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© 2018, Springer Science+Business Media, LLC, part of Springer Nature.  The polypeptide analgesic compounds APCH3 (a TRPV1 receptor inhibitor) and PT1 (a P 2 X 3 receptor inhibitor) were shown not to act on the cardiovascular system or respiratory system when given either as single or multiple doses in mice. The low molecular weight compound sevanol (an ASIC3 receptor inhibitor) had no effect on the cardiovascular system, but prolonged use for 14 days affected measures of the respiratory system, significantly increasing respiratory rate and peak expiratory flow rate.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. We studied the reactions of spinal ganglion neurons accompanying regeneration of the skin wound complicated by S. aureus sp. infection. The appearance of neuron groups with different morphofunctional changes was noted: reversible dystrophic and compensatory reactions and irreversible degenerative changes. The proportion of small B neurons was higher than the proportion of large type A neurons at all terms of the experiment. Application of plateletrich plasma to the wound after preliminary hydroimpulsive treatment considerably reduced cell destruction and stimulated regenerative effects in neurons starting from day 7 of the experiment. Application of platelet-rich plasma without hydroimpulsive treatment decelerated wound regeneration and increased the number of destructively changed neurons even in comparison with spontaneous wound healing. Close correlations between protein synthesis markers and stages of the wound process and its characteristics were revealed.

© 2018 Schaefer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Sodium-glucose transporters (SGLT) belong to the solute carrier 5 family, which is characterized by sodium dependent transport of sugars and other solutes. In contrast, the human SGLT3 (hSGLT3) isoform, encoded by SLC5A4, acts as a glucose sensor that does not transport sugar but induces membrane depolarization by Na+ currents upon ligand binding. Whole-exome sequencing (WES) of several extended pedigrees with high density of attention- deficit/hyperactivity disorder (ADHD) identified a triplet ATG deletion in SLC5A4 leading to a single amino acid loss (ΔM500) in the hSGLT3 protein imperfectly co-segregating with the clinical phenotype of ADHD. Since mutations in homologous domains of hSGLT1 and hSGLT2 were found to affect intestinal and renal function, respectively, we analyzed the functional properties of hSGLT3[wt] and [ΔM500] by voltage clamp and current clamp recordings from cRNA-injected Xenopus laevis oocytes. The cation conductance of hSGLT3[wt] was activated by application of glucose or the specific agonist 1-desoxynojirimycin (DNJ) as revealed by inward currents in the voltage clamp configuration and cell depolarization in the current clamp mode. Almost no currents and changes in membrane potential were observed when glucose or DNJ were applied to hSGLT3 [ΔM500]-injected oocytes, demonstrating a loss of function by this amino acid deletion in hSGLT3. To monitor membrane targeting of wt and mutant hSGLT3, fusion constructs with YFP were generated, heterologously expressed in Xenopus laevis oocytes and analyzed for membrane fluorescence by confocal microscopy. In comparison to hSGLT3[wt] the fluorescent signal of mutant [ΔM500] was reduced by 43% indicating that the mutant phenotype might mainly result from inaccurate membrane targeting. As revealed by homology modeling, residue M500 is located in TM11 suggesting that in addition to the core structure (TM1-TM10) of the transporter, the surrounding TMs are equally crucial for transport/sensor function. In conclusion, our findings indicate that the deletion [ΔM500] in hSGLT3 inhibits membrane targeting and thus largely disrupts glucose-induced sodium conductance, which may, in interaction with other ADHD risk-related gene variants, influence the risk for ADHD in deletion carriers.

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Abstract: Osteoarthritis (OA), the most common form of arthritis, is characterized by inflammation of joints and cartilage degradation leading to disability, discomfort, severe pain, inflammation, and stiffness of the joint. It has been shown that adenosine, a purine nucleoside composed of adenine attached to ribofuranose, is enzymatically produced by the human synovium. However, the functional significance of adenosine signaling in homeostasis and pathology of synovial joints remains unclear. Adenosine acts through four cell surface receptors, i.e., A1, A2A, A2B, and A3, and here, we have systematically analyzed mice with a deficiency for A3 receptor as well as pharmacological modulations of this receptor with specific analogs. The data show that adenosine receptor signaling plays an essential role in downregulating catabolic mechanisms resulting in prevention of cartilage degeneration. Ablation of A3 resulted in development of OA in aged mice. Mechanistically, A3 signaling inhibited cellular catabolic processes in chondrocytes including downregulation of Ca2+/calmodulin-dependent protein kinase (CaMKII), an enzyme that promotes matrix degradation and inflammation, as well as Runt-related transcription factor 2 (RUNX2). Additionally, selective A3 agonists protected chondrocytes from cell apoptosis caused by pro-inflammatory cytokines or hypo-osmotic stress. These novel data illuminate the protective role of A3, which is mediated via inhibition of intracellular CaMKII kinase and RUNX2 transcription factor, the two major pro-catabolic regulators in articular cartilage. Key messages: Adenosine receptor A3 (A3) knockout results in progressive loss of articular cartilage in vivo.Ablation of A3 results in activation of matrix degradation and cartilage hypertrophy.A3 agonists downregulate RUNX2 and CaMKII expression in osteoarthritic human articular chondrocytes.A3 prevents articular cartilage matrix degradation induced by inflammation and osmotic fluctuations.A3 agonist inhibits proteolytic activity of cartilage-degrading enzymes.

© 2018 Elsevier Ltd The variation of blood flow waveform in the internal carotid artery (ICA) with age is a well-documented hemodynamic phenomenon, but little is known about how such variation affects the characteristics of blood flow in aneurysms present in the region. In the study, hemodynamic simulations were conducted for 26 ICA aneurysms, with flow waveforms measured in the ICAs of young and older adults being used respectively to set the inflow boundary conditions. Obtained results showed that replacing the young-adult flow waveform with the older-adult one led to little changes (<10%) in simulated time-averaged wall shear stress (WSS), transient maximum WSS, relative residence time and trans-aneurysm pressure loss coefficient, but resulted in a marked increase (32.36 ± 17.24%) in oscillatory shear index (OSI). Frequency-domain wave analysis revealed that the progressive enhancement of low-frequency harmonics dominated the observed flow waveform variation with age and was a major factor contributing to the increase in OSI. Cross-sectional comparisons among the aneurysms further revealed that the degree of increase in OSI correlated positively with some specific morphological features of aneurysm, such as aspect ratio and size ratio. In summary, the study demonstrates that the variation in flow waveform with age augments the oscillation of WSS in ICA aneurysms, which underlies the importance of setting patient-specific boundary conditions in hemodynamic studies on cerebral aneurysms, especially those involving long-term patient follow-up or cross-sectional comparison among patients of different ages.

© 2018 Elsevier B.V.  Polymer frameworks have been for the first time impregnated with rhodium and palladium compounds in a supercritical carbon dioxide medium. The polymeric carriers were the mesoporous phenol-formaldehyde resin and cross-linked dendrimer networks, based on poly(propylene imine) and poly(amido amine) dendrimers. The metal compounds were rhodium acetylacetonate and palladium carboxylates including their fluoro-substituted derivatives and palladium hexafluoroacetylacetonate. Using the IR-spectroscopy method, we have shown that the metal content in the polymers was in the range of 0.3–2.0 wt.% depending on the polymer nature, cross-linking agent type and cross-linking degree. We have obtained the samples of polymer supports with nanosized metal particles through hydrogen reduction of immobilized rhodium and palladium compounds at P(H 2 ) = 6–10 MPa, T = 60 °C, 4 h time. The average rhodium particle size was 1–2 nm. It has been shown that the obtained nanocomposites were extremely active catalysts for hydrogenation of unsaturated hydrocarbons.

© 2018, Pleiades Publishing, Ltd. Aptamers are widely used as molecular recognition elements for detecting and blocking functional biological molecules. Since the common “alphabet” of DNA and RNA consists of only four letters, the chemical diversity of aptamers is less than the diversity of protein recognition elements built of 20 amino acids. Chemical modification of nucleotides enlarges the potential of DNA/RNA aptamers. This review describes the latest achievements in a variety of approaches to aptamers selection with an extended genetic alphabet.

© 2018 American Association of Endodontists Introduction: The aim of the study was to determine long-term tooth survival after endodontic retreatment and whether the presence of intraradicular posts influences the outcome. Methods: Ninety-five teeth were randomly assigned to surgical or nonsurgical endodontic retreatment. Forty-seven teeth in 45 patients were treated by conventional endodontic surgery and 48 teeth (47 patients) by nonsurgical retreatment, including the removal of intraradicular posts in 37 (77%). The outcome was tooth survival; follow-up continued until the tooth had been extracted, at least 10 years had elapsed since retreatment, the patient declined further follow-up, or the patient died. The Fisher exact test was used to analyze differences between the groups. Results: The median follow-up time was 10.1 years (range, 0.0–15.6 years). The overall survival rate was 76%, with no significant differences in long-term tooth survival between retreatment methods or the presence of an intraradicular post. The reasons for tooth extraction were related to the retreatment method. Vertical root fractures were significantly more frequent in the nonsurgical group when retreatment included post removal (P =.036). Conclusions: There was no significant difference in long-term tooth survival after surgical or nonsurgical retreatment. The presence of intraradicular posts did not affect long-term tooth survival, but for teeth with posts, those retreated nonsurgically were more frequently extracted because of vertical root fractures than those retreated surgically (P =.036). The major limitations of the study were a smaller sample size and the use of outmoded retreatment techniques.

© 2018, The Publisher. In the version of this Article originally published, the competing interests statement was missing. The authors declare no competing interests; this statement has now been added in all online versions of the Article.

© 2018 American Society for Clinical Investigation. All rights reserved. Ferroptosis is a death program executed via selective oxidation of arachidonic acid-phosphatidylethanolamines (AA-PE) by 15-lipoxygenases. In mammalian cells and tissues, ferroptosis has been pathogenically associated with brain, kidney, and liver injury/diseases. We discovered that a prokaryotic bacterium, Pseudomonas aeruginosa, that does not contain AA-PE can express lipoxygenase (pLoxA), oxidize host AA-PE to 15-hydroperoxy-AA-PE (15-HOO-AA-PE), and trigger ferroptosis in human bronchial epithelial cells. Induction of ferroptosis by clinical P. aeruginosa isolates from patients with persistent lower respiratory tract infections was dependent on the level and enzymatic activity of pLoxA. Redox phospholipidomics revealed elevated levels of oxidized AA-PE in airway tissues from patients with cystic fibrosis (CF) but not with emphysema or CF without P. aeruginosa. We believe that the evolutionarily conserved mechanism of pLoxA-driven ferroptosis may represent a potential therapeutic target against P. aeruginosa-associated diseases such as CF and persistent lower respiratory tract infections.

© 2018 Elsevier Ltd Novel psychoactive substances are intoxicating compounds developed to mimic the effects of well-established drugs of abuse. They are not controlled by the United Nations drug convention and pose serious health concerns worldwide. Among them, the dissociative drug methoxetamine (MXE) is structurally similar to ketamine (KET) and phencyclidine (PCP) and was created to purposely mimic the psychotropic effects of its “parent” compounds. Recent animal studies show that MXE is able to stimulate the mesolimbic dopaminergic transmission and to induce KET-like discriminative and rewarding effects. In light of the renewed interest in KET and PCP analogs, we decided to deepen the investigation of MXE-induced effects by a battery of behavioral tests widely used in studies of “safety-pharmacology” for the preclinical characterization of new molecules. To this purpose, the acute effects of MXE on neurological and sensorimotor functions in mice, including visual, acoustic and tactile responses, thermal and mechanical pain, motor activity and acoustic startle reactivity were evaluated in comparisons with KET and PCP to better appreciate its specificity of action. Cardiorespiratory parameters and blood pressure were also monitored in awake and freely moving animals. Acute systemic administrations of MXE, KET and PCP (0.01–30 mg/kg i.p.) differentially alter neurological and sensorimotor functions in mice depending in a dose-dependent manner specific for each parameter examined. MXE and KET (1 and 30 mg/kg i.p.) and PCP (1 and 10 mg/kg i.p.) also affect significantly cardiorespiratory parameters, systolic and diastolic blood pressure in mice.

© 2018 John Wiley  &  Sons, Ltd. Distribution of blood flow in myocardium is a key determinant of the localization and severity of myocardial ischemia under impaired coronary perfusion conditions. Previous studies have extensively demonstrated the transmural difference of ischemic vulnerability. However, it remains incompletely understood how transmural myocardial flow is regulated under in vivo conditions. In the present study, a computational model of the coronary circulation was developed to quantitatively evaluate the sensitivity of transmural flow distribution to various cardiovascular and hemodynamic factors. The model was further incorporated with the flow autoregulatory mechanism to simulate the regulation of myocardial flow in the presence of coronary artery stenosis. Numerical tests demonstrated that heart rate (HR), intramyocardial tissue pressure (Pim), and coronary perfusion pressure (Pper) were the major determinant factors for transmural flow distribution (evaluated by the subendocardial-to-subepicardial (endo/epi) flow ratio) and that the flow autoregulatory mechanism played an important compensatory role in preserving subendocardial perfusion against reduced Pper. Further analysis for HR variation-induced hemodynamic changes revealed that the rise in endo/epi flow ratio accompanying HR decrease was attributable not only to the prolongation of cardiac diastole relative to systole, but more predominantly to the fall in Pim. Moreover, it was found that Pim and Pper interfered with each other with respect to their influence on transmural flow distribution. These results demonstrate the interactive effects of various cardiovascular and hemodynamic factors on transmural myocardial flow, highlighting the importance of taking into account patient-specific conditions in the explanation of clinical observations.

© 2018 Elsevier B.V. Cardiolipin (CL) is a key mitochondrial phospholipid essential for mitochondrial energy production. CL is remodeled from monolysocardiolipin (MLCL) by the enzyme tafazzin (TAZ). Loss-of-function mutations in the gene which encodes TAZ results in a rare X-linked disorder called Barth Syndrome (BTHS). The mutated TAZ is unable to maintain the physiological CL:MLCL ratio, thus reducing CL levels and affecting mitochondrial function. BTHS is best known as a cardiac disease, but has been acknowledged as a multi-syndrome disorder, including cognitive deficits. Since reduced CL levels has also been reported in numerous neurodegenerative disorders, we examined how TAZ-deficiency impacts cognitive abilities, brain mitochondrial respiration and the function of hippocampal neurons and glia in TAZ knockdown (TAZ kd) mice. We have identified for the first time the profile of changes that occur in brain phospholipid content and composition of TAZ kd mice. The brain of TAZ kd mice exhibited reduced TAZ protein expression, reduced total CL levels and a 19-fold accumulation of MLCL compared to wild-type littermate controls. TAZ kd brain exhibited a markedly distinct profile of CL and MLCL molecular species. In mitochondria, the activity of complex I was significantly elevated in the monomeric and supercomplex forms with TAZ-deficiency. This corresponded with elevated mitochondrial state I respiration and attenuated spare capacity. Furthermore, the production of reactive oxygen species was significantly elevated in TAZ kd brain mitochondria. While motor function remained normal in TAZ kd mice, they showed significant memory deficiency based on novel object recognition test. These results correlated with reduced synaptophysin protein levels and derangement of the neuronal CA1 layer in hippocampus. Finally, TAZ kd mice had elevated activation of brain immune cells, microglia compared to littermate controls. Collectively, our findings demonstrate that TAZ-mediated remodeling of CL contributes significantly to the expansive distribution of CL molecular species in the brain, plays a key role in mitochondria respiratory activity, maintains normal cognitive function, and identifies the hippocampus as a potential therapeutic target for BTHS.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. The aim of present study was to evaluate the effects of 3- and 6-week swimming exercise on cardiodynamics and coronary flow in high salt-induced hypertensive and normotensive rats. 80 male Wistar albino rats (6 weeks old) were divided into 8 groups: hypertensive animals that swam for 3 weeks; hypertensive animals that swam for 6 weeks and their respective sedentary controls; normotensive animals that swam for 3 weeks; normotensive animals that swam for 6 weeks and their respective sedentary controls. Hypertensive animals were on high sodium (8% NaCl solution) diet for 4 weeks, and these animals did not drink tap water during the experimental protocol. After sacrificing, hearts were isolated and perfused according to Langendorff technique at gradually increased coronary perfusion pressure (40–120 cmH2O). The following parameters of cardiac function were continuously recorded: maximum and minimum rate of pressure development in LV, systolic, and diastolic left ventricular pressure, and heart rate. Coronary flow was measured flowmetrically. Findings of the present study may help in better understanding of short- to medium-term exercise-induced direct effects on cardiac function and perfusion. Generally viewed, swimming of both durations did not change myocardial function and perfusion in hypertensive and normotensive conditions.

© 2018, Pleiades Publishing, Inc. Abstract: The paper reports the first study of genetic diversity of the domestic yak in the Sayan-Altai region of Russia (Altai and Tuva) and Mongolia (Khuvsgul and Gobi) on the basis of the polymorphism analysis of the mtDNA D-loop hypervariable region. It has been demonstrated that, among all the studied populations, Tuva yaks are characterized by the highest haplotype diversity. Four new haplotypes, A4, A13, D9, and E3, have been described for the first time. The analysis of the contribution of maternal genetic component to the yak intrabreed and interbreed mtDNA diversity revealed two large clades. For the first time, comparative analysis of genetic structure of the Russian yak populations was carried out using 15 microsatellite loci. Low genetic difference between the populations was revealed, which may apparently be accounted for by the specific features of farm breeding, in particular, by animal exchange between the adjacent territories of the Sayan-Altai region.

© 2018 Elsevier Ltd Human stem cells, including pluripotent, embryonic and mesenchymal, stem cells play pivotal roles in cell-based therapies. Over the past decades, various methods for expansion and differentiation of stem cells have been developed to satisfy the burgeoning clinical demands. One of the most widely endorsed technologies for producing large cell quantities is using microcarriers (MCs) in bioreactor culture systems. In this review, we focus on microcarriers properties that can manipulate the expansion and fate of stem cells. Here, we provide an overview of commercially available MCs and focus on novel stimulus responsive MCs controlled by temperature, pH and field changes. Different features of MCs including composition, surface coating, morphology, geometry/size, surface functionalization, charge and mechanical properties, and their cellular effects are also highlighted. We then conclude with current challenges and outlook on this promising technology.

© 2018, Mary Ann Liebert, Inc. Background: Laparoscopic D3 anterior posterior extended mesenterectomy (D3APEM) in right colectomy has received increased attention. The aim of this study is to prove feasibility, systemize technical accomplishment, and provide short-term outcomes data. Methods: From July 2013 to February 2017, 18 patients with adenocarcinoma in the right colon underwent right colectomy with laparoscopic D3APEM, including lymph nodes anterior and posterior to the superior mesenteric vessels. A reconstructed three-dimensional anatomy map derived from the staging computed tomography was used as a road map at surgery. The procedure was systematized into seven operative steps: Step 1, trocar placement and inspection; Step 2, release of the transverse colon; Step 3, identification of the terminal mesenteric vessels; Step 4, release of the anterior flap; Step 5, division of the transverse mesocolon; Step 6, release of the posterior flap; and Step 7, anastomosis and specimen removal. Patient disposition and variations regarding vascular anatomy and ability to expose consequentially may necessitate a variation in the sequence of the steps. Results: A total of 7 (39%) cases were converted, 3 due to bleeding and 4 due to challenging dissection. Median operative time and blood loss were 276 minutes (168-439 minutes) and 200 mL (< 50-1300 mL), respectively. Postoperative complications occurred in 6 (33%), including 2 (11%) major complication requiring reoperation. Median hospital stay was 5 days (3-13 days). R0 resection was achieved in all cases. Median number of the lymph nodes harvested was 40 (25-86), including 11.5 (4-35) in the D3 volume. Six patients (33%) had positive nodes, 3 of them affecting the D3 zone, including 1 case of a skip metastasis. There was no mortality, and at present all the patients are alive. One patient developed distant lymph node metastases. Conclusion: Laparoscopic right colectomy with D3APEM is feasible, associated with acceptable morbidity and fast recovery; now in readiness for introduction in specialized colorectal institutions.

© 2018 Elsevier B.V. Aiming to explore elevated temperatures as a tool for miniaturization of biodegradable polymer multilayer capsules, assembled on spherical vaterite micron- and submicron-sized particles, we subject the shells composed of dextran sulfate (DS) and poly-L-arginine (Parg) to a heat treatment. Changes of the capsule size are studied at various temperatures and ionic strengths of the continuous phase. Unlike some synthetic polymer multilayer shells (their response to heat treatment depends on the number of layers and their arrangement), the biodegradable Parg/DS capsules exhibit size reduction and profound compaction regardless of their initial size, number of polymer layers and polymer layer sequence. The capsule response to heat is stable at ionic strengths of the continuous phase not exceeding 0.1 M NaCl.

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs may prevent or postpone acquired resistance, thus increasing treatment efficiency. We cultured human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cancer cell lines in the presence of Tyrosine Kinase Inhibitors (Pazopanib, Sorafenib, and Sunitinib) and Rapalogues (Temsirolimus and Everolimus) for four months and obtained cell lines demonstrating increased drug resistance. We investigated gene expression profiles of intact and resistant cells by microarrays and analyzed alterations in 378 cancer-related signaling pathways using the bioinformatical platform Oncobox. This revealed numerous pathways linked with development of drug resistant phenotypes. Our approach is based on targeting proteins involved in as many as possible signaling pathways upregulated in resistant cells. We tested 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs.

© 2018 European Academy of Dermatology and Venereology Background: Tuberous sclerosis complex (TSC) is a genetic disorder associated with tumour growth in various organs, including the brain, kidneys, heart and skin. Cutaneous lesions are prevalent manifestations of TSC, occurring in up to 90% of patients. Oral mammalian target of rapamycin inhibitors, such as everolimus, is believed to be effective for treatment of TSC-associated lesions because they act on the underlying disease pathophysiology. Objective: We evaluated the long-term effect of oral everolimus on TSC-associated skin lesions as a secondary objective in the phase III studies EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400) after approximately 4 years of treatment. Materials and methods: Everolimus was dosed 4.5 mg/m2/day (titrated to trough 5–15 ng/mL) in patients with TSC-associated subependymal giant cell astrocytoma in EXIST-1, and 10 mg/day initially in adult patients with TSC- or sporadic lymphangioleiomyomatosis–associated renal angiomyolipoma in EXIST-2. Following positive results from the core phase, remaining patients were offered open-label everolimus in an extension. Skin lesion response rate was the proportion of patients achieving complete or partial clinical response. Results: A total of 105 patients in EXIST-1 and 107 in EXIST-2 received everolimus and had ≥1 skin lesion at baseline. Skin lesion response rate (95% confidence interval) was 58.1% (48.1–67.7%) in EXIST-1 and 68.2% (58.5–76.9%) in EXIST-2; most were partial responses. At week 192 (EXIST-1: n = 55; EXIST-2: n = 56), 69% and 66% had a response. Most common drug-related adverse event was stomatitis (41–45%). Conclusion: Oral everolimus improved TSC-related skin lesions, with responses sustained over 4 years of treatment in EXIST-1 and EXIST-2.