene mutation (sarcomere mutation-positive, HCM), the genetic background is unknown in the other half of the patients (sarcomere mutation-negative, HCM). Genotype-specific differences have been reported in cardiac function.

Mutation location of HCM-causing troponin T mutations defines the degree of myofilament dysfunction in human cardiomyocytes.

Background: The clinical outcome of hypertrophic cardiomyopathy patients is not only determined by the disease-causing mutation but influenced by a variety of disease modifiers. Here, we defined the role of the mutation location and the mutant protein dose of the troponin T mutations I79N, R94C and R278C.

Methods And Results: We determined myofilament function after troponin exchange in permeabilized single human cardiomyocytes as well as in cardiac patient samples harboring the R278C mutation.

Strength of patient cohorts and biobanks for cardiomyopathy research.

In 2011 the Netherlands Heart Foundation allocated funding (CVON, Cardiovasculair Onderzoek Nederland) to stimulate collaboration between clinical and preclinical researchers on specific areas of research. One of those areas involves genetic heart diseases, which are frequently caused by pathogenic variants in genes that encode sarcomere proteins. In 2014, the DOSIS (Determinants of susceptibility in inherited cardiomyopathy: towards novel therapeutic approaches) consortium was initiated, focusing their research on secondary disease hits involved in the onset and progression of cardiomyopathies.

Wnt Activation and Reduced Cell-Cell Contact Synergistically Induce Massive Expansion of Functional Human iPSC-Derived Cardiomyocytes.

Modulating signaling pathways including Wnt and Hippo can induce cardiomyocyte proliferation in vivo. Applying these signaling modulators to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in vitro can expand CMs modestly (<5-fold). Here, we demonstrate massive expansion of hiPSC-CMs in vitro (i.