A Central Role for TRPM4 in Ca2+-Signal Amplification and Vasoconstriction

Transient receptor potential melastatin-4 (TRPM4) is activated by an increase in intracellular Ca²⁺ concentration and is expressed on smooth muscle cells (SMCs). It is implicated in the myogenic constriction of cerebral arteries. We hypothesized that TRPM4 has a general role in intracellular Ca²⁺ signal amplification in a wide range of blood vessels. TRPM4 function was tested with the TRPM4 antagonist 9-phenanthrol and the TRPM4 activator A23187 on the cardiovascular responses of the rat, in vivo and in isolated basilar, mesenteric, and skeletal muscle arteries. TRPM4 inhibition by 9-phenanthrol resulted in hypotension and a decreased heart rate in the rat. TRPM4 inhibition completely antagonized myogenic tone development and norepinephrine-evoked vasoconstriction, and depolarization (high extracellular KCl concentration) evoked vasoconstriction in a wide range of peripheral arteries. Vasorelaxation caused by TRPM4 inhibition was accompanied by a significant decrease in intracellular Ca²⁺ concentration, suggesting an inhibition of Ca²⁺ signal amplification. Immunohistochemistry confirmed TRPM4 expression in the smooth muscle cells of the peripheral arteries. Finally, TRPM4 activation by the Ca²⁺ ionophore A23187 was competitively inhibited by 9-phenanthrol. In summary, TRPM4 was identified as an essential Ca²⁺-amplifying channel in peripheral arteries, contributing to both myogenic tone and agonist responses. These results suggest an important role for TRPM4 in the circulation. The modulation of TRPM4 activity may be a therapeutic target for hypertension. Furthermore, the Ca²⁺ ionophore A23187 was identified as the first high-affinity (nanomolar) direct activator of TRPM4, acting on the 9-phenanthrol binding site.     

Implication of microRNAs in Carcinogenesis with Emphasis on Hematological Malignancies and Clinical Translation

MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs, that are involved in the multistep process of carcinogenesis, contributing to all established hallmarks of cancer. In this review, implications of miRNAs in hematological malignancies and their clinical utilization fields are discussed. As components of the complex regulatory network of gene expression, influenced by the tissue microenvironment and epigenetic modifiers, miRNAs are “micromanagers” of all physiological processes including the regulation of hematopoiesis and metabolic pathways. Dysregulated miRNA expression levels contribute to both the initiation and progression of acute leukemias, the metabolic reprogramming of malignantly transformed hematopoietic precursors, and to the development of chemoresistance. Since they are highly stable and can be easily quantified in body fluids and tissue specimens, miRNAs are promising biomarkers for the early detection of hematological malignancies. Besides novel opportunities for differential diagnosis, miRNAs can contribute to advanced chemoresistance prediction and prognostic stratification of acute leukemias. Synthetic oligonucleotides and delivery vehicles aim the therapeutic modulation of miRNA expression levels. However, major challenges such as efficient delivery to specific locations, differences of miRNA expression patterns between pediatric and adult hematological malignancies, and potential side effects of miRNA-based therapies should be considered.     

An Ultra-Rare Manifestation of an X-Linked Recessive Disorder: Duchenne Muscular Dystrophy in a Female Patient

Duchenne muscular dystrophy (DMD) is the most common inherited muscle dystrophy. Patients are characterized by muscle weakness, gross motor delay, and elevated serum creatinine kinase (CK) levels. The disease is caused by mutations in the DMD gene located on the X chromosome. Due to the X-linked recessive inheritance pattern, DMD most commonly affects males, who are generally diagnosed between the age of 3–5 years. Here we present an ultra-rare manifestation of DMD in a female patient. Cytogenetic examination showed that she has a t(X;10)(p21.1;p12.1) translocation, which turned out to affect the DMD gene with one of the breakpoints located in exon 54 (detected by genome sequencing). The X-inactivation test revealed skewed X-inactivation (ratio 99:1). Muscle histology and dystrophin immunohistochemistry showed severe dystrophic changes and highly reduced dystrophin expression, respectively. These results, in accordance with the clinical picture and a highly elevated serum CK, led to the diagnosis of DMD. In conclusion, although in very rare cases, DMD can manifest in female patients as well. In this case, a balanced X-autosome reciprocal translocation disrupts the DMD gene and skewed X-inactivation leads to the manifestation of the DMD phenotype.     

The Role of Telocytes and Telocyte-Derived Exosomes in the Development of Thoracic Aortic Aneurysm

A hallmark of thoracic aortic aneurysms (TAA) is the degenerative remodeling of aortic wall, which leads to progressive aortic dilatation and resulting in an increased risk for aortic dissection or rupture. Telocytes (TCs), a distinct type of interstitial cells described in many tissues and organs, were recently observed in the aortic wall, and studies showed the potential regulation of smooth muscle cell (SMC) homeostasis by TC-released shed vesicles. The purpose of the present work was to study the functions of TCs in medial degeneration of TAA. During aneurysmal formation an increase of aortic TCs was identified in human surgical specimens of TAA-patients, compared to healthy thoracic aortic (HTA)-tissue. We found the presence of epithelial progenitor cells in the adventitial layer, which showed increased infiltration in TAA samples. For functional analysis, HTA- and TAA-telocytes were isolated, characterized, and compared by their protein levels, mRNA- and miRNA-expression profiles. We detected TC and TC-released exosomes near SMCs. TAA-TC-exosomes showed a significant increase of the SMC-related dedifferentiation markers KLF-4-, VEGF-A-, and PDGF-A-protein levels, as well as miRNA-expression levels of miR-146a, miR-221 and miR-222. SMCs treated with TAA-TC-exosomes developed a dedifferentiation-phenotype. In conclusion, the study shows for the first time that TCs are involved in development of TAA and could play a crucial role in SMC phenotype switching by release of extracellular vesicles.     

The Effect of Temperature on the Color of Red Wines

The effect of increased temperature on the color of red wines was studied due to its importance during storage and transport. The chemical reactions induced by elevated temperature were investigated by measuring the UV-VIS spectra. The temperature of the wines was increased from its common storage temperature (about 14 °C) to higher temperatures (t= 20 °C, 25 °C, 30 °C, 35 °C, and 40 °C) and the UV/VIS spectra were recorded during several hours. The spectral changes obtained indicate the presence of quasi-first-order chemical processes justifying determination of the activation energies using their temperature dependence. The determined decay values (Villányi Portugieser: E(VP) (a,420 nm) = 90.02 kJ/mol, E(VP) (a,520 nm) = 34.18 kJ/mol, E(VP) (a,620 nm) = 54.55 kJ/mol; half-life values of 46.5 d [25 °C] and 9.5 d [35 °C] at 420 nm; 4.67 d [25 °C] and 2.0 d [35 °C] at 520 nm; 9.5 d [25 °C] and 2.4 d [35 °C] at 620 nm; Bikatory wine: E(Bk) (a,420 nm) = 82.07 kJ/mol and half-life values of 41.35 d [25 °C] and 4.001 d [35 °C] at 420 nm) of these reactions highlight a considerable change in the quality of wines stored for a few hours at elevated temperatures. Depending on polyphenol composition the wines show different half-life with regard to their color stability and browning reactions. Higher polyphenolic content helps to stabilize the wine against detrimental temperature effects. Practical Application: This research can be applicable to estimate the optimal temperature of red wines during storage and transport.     

Comparison of directly compressed vitamin B12 tablets prepared from micronized rotary-spun microfibers and cast films

Fiber-based dosage forms are potential alternatives of conventional dosage forms from the point of the improved extent and rate of drug dissolution. Rotary-spun polymer fibers and cast films were prepared and micronized in order to direct compress after homogenization with tabletting excipients. Particle size distribution of powder mixtures of micronized fibers and films homogenized with tabletting excipients were determined by laser scattering particle size distribution analyzer. Powder rheological behavior of the mixtures containing micronized fibers and cast films was also compared. Positron annihilation lifetime spectroscopy was applied for the microstructural characterization of micronized fibers and films. The water-soluble vitamin B₁₂ release from the compressed tablets was determined. It was confirmed that the rotary spinning method resulted in homogeneous supramolecularly ordered powder mixture, which was successfully compressed after homogenization with conventional tabletting excipients. The obtained directly compressed tablets showed uniform drug release of low variations. The results highlight the novel application of micronized rotary-spun fibers as intermediate for further processing reserving the original favorable powder characteristics of fibrous systems.     

Unexpected effect of potassium ions on the copigmentation in red wines

The effect of potassium ions on the Glories color parameters of red wine has been investigated. The results show that temperature dependence of color intensity is high, while no considerable effect of temperature on color hue was obtained. Enhanced color intensity was observed in the presence of potassium ions. Color intensity reaches a maximum, when potassium is added in concentrations of about 0.5 g/dm³. Furthermore, the temperature-dependence of the color intensity was decreased at higher potassium ion concentrations. According to the possible dissociation of phenolic OH, independent measurements validate that changes in pH itself could not be responsible for this unexpected phenomenon.     

Network coding based resource efficient congestion control for video streaming

The paper proposes a resource efficient solution for Network Coding (NC) based congestion control consisting in identification around the congested links of multiple butterfly or other low complexity NC-capable topologies by using the Discrete Lagrange Multiplier optimization algorithm. The identification of the NC-capable topologies is based on the resource management capabilities foreseen for the network entities of the Future Internet. The congestion control issue is tackled by separate encoding of appropriately selected groups of data flows passing through the bottleneck link. By optimal selection of the data flows to be encoded, the additional network resources required by the NC operations can be minimized. The encoding is realized by using an XOR-based algorithm adapted for unequal bit rate data flows, and the experimental performances are reported here. Due to its efficient usage of the network resources and high degree of scalability, the congestion control solution proposed in this paper is suitable for large bit rate transmissions, like video streaming.