Search

Background: Rare, monogenic forms of hypertension may give insight into novel mechanisms relevant to essential hypertension. Autosomal dominant hypertension with brachydactyly has been documented in a single Turkish kindred; the gene was mapped to chromosome 12p.Objective: To describe the molecular genetics of additional families with autosomal dominant hypertension and brachydactyly.Design: Case series.Setting: Tertiary care medical centers.Patients: An 11-member Canadian family and a 7-member U.S. family, neither of Turkish background, with autosomal dominant hypertension and type E brachydactyly.Measurements: Clinical evaluation, genotyping, and haplotype analyses.Results: The mode of inheritance, the type E brachydactyly, and the propensity for stroke were consistent with autosomal dominant hypertension with brachydactyly. The same markers on chromosome 12p cosegregated with the phenotype in the families. A haplotype analysis strongly supported the conclusion that these families have a molecular defect in the same gene.Conclusions: The syndrome of autosomal dominant hypertension and brachydactyly is not confined to patients of Turkish origin. All persons with brachydactyly should have their blood pressure measured, and the syndrome should be considered if hypertension is found. [ABSTRACT FROM AUTHOR]

Translocations are chromosomal rearrangements that are frequently associated with a variety of disease states and developmental disorders. We identified 2 families with brachydactyly type E (BDE) resulting from different translocations affecting chromosome 12p. Both translocations caused downregulation of the parathyroid hormone-like hormone (PTHLH) gene by disrupting the cis-regulatory landscape. Using chromosome conformation capturing, we identified a regulator on chromosome 12q that interacts in cis with PTHLH over a 24.4-megabase distance and in trans with the sex-determining region Y-box 9 (SOX9) gene on chromosome 17q. The element also harbored a long noncoding RNA (lncRNA). Silencing of the lncRNA, PTHLH, or SOX9 revealed a feedback mechanism involving an expression-dependent network in humans. In the BDE patients, the human lncRNA was upregulated by the disrupted chromosomal association. Moreover, the lncRNA occupancy at the PTHLH locus was reduced. Our results document what we believe to be a novel in cis- and in trans-acting DNA and lncRNA regulatory feedback element that is reciprocally regulated by coding genes. Furthermore, our findings provide a systematic and combinatorial view of how enhancers encoding lncRNAs may affect gene expression in normal development. [ABSTRACT FROM AUTHOR]

A large supravalvular aortic stenosis kindred, with a point mutation in exon 18 and a stop codon in exon 22 of the elastin gene, is described. Clinically, the disease severity appeared to increase in successive generations in this family. [ABSTRACT FROM AUTHOR]

Objective: Aortic valve neocuspidization (AVNeo) using autologous pericardium is a promising technique. Expected advantages are reduced immune response, appropriate biomechanics and lower treatment expenses. Nevertheless, autologous pericardium can be affected by patient's age and comorbidities. Usually, glutaraldehyde (GA) - fixed bovine pericardium is the basic material for aortic valve prostheses, easy available and carefully pre-examined in a standardized fabrication process. Aim of the study is the verification of autologous pericardial tissue homogeneity by analysing tissue thickness, biomechanics and extracellular matrix (ECM) composition., Methods: Segments of human GA-fixed pericardium selected by the surgeon based on visual criteria for cusp pre-cut and remaining after surgical AV replacement were investigated in comparison to bovine standard tissue treated equivalently. Pericardium sampling was performed at up to three positions of each sutured cusp for histological or biomechanical analysis, according to tissue availability., Results and Conclusions: Human pericardia exhibited a higher heterogeneity in collagen content, density of vessel structures and elastic moduli. Thickness, vessel density and collagen and elastin content differed significantly between the species. In contrast, significant interindividual differences were detected in most properties investigated for human pericardial samples but only for tissue thickness in bovine tissues. Higher heterogeneity of human pericardium, differing vessel and collagen content compared to bovine state-of-the-art material might be detrimental for long term AV functionality or deterioration and have to be intensely investigated in patients follow up after autologous cusp replacement., (© 2024. The Author(s).)

Brachydactyly type E (BDE), shortened metacarpals, metatarsals, cone-shaped epiphyses, and short stature commonly occurs as a sole phenotype. Parathyroid hormone-like protein (PTHrP) has been shown to be responsible in all forms to date, either directly or indirectly. We used linkage and then whole genome sequencing in a small pedigree, to elucidate BDE and identified a truncated disintegrin-and-metalloproteinase-19 (ADAM19) allele in all affected family members, but not in nonaffected persons. Since we had shown earlier that the extracellular domain of the parathyroid hormone receptor (PTHR1) is subject to an unidentified metalloproteinase cleavage, we tested the hypothesis that ADAM19 is a sheddase for PTHR1. WT ADAM19 cleaved PTHR1, while mutated ADAM-19 did not. We mapped the cleavage site that we verified with mass spectrometry between amino acids 64-65. ADAM-19 cleavage increased G q and decreased G s activation. Moreover, perturbed PTHR1 cleavage by ADAM19 increased ß-arrestin2 recruitment, while cAMP accumulation was not altered. We suggest that ADAM19 serves as a regulatory element for PTHR1 and could be responsible for BDE. This sheddase may affect other PTHrP or PTH-related functions., (© 2024 Aydin et al.)

We report here a nanosized "buckytrap", 1 , constructed from two bis-zinc(II) expanded-TTF (exTTF) porphyrin subunits. Two forms, 1a and 1b , differing in the axial ligands, H 2 O vs tetrahydrofuran (THF), were isolated and characterized. Discrete host-guest inclusion complexes are formed upon treatment with fullerenes as inferred from a single-crystal X-ray structural analyses of 1a with C 70 . The fullerene is found to be encapsulated within the inner pseudohexagonal cavity of 1a . In contrast, the corresponding free-base derivative ( 2 ) was found to form infinite ball-and-socket type supramolecular organic frameworks (3D-SOFs) with fullerenes, ( 2• C 60 ) n or ( 2 •C 70 ) n . This difference is ascribed to the fact that in 1a and 1b the axial positions are blocked by a H 2 O or THF ligand. Emission spectroscopic studies supported a 1:1 host-guest binding stoichiometry, allowing association constants of (2.0 ± 0.5) × 10 4 M -1 and (4.3 ± 0.9) × 10 4 M -1 to be calculated for C 60 and C 70 , respectively. Flash-photolysis time-resolved microwave conductivity (FP-TRMC) studies of solid films of the Zn-complex 1a revealed that the intrinsic charge carrier transport, i.e., pseudo-photoconductivity (ϕ∑μ), increases upon fullerene inclusion (e.g., ϕ∑μ = 1.53 × 10 -4 cm 2 V -1 s -1 for C 60 ⊂( 1a ) 2 and ϕ∑μ = 1.45 × 10 -4 cm 2 V -1 s -1 for C 70 ⊂( 1a ) 2 vs ϕ∑μ = 2.49 × 10 -5 cm 2 V -1 s -1 for 1a ) at 298 K. These findings provide support for the notion that controlling the nature of self-assembly supramolecular constructs formed from exTTF-porphyrin dimers through metalation or choice of fullerene can be used to regulate key functional features, including photoconductivity.

Background: Phosphodiesterase 3A ( PDE3A ) gain-of-function mutations cause hypertension with brachydactyly (HTNB) and lead to stroke. Increased peripheral vascular resistance, rather than salt retention, is responsible. It is surprising that the few patients with HTNB examined so far did not develop cardiac hypertrophy or heart failure. We hypothesized that, in the heart, PDE3A mutations could be protective., Methods: We studied new patients. CRISPR-Cas9-engineered rat HTNB models were phenotyped by telemetric blood pressure measurements, echocardiography, microcomputed tomography, RNA-sequencing, and single nuclei RNA-sequencing. Human induced pluripotent stem cells carrying PDE3A mutations were established, differentiated to cardiomyocytes, and analyzed by Ca 2+ imaging. We used Förster resonance energy transfer and biochemical assays., Results: We identified a new PDE3A mutation in a family with HTNB. It maps to exon 13 encoding the enzyme's catalytic domain. All hitherto identified HTNB PDE3A mutations cluster in exon 4 encoding a region N-terminally from the catalytic domain of the enzyme. The mutations were recapitulated in rat models. Both exon 4 and 13 mutations led to aberrant phosphorylation, hyperactivity, and increased PDE3A enzyme self-assembly. The left ventricles of our patients with HTNB and the rat models were normal despite preexisting hypertension. A catecholamine challenge elicited cardiac hypertrophy in HTNB rats only to the level of wild-type rats and improved the contractility of the mutant hearts, compared with wild-type rats. The β-adrenergic system, phosphodiesterase activity, and cAMP levels in the mutant hearts resembled wild-type hearts, whereas phospholamban phosphorylation was decreased in the mutants. In our induced pluripotent stem cell cardiomyocyte models, the PDE3A mutations caused adaptive changes of Ca 2+ cycling. RNA-sequencing and single nuclei RNA-sequencing identified differences in mRNA expression between wild-type and mutants, affecting, among others, metabolism and protein folding., Conclusions: Although in vascular smooth muscle, PDE3A mutations cause hypertension, they confer protection against hypertension-induced cardiac damage in hearts. Nonselective PDE3A inhibition is a final, short-term option in heart failure treatment to increase cardiac cAMP and improve contractility. Our data argue that mimicking the effect of PDE3A mutations in the heart rather than nonselective PDE3 inhibition is cardioprotective in the long term. Our findings could facilitate the search for new treatments to prevent hypertension-induced cardiac damage.

We report a fully organic pyridine-tetrapyrrolic U-shaped acyclic receptor 10 , which prefers a supramolecular pseudo-macrocyclic dimeric structure ( 10 ) 2 in a less polar, non-coordinating solvent (e.g., CHCl 3 ). Conversely, when it is crystalized from a polar, coordinating solvent (e.g., N , N -dimethylformamide, DMF), it exhibited an infinite supramolecular one-dimensional (1D) "zig-zag" polymeric chain, as inferred from the single-crystal X-ray structures. This supramolecular system acts as a potential receptor for strong acids, e.g., p -toluenesulfonic acid (PTSA), methane sulfonic acid (MSA), H 2 SO 4 , HNO 3 , and HCl, with a prominent colorimetric response from pale yellow to deep red. The receptor can easily be recovered from the organic solution of the host-guest complex by simple aqueous washing. It was observed that relatively stronger acids with p K a < -1.92 in water were able to interact with the receptor, as inferred from 1 H NMR titration in tetrahydrofuran- d 8 (THF- d 8 ) and ultraviolet-visible (UV-vis) spectroscopic titrations in anhydrous THF at 298 K. Therefore, this new dynamic supramolecular receptor system may have potentiality in materials science research.

There is a recognized need in the area of explosives detection for fluorescence-based sensing systems that are capable of not only producing a turn-on response but also generating a distinctive spectral signature for a given analyte. Here, we report several supramolecular ensembles displaying efficient fluorophore displacement that give rise to an increase in fluorescence intensity upon exposure to various nitroaromatic compounds. The synthetic supramolecular constructs in question consist of a tetrathiafulvalene (TTF)-based pyrrolic macrocycle, benzo-TTF-calix[4]pyrrole (Bz-TTF-C4P), and fluorescent dyes, monomeric or dimeric naphthalenediimide (NDI) and perylenediimide (PDI) derivatives, as well as chloride or hexafluorophosphate (PF 6 - ) salts of rhodamine 6G (Rh-6G). In chloroform solution, these assemblies exist in the form of discrete supramolecular complexes or oligomeric aggregates depending on the specific dye combinations in question. Each ensemble was tested as a potential explosive-responsive fluorescence indicator displacement assay (FIDA) by challenging it with a series of di- and trinitroaromatic compounds and examining the change in fluorescence spectral characteristics. Upon addition of nitroaromatic compounds (NACs), either a "turn-on" or a "turn-off" fluorescent response was observed depending on the nature of the constituent fluorophore and, where applicable, the counteranion. The FIDAs based on the PDI derivatives were found to display not only a ratiometric fluorescence enhancement but also analyte-dependent spectral changes when treated with NACs. The NAC-induced fluorescence spectral response of each ensemble was rationalized on the basis of various solution-phase spectroscopic studies, as well as single-crystal X-ray diffraction analyses.

The peroxidase activity of hemin-peptide complexes remains a potential factor in oxidative damage relevant to neurodegeneration. Here, we present the effect of temperature, ionic strength, and pH relevant to pathophysiological conditions on the dynamic equilibrium between high-spin and low-spin hemin-Aβ 40 constructs. This influence on peroxidase activity was also demonstrated using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and dopamine (DA) oxidation rate analyses with increasing ratios of Aβ 16 and Aβ 40 (up to 100 equivalents). Interaction and reactivity studies of aggregated Aβ 40 -hemin revealed enhanced peroxidase activity versus hemin alone. Comparison of the results obtained using Aβ 16 and Aβ 40 amyloid beta peptides revealed marked differences and provide insight into the potential effects of hemin-Aβ on neurological disease progression.

Congenital hearing loss is a common disorder worldwide. Heterogeneous gene variation accounts for approximately 20-25% of such patients. We investigated a five-generation Chinese family with autosomal-dominant nonsyndromic sensorineural hearing loss (SNHL). No wave was detected in the pure-tone audiometry, and the auditory brainstem response was absent in all patients. Computed tomography of the patients, as well as of two sporadic SNHL cases, showed bilateral inner ear anomaly, cochlear maldevelopment, absence of the osseous spiral lamina, and an enlarged vestibular aqueduct. Such findings were absent in nonaffected persons. We used linkage analysis and exome sequencing and uncovered a heterozygous missense mutation in the PI4KB gene (p.Gln121Arg) encoding phosphatidylinositol 4-kinase β (PI4KB) from the patients in this family. In addition, 3 missense PI4KB (p.Val434Gly, p.Glu667Lys, and p.Met739Arg) mutations were identified in five patients with nonsyndromic SNHL from 57 sporadic cases. No such mutations were present within 600 Chinese controls, the 1000 genome project, gnomAD, or similar databases. Depleting pi4kb mRNA expression in zebrafish caused inner ear abnormalities and audiosensory impairment, mimicking the patient phenotypes. Moreover, overexpression of 4 human missense PI4KB mutant mRNAs in zebrafish embryos resulted in impaired hearing function, suggesting dominant-negative effects. Taken together, our results reveal that PI4KB mutations can cause SNHL and inner ear malformation. PI4KB should be included in neonatal deafness screening., (Copyright © 2020 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.)

Background: High blood pressure is the primary risk factor for cardiovascular death worldwide. Autosomal dominant hypertension with brachydactyly clinically resembles salt-resistant essential hypertension and causes death by stroke before 50 years of age. We recently implicated the gene encoding phosphodiesterase 3A ( PDE3A ); however, in vivo modeling of the genetic defect and thus showing an involvement of mutant PDE3A is lacking., Methods: We used genetic mapping, sequencing, transgenic technology, CRISPR-Cas9 gene editing, immunoblotting, and fluorescence resonance energy transfer. We identified new patients, performed extensive animal phenotyping, and explored new signaling pathways., Results: We describe a novel mutation within a 15 base pair (bp) region of the PDE3A gene and define this segment as a mutational hotspot in hypertension with brachydactyly. The mutations cause an increase in enzyme activity. A CRISPR/Cas9-generated rat model, with a 9-bp deletion within the hotspot analogous to a human deletion, recapitulates hypertension with brachydactyly. In mice, mutant transgenic PDE3A overexpression in smooth muscle cells confirmed that mutant PDE3A causes hypertension. The mutant PDE3A enzymes display consistent changes in their phosphorylation and an increased interaction with the 14-3-3θ adaptor protein. This aberrant signaling is associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function., Conclusions: The mutated PDE3A gene drives mechanisms that increase peripheral vascular resistance causing hypertension. We present 2 new animal models that will serve to elucidate the underlying mechanisms further. Our findings could facilitate the search for new antihypertensive treatments.

We report here a new extended tetrathiafulvalene (exTTF)-porphyrin scaffold, 2 , that acts as a ball-and-socket receptor for C 60 and C 70 . Supramolecular interactions between 2 and these fullerenes serve to stabilize 3D supramolecular organic frameworks (SOFs) in the solid state formally comprising peapod-like linear assemblies. The SOFs prepared via self-assembly in this way act as "tunable functional materials", wherein the complementary geometry of the components and the choice of fullerene play crucial roles in defining the conductance properties. The highest electrical conductivity (σ = 1.3 × 10 -8 S cm -1 at 298 K) was observed in the case of the C 70 -based SOF. In contrast, low conductivity was seen for the SOF based on pristine 2 (σ = 5.9 × 10 -11 S cm -1 at 298 K). The conductivity seen for the C 70 -based SOF approaches that seen for other TTF- and fullerene-based supramolecular materials despite the fact that the present systems are metal-free and constructed entirely from neutral building blocks. Transient absorption spectroscopic measurements corroborated the formation of charge-transfer states (i.e., 2 δ+ /C 60 δ- and 2 δ+ /C 70 δ- , respectively) rather than fully charge separated states (i.e., 2 •+ /C 60 •- and 2 •+ /C 70 •- , respectively) both in solution (toluene and benzonitrile) and in the solid state at 298 K. Such findings are considered consistent with an ability to transfer charges effectively over long distances within the present SOFs, rather than, for example, the formation of energetically trapped ionic species.

We report here a fully organic, self-assembled dimeric receptor, constructed from acyclic naphthyridyl-polypyrrolic building blocks. The cagelike dimer is stable in the solid state, in solution, and in gas phase, as inferred from X-ray diffraction and spectroscopic analyses. This system acts as a receptor for oxalic acid, maleic acid, and malonic acid in the solid state and in THF solution. In contrast, acetic acid, propionic acid, adipic acid, and succinic acid, with p K a values > ca. 2.8, were not bound effectively within the cagelike cavity. It is speculated that oxalic acid, maleic acid, and malonic acid serve to protonate the naphthyridine moieties of the host, which then favors binding of the corresponding carboxylate anions via hydrogen-bonding to the pyrrolic NH protons. The present naphthyridine-polypyrrole dimer is stable under acidic conditions, including in the presence of 100 equiv trifluoroacetic acid (TFA), p -toluenesulfonic acid (PTSA), H 2 SO 4 , and HCl. However, disassembly may be achieved by exposure to tetrabutylammonium fluoride (TBAF). Washing with water then regenerates the cage. This process of assembly and disassembly could be repeated >20 times with little evidence of degradation. The reversible nature of the present system, coupled with its dicarboxylic acid recognition features, leads us to suggest it could have a role to play in effecting the controlled "capture" and "release" of biologically relevant dicarboxylic acids.

The first tetrakis-tetrathiafulvalene-calix[4]pyrrole (TTF-C[4]P) was reported in 2004. Early on it and related π-extended TTF-C[4]Ps were found to function as both anion receptors and as hosts for planar electron deficient neutral guests, including nitroaromatic explosives. Anion binding was found to occur with a 1 : 1 binding stoichiometry and to stabilise the cone C[4]P conformation, whereas planar electron deficient guests were bound in a cooperative 1 : 2 fashion to the 1,3-alternate conformer. Addition of strongly complexing anions was found to trigger release of the electron deficient guests concurrent with a conformational change to the cone form. Subsequent studies led to the discovery of anion-induced complexation with C60, and the finding that the resulting complexes would support fast photoinduced electron transfer events. Synthetic advances then led to the preparation of nonsymmetric TTF-C[4]Ps where a single moiety organises the receptor in either the 1,3-alternate conformation or the partial cone conformation, thus modifying both selectivity and sensitivity. TTF-C[4]P-based stimulus responsive systems, that rely on anions and cations as controlling inputs, have also been developed and studied in recent years. This review provides a summary of TTF-C[4]P-related chemistry.

Chromosomes occupy distinct interphase territories in the three-dimensional nucleus. However, how these chromosome territories are arranged relative to one another is poorly understood. Here, we investigated the inter- chromosomal interactions between chromosomes 2q, 12, and 17 in human mesenchymal stem cells (MSCs) and MSC-derived cell types by DNA-FISH We compared our findings in normal karyotypes with a three-generation family harboring a 2q37-deletion syndrome, featuring a heterozygous partial deletion of histone deacetylase 4 ( HDAC4 ) on chr2q37. In normal karyotypes, we detected stable, recurring arrangements and interactions between the three chromosomal territories with a tissue-specific interaction bias at certain loci. These inter- chromosomal interactions were confirmed by Hi-C. Interestingly, the disease-related HDAC4 deletion resulted in displaced inter- chromosomal arrangements and altered interactions between the deletion-affected chromosome 2 and chromosome 12 and/or 17 in 2q37-deletion syndrome patients. Our findings provide evidence for a direct link between a structural chromosomal aberration and altered interphase architecture that results in a nuclear configuration, supporting a possible molecular pathogenesis., (© 2018 The Authors.)

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".

The recognition of nitroaromatic explosives by a tetrakis-tetrathiafulvalene-calix[4]pyrrole receptor (TTF-C[4]P) yields a "turn on" and fingerprinting response in the resonance Raman scattering observed in solution and the solid state. Intensity changes in nitro vibrations with analyte complexation occur via a mechanism of resonance between the 785 nm laser line and the strongly absorbing charge-transfer chromophore arising from the complex between electron-donating TTF-C[4]P and electron-accepting nitroaromatic explosives. The addition of chloride forms the Cl - ·TTF-C[4]P complex resetting the system for reuse.

A cage molecule incorporating three electron donating monopyrrolotetrathiafulvalene units was synthesised to host electron accepting [60]fullerenes. Formation of a strong 1 : 1 donor-acceptor (D-A) complex C 60 ⊂1 was confirmed by solid state X-ray analysis as well as 1 H NMR and absorption spectroscopic analyses of the arising charge-transfer (CT) band (λ = 735 nm, ε ≈ 840 M -1 cm -1 ). Inserting Li + inside the [60]fullerene increased the binding 28-fold (K a = 3.7 × 10 6 M -1 ) and a large bathochromic shift of the CT band to the near infrared (NIR) region (λ = 1104 nm, ε ≈ 4800 M -1 cm -1 ) was observed.

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., (© 2017 Eulenberg-Gustavus et al.)

Herein we describe a large capsule-like bis-calix[4]pyrrole 1, which is able to host concurrently two dihydrogen phosphate anions within a relatively large internal cavity. Evidence for the concurrent, dual recognition of the encapsulated anions came from 1 H NMR and UV-vis spectroscopies and ITC titrations carried out in CD 2 Cl 2 /CD 3 OD (9/1, v/v) or dichloroethane (DCE), as well as single crystal X-ray diffraction analyses. Receptor 1 was also found to bind two dianionic sulfate anions bridged by two water molecules in the solid state. The resulting sulfate dimer was retained in DCE solution, as evidenced by spectroscopic analyses. Finally, receptor 1 was found capable of accommodating two trianionic pyrophosphate anions in the cavity. The present experimental findings are supported by DFT calculations along with 1 H NMR and UV-vis spectroscopies, ITC studies, and single crystal X-ray diffraction analyses.

After the epochal discovery of the "organic metal", namely, tetrathiafulvalene (TTF)-7,7,8,8-tetracyano-p-quinodimethane (TCNQ) dyad in 1973, scientists have made efforts to derivatize TTF for constructing various supramolecular architectures to control the charge-transfer processes by adjusting the donor-acceptor strength of the dyads for numerous applications. The interesting inherent electronic donor properties of TTFs control the overall electrochemical properties of the supramolecular structures, leading to the construction of highly efficient optoelectronic materials, photovoltaic solar cells, organic field-effect transistors, and optical sensors. Modified TTF structures thus constitute promising candidates for the development of so-called "functional materials" that could see use in modern technological applications. The versatility of the TTF unit and the pioneering synthetic strategies that have been developed over the past few decades provide opportunities to tune the architecture and function for specific purposes. This review covers the "state of the art" associated with TTF-annulated oligopyrrolic macrocyclic compounds. Points of emphasis include synthesis, properties, and potential applications.

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 K a = 3 × 10 10 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 (2 2 ⊂1) as visualized by a readily apparent color change from yellow to brown.

Supramolecular polymers are a class of macromolecules stabilized by weak non-covalent interactions. These self-assembled aggregates typically undergo stimuli-induced reversible assembly and disassembly. They thus hold great promise as so-called functional materials. In this work, we present the design, synthesis, and responsive behavior of a short supramolecular oligomeric system based on two hetero-complementary subunits. These "monomers" consist of a tetrathiafulvalene-functionalized calix[4]pyrrole (TTF-C[4]P) and a glycol diester-linked bis-2,5,7-trinitrodicyanomethylenefluorene-4-carboxylate (TNDCF), respectively. We show that when mixed in organic solvents, such as CHCl 3 , CH 2 ClCH 2 Cl, and methylcyclohexane, supramolecular aggregation takes place to produce short oligomers stabilized by hydrogen bonding and donor-acceptor charge-transfer (CT) interactions. The self-associated materials were characterized by 1 H NMR and UV/Vis/NIR absorption spectroscopy, as well as by concentration- and temperature-dependent absorption spectroscopy and dynamic light scattering (DLS) analyses of both the monomeric and oligomerized species. The self-associated system produced from TTF-C[4]P and TNDCF exhibits a concentration-dependent aggregation behavior typical of supramolecular polymers. Further support for the proposed self-assembly came from theoretical calculations. The fluorescence emitting properties of TNDCF are quenched under conditions that promote the formation of supramolecular aggregates containing TTF-C[4]P and TNDCF. This quenching effect has been utilized as a probe for the detection of substrates in the form of anions (i.e., chloride) and nitroaromatic explosives (i.e., 1,3,5-trinitrobenzene). Specifically, the addition of these substrates to mixtures of TTF-C[4]P and TNDCF produced a fluorescence "turn-on" response., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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., (© Georg Thieme Verlag KG Stuttgart · New York.)

Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the protein kinase A-mediated phosphorylation of phosphodiesterase 3A resulting in enhanced cAMP-hydrolytic affinity and accelerated cell proliferation. The phosphorylated vasodilator-stimulated phosphoprotein is diminished, and parathyroid hormone-related peptide is dysregulated, potentially accounting for all phenotypic features. Untreated patients die prematurely of stroke; however, hypertension-induced target-organ damage is otherwise hardly apparent. We conducted clinical studies of vascular function, cardiac functional imaging, platelet function in affected and nonaffected persons, and cell-based assays. Large-vessel and cardiac functions indeed seem to be preserved. The platelet studies showed normal platelet function. Cell-based studies demonstrated that available phosphodiesterase 3A inhibitors suppress the mutant isoforms. However, increasing cGMP to indirectly inhibit the enzyme seemed to have particular use. Our results shed more light on phosphodiesterase 3A activation and could be relevant to the treatment of severe hypertension in the general population., (© 2015 American Heart Association, Inc.)

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB). The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated. In vitro analyses of mesenchymal stem cell-derived vascular smooth muscle cells (VSMCs) and chondrocytes provided insights into molecular pathogenesis. The mutations increased protein kinase A-mediated PDE3A phosphorylation and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced cell proliferation. Levels of phosphorylated VASP were diminished, and PTHrP levels were dysregulated. We suggest that the identified PDE3A mutations cause the syndrome. VSMC-expressed PDE3A deserves scrutiny as a therapeutic target for the treatment of hypertension.

A π-extended tetrathiafulvalene-boradiazaindacene chimera, ex-TTF-BODIPY, has been prepared. The resulting system undergoes sequential one-electron oxidations, allowing access to both the mono-oxidized radical cationic and dicationic states. Additionally, ex-TTF-BODIPY displays electrochromic and electrofluorochromic behaviour in the near-IR portion of the electromagnetic spectrum and functions as a redox switched "on-off-on" emissive system.

Using a tetrathiafulvalene functionalised calix[4]pyrrole (TTF-C[4]P; ) and alkyl diester-linked bis-dinitrophenols (), it was found that the solvent polarity and linker length have an effect on the molecular aggregation behaviour. 2D (1)H NOESY, DOSY NMR and UV-vis-NIR spectroscopic studies, as well as single crystal X-ray diffraction analyses support these conclusions.

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.