Long non-coding RNA in health and disease

Long non-coding RNAs (lncRNAs) interact with the nuclear architecture and are involved in fundamental biological mechanisms, such as imprinting, histone-code regulation, gene activation, gene repression, lineage determination, and cell proliferation, all by regulating gene expression. Understanding the lncRNA regulation of transcriptional or post-transcriptional gene regulation expands our knowledge of disease. Several associations between altered lncRNA function and gene expression have been linked to clinical disease phenotypes. Early advances have been made in developing lncRNAs as biomarkers. Several mouse models reveal that human lncRNAs have very diverse functions. Their involvement in gene and genome regulation as well as disease underscores the importance of lncRNA-mediated regulatory networks. Because of their tissue-specific expression potential, their function as activators or repressors, and their selective targeting of genes, lncRNAs are of potential therapeutic interest. We review the regulatory mechanisms of lncRNAs, their major functional principles, and discuss their role in Mendelian disorders, cancer, cardiovascular disease, and neurological disorders

Gene silencing and a novel monoallelic expression pattern in distinct CD177 neutrophil subsets

CD177 presents antigens in allo- and autoimmune diseases on the neutrophil surface. Individuals can be either CD177-deficient or harbor distinct CD177(neg) and CD177(pos) neutrophil subsets. We studied mechanisms controlling subset-restricted CD177 expression in bimodal individuals. CD177(pos), but not CD177(neg) neutrophils, produced CD177 protein and mRNA. Haplotype analysis indicated a unique monoallelic CD177 expression pattern, where the offspring stably transcribed either the maternal or paternal allele. Hematopoietic stem cells expressed both CD177 alleles and silenced one copy during neutrophil differentiation. ChIP and reporter assays in HeLa cells with monoallelic CD177 expression showed that methylation reduced reporter activity, whereas demethylation caused biallelic CD177 expression. HeLa cell transfection with c-Jun and c-Fos increased CD177 mRNA. Importantly, CD177(pos) human neutrophils, but not CD177(neg) neutrophils, showed a euchromatic CD177 promoter, unmethylated CpGs, and c-Jun and c-Fos binding. We describe epigenetic mechanisms explaining the two distinct CD177 neutrophil subsets and a novel monoallelic CD177 expression pattern that does not follow classical random monoallelic expression or imprinting

Functionalised tetrathiafulvalene- (TTF-) macrocycles: recent trends in applied supramolecular chemistry

Tetrathiafulvalene (TTF) has been extensively explored as a π-electron donor in supramolecular systems. Over the last two decades substantial advances have been made in terms of constructing elaborate architectures based on TTF and in exploiting the resulting systems in the context of supramolecular host–guest recognition. The inherent electron-donating character of TTF derivatives has led to their use in the construction of highly efficient optoelectronic materials, optical sensors, and electron-transfer ensembles. TTFs are also promising candidates for the development of the so-called “functional materials” that might see use in a range of modern technological applications. Novel synthetic strategies, coupled with the versatility inherent within the TTF moiety, are now allowing the architecture of TTF-based systems to be tuned precisely and modified for use in specific purposes. In this critical review, we provide a “state-of-the-art” overview of research involving TTF-based macrocyclic systems with a focus on their use in supramolecular host–guest recognition, as components in non-covalent electron transfer systems, and in the construction of “molecular machines”

Very Strong Binding for a Neutral Calix[4]pyrrole Receptor Displaying Positive Allosteric Binding

The dual-analyte responsive behavior of tetraTTF-calix[4]pyrrole receptor 1 has been shown to complex electron-deficient planar guests in a 2:1 fashion by adopting a so-called 1,3-alternate conformation. However, stronger 1:1 complexes have been demonstrated with tetraalkylammonium halide salts that defer receptor 1 to its cone conformation. Herein, we report the complexation of an electron-deficient planar guest, 1,4,5,8-naphthalenetetracarboxylic dianhydride (NTCDA, 2) that champions the complexation with 1, resulting in a high association constant Ka = 3 × 1010 M–2. The tetrathiafulvalene (TTF) subunits in the tetraTTF-calix[4]pyrrole receptor 1 present a near perfect shape and electronic complementarity to the NTCDA guest, which was confirmed by X-ray crystal structure analysis, DFT calculations, and electron density surface mapping. Moreover, the complexation of these species results in the formation of a charge transfer complex (22⊂1) as visualized by a readily apparent color change from yellow to brown

Intramolecular Cooperative Effects in Multichromophoric Cavitands Exhibiting Nonlinear Optical Properties

We report on the design, synthesis, and characterization of a new class of multichromophoric cavitands based on resorcin[4]arenes. The novel compounds have exhibited high values of second-order nonlinear optical (NLO) properties, as evidenced by electric-field-induced second harmonic generation (EFISHG) measurements. Theoretical calculations indicate the presence of edge-to-face T-shaped interactions between the aromatic building blocks within these multichromophoric systems, which is further supported by the detection of hypsochromic shifts in UV-vis and upfield aromatic chemical shifts in 1H NMR. We proved for the first time that the gain in the quadratic hyperpolarizabilities of multichromophoric NLO macrocycles, originating from the near parallel orientations of the subchromophores, can be partially suppressed if the distance between the dipolar subunits falls into a specific range, where intramolecular cooperative and/or collective effects are operative. Our finding will contribute to the better understanding of the phenomenon of cooperativity in new molecular materials with promising NLO properties. (Figure Presented). © 2015 American Chemical Society

Validation of fluorescence-labeled artificial nonhuman sequences for single-strand conformation polymorphism mutation detection in familial hypercholesterolemia

We developed a two-in-one, polymerase chain reaction (PCR)-based method with a specific amplification step and a universal amplification step in one tube to screen for the presence of DNA variations. The method relies on fluorescence-labeled artificial nonhuman sequences for mutation detection. To document utility, we applied this method as a high-throughput capillary single-strand conformation polymorphism screening system to identify 30 mutations in the low-density lipoprotein receptor gene. The sensitivity of mutant allele detection compared to wild-type allele detection was 93%. We conclude that the “two-in-one PCR“ is sensitive, simple, and cost effective

Die Reise vom Phaenotyp zum Genotyp : ein Blick hinter die Kulissen einer monogenen Form der Hypertonie [From phenotype to genotype : a glimpse behind the scenes of an unending story]

Mendelian conditions direct attention at basic mechanisms. In the 1990's DNA sequencing allowed elucidating such conditions. We embarked on an unexpected adventure to study a monogenic autosomal-dominant form of hypertension causing also a specific form of short fingers. The gene locus caused a 50 mmHg increase in blood pressure at age of 50. Our clinically based group stumbled to the finish line after 20 years of study. We remained together and proudly persevered. Our findings could be relevant for essential hypertension