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In this work we prove that the original (Bassi and Rebay in J Comput Phys 131:267-279, 1997) scheme (BR1) for the discretization of second order viscous terms within the discontinuous Galerkin collocation spectral element method (DGSEM) with Gauss Lobatto nodes is stable. More precisely, we prove in the first part that the BR1 scheme preserves energy stability of the skew-symmetric advection term DGSEM discretization for the linearized compressible Navier-Stokes equations (NSE). In the second part, we prove that the BR1 scheme preserves the entropy stability of the recently developed entropy stable compressible Euler DGSEM discretization of Carpenter et al. (SIAM J Sci Comput 36:B835-B867, 2014) for the non-linear compressible NSE, provided that the auxiliary gradient equations use the entropy variables. Both parts are presented for fully three-dimensional, unstructured curvilinear hexahedral grids. Although the focus of this work is on the BR1 scheme, we show that the proof naturally includes the Local DG scheme of Cockburn and Shu. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy-induced vomiting is a common adverse effect of cancer treatment. We assessed the non-inferiority of palonosetron versus ondansetron in prevention of acute chemotherapy-induced vomiting in children with cancer in 2-18 years of age.Methods: In this single-center, open-label, randomized study, children receiving moderate and high emetogenic chemotherapy were assigned to get either ondansetron or palonosetron in addition to other antiemetic prophylaxis. The primary efficacy endpoint was the proportion of children with complete response during the acute phase of the first on-study chemotherapy cycle. Non-inferiority was assessed by demonstration of lower limit of the 97.5% confidence interval for differences in complete response rates in palonosetron arm to be superior by - 15%. Risk factors for suboptimal response and the cost of administration of two drugs were also analyzed.Results: A total of 108 children were analyzed and various factors likely to influence response were equally distributed in two arms. These 108 patients received 412 blocks of chemotherapy. During the acute phase, complete responses were recorded in 72.2% (39/54) and 83.3% (45/54) receiving ondansetron and palonosetron, respectively (ΔCR + 11.1%). The lower limit of 97.5% confidence interval (- 6.95-28.39) for this difference was greater than - 15% in palonosetron arm. Only statistically significant risk factor that predisposed response was use of dexamethasone (p value < 0.01). The cost associated with ondansetron administration was significantly higher compared to palonosetron.Conclusion: Palonosetron is non-inferior and cost-effective compared to ondansetron for prevention of acute chemotherapy-induced vomiting (CIV) in children receiving moderate and high emetogenic chemotherapy. [ABSTRACT FROM AUTHOR]

Summary: Objective: The cholinergic deficit is thought to underlie progressed cognitive decline in Alzheimer Disease. The lineage reprogramming of somatic cells into cholinergic neurons may provide strategies toward cell‐based therapy of neurodegenerative diseases. Methods and results: Here, we found that a combination of neuronal transcription factors, including Ascl1, Myt1l, Brn2, Tlx3, and miR124 (5Fs) were capable of directly converting human brain vascular pericytes (HBVPs) into cholinergic neuronal cells. Intriguingly, the inducible effect screening of reprogramming factors showed that a single reprogramming factor, Myt1l, induced cells to exhibit similarly positive staining for Tuj1, MAP2, ChAT, and VAChT upon lentivirus infection with the 5Fs after 30 days. HBVP‐converted neurons were rarely labeled even after long‐term incubation with BrdU staining, suggesting that induced neurons were directly converted from HBVPs rather than passing through a proliferative state. In addition, the overexpression of Myt1l induced the elevation of Ascl1, Brn2, and Ngn2 levels that contributed to reprogramming. Conclusions: Our findings provided proof of the principle that cholinergic neurons could be produced from HBVPs by reprogramming factor‐mediated fate instruction. Myt1l was a critical mediator of induced neuron cell reprogramming. HBVPs represent another excellent alternative cell resource for cell‐based therapy to treat neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Oxygen-ozone (O3) therapy serves as an alternative medical technique that increases the oxygen in the body along with the introduction of O3. O3 therapy has finally reached a level where the biological mechanisms of action have been understood, showing that they are in the domain of physiology, biochemistry, and pharmacology. Few clinical applications have been reviewed here as well as exemplifying that O3 therapy is particularly useful in musculoskeletal disorders. In the therapeutic range, O3 can be used as a more effective and safe substitute of standard medications. O3 therapy has been used for many years for its ability to inactivate various viruses, cancer, and acquired immune deficiency syndrome but is now making strides in the treatment of musculoskeletal disorders such as rheumatoid arthritis, lumbar facet joint syndrome, subacromial bursitis, carpal tunnel syndrome, osteoarthritis, hip bursitis, shoulder adhesive capsulitis, herniated disc, and temporomandibular joint disorder. [ABSTRACT FROM AUTHOR]

The paper deals with high-order discontinuous Galerkin (DG) method with the approximation order that exceeds 20 and reaches 100 and even 1000 with respect to one-dimensional case. To achieve such a high order solution, the DG method with finite difference method has to be applied. The basis functions of this method are high-order orthogonal Legendre or Chebyshev polynomials. These polynomials are defined in one-dimensional space (1D), but they can be easily adapted to two-dimensional space (2D) by cross products. There are no nodes in the elements and the degrees of freedom are coefficients of linear combination of basis functions. In this sort of analysis the reference elements are needed, so the transformations of the reference element into the real one are needed as well as the transformations connected with the mesh skeleton. Due to orthogonality of the basis functions, the obtained matrices are sparse even for finite elements with more than thousands degrees of freedom. In consequence, the truncation errors are limited and very high-order analysis can be performed. The paper is illustrated with a set of benchmark examples of 1D and 2D for the elliptic problems. The example presents the great effectiveness of the method that can shorten the length of calculation over hundreds times. [ABSTRACT FROM AUTHOR]

We perform stability analyses for discontinuous Galerkin spectral element approximations of linear variable coefficient hyperbolic systems in three dimensional domains with curved elements. Although high order, the precision of the quadratures used are typically too low with respect to polynomial order associated with their arguments, which introduces errors that can destabilize an approximation, especially when the solution is underresolved. We show that using a larger number of points in the volume quadrature, often called “overintegration”, can eliminate the destabilizing errors associated with the volume, but introduces new errors at the surfaces that can also destabilize the solution. Increased quadrature precision on both the volume and surface terms, on the other hand, leads to a stable approximation. The results support the findings of Mengaldo et al. (J Comput Phys 299:56-81, 2015) who found that fully consistent integration was more robust for the solution of compressible flows than the volume only version. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a disorder which affects 1-10% of pregnant women worldwide. It is characterised by hypertension and proteinuria in the later stages of gestation and can lead to maternal and perinatal morbidity and mortality. Other than the delivery of the foetus and the removal of the placenta, to date there are no therapeutic approaches to treat or prevent PE. It is thus only possible to reduce PE-related mortality through early detection, careful monitoring, and treatment of the symptoms. For these reasons the search for noninvasive, blood-borne, or urinary biochemical markers that could be used for the screening, presymptomatic diagnosis, and prediction of the development of PE is of great urgency. So far, a number of biomarkers have been proposed for predicting PE, based on pathophysiological observations, but these have mostly proven to be unreliable and inconsistent between different studies. The clinical presentation of PE and data gathered for the biochemical markers placental growth factor (PlGF), soluble Feline McDonough Sarcoma- (fms-) like tyrosine kinase-1 (sFlt-1), asymmetric dimethylarginine (ADMA), and methyl-lysine is being reviewed with the aim of providing both a clinical and biochemical understanding of how these biomarkers might assist in the diagnosis of PE or indicate its severity. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is a quite common neurodegenerative disorder with a prevalence of approximately 1:800–1,000 in subjects over 60 years old. The aim of our study was to determine the candidate target genes in PD through meta-analysis of multiple gene expression arrays datasets and to further combine mRNA and miRNA expression analyses to identify more convincing biological targets and their regulatory factors. Six included datasets were obtained from the Gene Expression Omnibus database by systematical search, including five mRNA datasets (150 substantia nigra samples in total) and one miRNA dataset containing 32 peripheral blood samples. A chip meta-analysis of five microarray data was conducted by using the metaDE package and 94 differentially expressed (DE) mRNAs were comprehensively obtained. And 19 deregulated DE miRNAs were obtained through the analysis of one miRNAs dataset by Qlucore Omics Explorer software. An interaction network formed by DE mRNAs, DE miRNAs, and important pathways was discovered after we analyzed the functional enrichment, protein–protein interactions, and miRNA targetome prediction analysis. In conclusion, this study suggested that five significantly downregulated mRNAs (MAPK8, CDC42, NDUFS1, COX4I1, and SDHC) and three significantly downregulated miRNAs (miR-126-5p, miR-19-3p, and miR-29a-3p) were potentially useful diagnostic markers in clinic, and lipid metabolism (especially non-alcoholic fatty liver disease pathway) and mitochondrial dysregulation may be the keys to biochemically detectable molecular defects. However, the role of these new biomarkers and molecular mechanisms in PD requires further experiments in vivo and in vitro and further clinical evidence. [ABSTRACT FROM AUTHOR]

Sleep represents an active phenomenon regulated by a highly integrated network of cortical and subcortical structures. This complex model results in disruptions at various levels during physiological aging and more deeply during neurodegenerative disorders, thus leading to different sleep alterations. In Alzheimer's disease (AD), sleep-wake abnormalities were described to occur even in the preclinical phase, thus suggesting they could be a possible AD biomarker. On the other hand, they also favor the progression of the disease. In this paper, we review current theories regarding sleep regulations and functions to highlight the pathophysiological mechanisms at the basis of the bidirectional relationship between sleep and AD. A better understanding of these complex interactions might also be useful to target both sleep disorder management and AD-related symptoms. [ABSTRACT FROM AUTHOR]

The effect of the inclusion of chestnuts in the finishing diet of Celta pig breed on the characteristics of dry-cured loin, a traditional Spanish dry-cured meat product, after the manufacturing process and the vacuum-packed storage was studied. In general, no significant differences between the diets (chestnut, mixed, and concentrate diet) were obtained for physicochemical (moisture, intramuscular fat, and titratable acidity) and lipolytic parameters. Lower pH and higher values for oxidation parameters (peroxide and TBA values) were obtained in loins from pigs fed with chestnuts. However, no differences were found for fatty acids from the different lipid fractions when diets were compared, with the exception of some minor fatty acids. Free fatty acids represented over 2.7% of the fat in the final product. The distinction between diets was procured when a discriminant canonical analysis was performed for fatty acid contents. After vacuum-packed storage, only a slight evolution of the studied parameters was obtained. [ABSTRACT FROM AUTHOR]

FEMPAR is an open source object oriented Fortran200X scientific software library for the high-performance scalable simulation of complex multiphysics problems governed by partial differential equations at large scales, by exploiting state-of-the-art supercomputing resources. It is a highly modularized, flexible, and extensible library, that provides a set of modules that can be combined to carry out the different steps of the simulation pipeline. FEMPAR includes a rich set of algorithms for the discretization step, namely (arbitrary-order) grad, div, and curl-conforming finite element methods, discontinuous Galerkin methods, B-splines, and unfitted finite element techniques on cut cells, combined with h-adaptivity. The linear solver module relies on state-of-the-art bulk-asynchronous implementations of multilevel domain decomposition solvers for the different discretization alternatives and block-preconditioning techniques for multiphysics problems. FEMPAR is a framework that provides users with out-of-the-box state-of-the-art discretization techniques and highly scalable solvers for the simulation of complex applications, hiding the dramatic complexity of the underlying algorithms. But it is also a framework for researchers that want to experience with new algorithms and solvers, by providing a highly extensible framework. In this work, the first one in a series of articles about FEMPAR, we provide a detailed introduction to the software abstractions used in the discretization module and the related geometrical module. We also provide some ingredients about the assembly of linear systems arising from finite element discretizations, but the software design of complex scalable multilevel solvers is postponed to a subsequent work. [ABSTRACT FROM AUTHOR]

Ozone, one of the most important air pollutants, is a triatomic molecule containing three atoms of oxygen that results in an unstable form due to its mesomeric structure. It has been well-known that ozone has potent ability to oxidize organic compounds and can induce respiratory irritation. Although ozone has deleterious effects, many therapeutic effects have also been suggested. Since last few decades, the therapeutic potential of ozone has gained much attention through its strong capacity to induce controlled and moderated oxidative stress when administered in precise therapeutic doses.Aplethora of scientific evidence showed that the activation of hypoxia inducible factor-1α (HIF-1a), nuclear factor of activated T-cells (NFAT), nuclear factor-erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE), and activated protein-1 (AP-1) pathways are the main molecular mechanisms underlying the therapeutic effects of ozone therapy. Activation of these molecular pathways leads to upregulation of endogenous antioxidant systems, activation of immune functions as well as suppression of inflammatory processes, which is important for correcting oxidative stress in diabetes and spinal pain. The present study intended to review critically the available scientific evidence concerning the beneficial properties of ozone therapy for treatment of diabetic complications and spinal pain. It finds benefit for integrating the therapy with ozone into pharmacological procedures, instead of a substitutive or additional option to therapy. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Recombinant Newcastle Disease virus (rNDV) vectored vaccines are safe mucosal applicable vaccines with intrinsic immune‐modulatory properties for the induction of efficient immunity. Like all viral vectored vaccines repeated inoculation via mucosal routes invariably results to immunity against viral vaccine vectors. To obviate immunity against viral vaccine vectors and improve the ability of rNDV vectored vaccines in inducing T cell immunity in murine air way we have directed dendritic cell targeted HIV‐1 gag protein (DEC‐Gag) vaccine; for the induction of helper CD4+ T cells to a Recombinant Newcastle disease virus expressing codon optimized HIV‐1 Gag P55 (rNDV‐L‐Gag) vaccine. Methods: We do so through successive administration of anti‐DEC205‐gagP24 protein plus polyICLC (DEC‐Gag) vaccine and rNDV‐L‐Gag. First strong gag specific helper CD4+ T cells are induced in mice by selected targeting of anti‐DEC205‐gagP24 protein vaccine to dendritic cells (DC) in situ together with polyICLC as adjuvant. This targeting helped T cell immunity develop to a subsequent rNDV‐L‐Gag vaccine and improved both systemic and mucosal gag specific immunity. Results: This sequential DEC‐Gag vaccine prime followed by an rNDV‐L‐gag boost results to improved viral vectored immunization in murine airway, including mobilization of protective CD8+ T cells to a pathogenic virus infection site. Conclusion: Thus, complementary prime boost vaccination, in which prime and boost favor distinct types of T cell immunity, improves viral vectored immunization, including mobilization of protective CD8+T cells to a pathogenic virus infection site such as the murine airway. [ABSTRACT FROM AUTHOR]

Norovirus (NoV) GII.4 is the predominant genotype associated with gastroenteritis pandemics and new strains emerge every 2–3 years. Between 2008 and 2011, environmental studies in South Africa (SA) reported NoVs in 63% of the sewage-polluted river water samples. The aim of this study was to assess whether wastewater samples could be used for routine surveillance of NoVs, including GII.4 variants. From April 2015 to March 2016, raw sewage and effluent water samples were collected monthly from five wastewater treatment plants in SA. A total of 108 samples were screened for NoV GI and GII using real-time RT-qPCR. Overall 72.2% (78/108) of samples tested positive for NoVs with 4.6% (5/108) GI, 31.5% (34/108) GII and 36.1% (39/108) GI + GII strains being detected. Norovirus concentrations ranged from 1.02 × 102 to 3.41 × 106 genome copies/litre for GI and 5.00 × 103 to 1.31 × 106 genome copies/litre for GII. Sixteen NoV genotypes (GI.2, GI.3, GI.4, GI.5, GI.6, GII.2, GII.3, GII.4, GII.7, GII.9, GII.10, GII.14, GII.16, GII.17, GII.20, and GII.21) were identified. Norovirus GII.2 and GII.17 co-dominated and the majority of GII.17 strains clustered with the novel Kawasaki 2014 variant. Sewage surveillance facilitated detection of Kawasaki 2014 in SA, which to date has not been detected with surveillance in children with gastroenteritis <5 years of age. Combined surveillance in the clinical setting and environment appears to be a valuable strategy to monitor emergence of NoV strains in countries that lack NoV outbreak surveillance. [ABSTRACT FROM AUTHOR]

The Flux Reconstruction (FR) approach to high-order methods is a flexible and robust framework that has proven to be a promising alternative to the traditional Discontinuous Galerkin (DG) schemes on parallel architectures like Graphical Processing Units (GPUs) since it pairs exceptionally well with explicit time-stepping methods. The FR formulation was originally proposed by Huynh (AIAA Pap 2007-4079:1–42, 2007). Vincent et al. (J Sci Comput 47(1):50–72, 2011) later developed a single parameter family of correction functions which provide energy stable schemes under this formulation in 1D. These schemes, known as Vincent–Castonguay–Jameson–Huynh (VCJH) schemes, offer control over properties like stability, dispersion and dissipation through the variation of the VCJH parameter. Classical schemes like nodal-DG and Spectral Difference (SD) can also be recovered under this formulation. Following the development of the FR approach in 1D, Castonguay et al. (J Sci Comput 51(1):224–256, 2012) and Williams et al. (J Comput Phys 250:53–76, 2013) and Williams and Jameson (J Sci Comput 59(3):721–759, 2014) developed correction functions that give rise to energy stable FR formulations for triangles and tetrahedra. For the case of tensor product elements like quadrilaterals and hexahedra however, a simple extension of the 1D FR approach utilizing the 1D VCJH correction functions was possible and has been adopted by several authors (Castonguay in High-order energy stable flux reconstruction schemes for fluid flow simulations on unstructured grids, 2012; Witherden et al. in Comput Fluids 120:173–186, 2015; Comput Phys Commun 185(11):3028–3040, 2014). But whether such an extension of the 1D approach to tensor product elements is stable remained an open question. A direct extension of the 1D stability analysis fails due to certain key difficulties which necessitate the formulation of a norm different from the one utilized for stability analysis in 1D and on simplex elements. We have recently overcome these issues and shown that the VCJH schemes are stable for the linear advection equation on Cartesian meshes for any non-negative value of the VCJH parameter (Sheshadri and Jameson in J Sci Comput 67(2):769–790, 2016; J Sci Comput 67(2):791–794, 2016). In this paper, we have extended the stability analysis to the advection–diffusion equation, demonstrating that the tensor product FR formulation is stable on Cartesian meshes for the advection–diffusion case as well. The analysis in this paper also provides additional insights into the dependence on the VCJH parameter of the diffusion and stability characteristics of these schemes. Several numerical experiments that support the theoretical results are included. [ABSTRACT FROM AUTHOR]

The genetic improvement of winemaking yeasts is a virtually infinite process, as the design of new strains must always cope with varied and ever-evolving production contexts. Good wine yeasts must feature both good primary traits, which are related to the overall fermentative fitness of the strain, and secondary traits, which provide accessory features augmenting its technological value. In this context, the superiority of “blind,” genetic improvement techniques, as those based on the direct selection of the desired phenotype without prior knowledge of the genotype, was widely proven. Blind techniques such as adaptive evolution strategies were implemented for the enhancement of many traits of interest in the winemaking field. However, these strategies usually focus on single traits: this possibly leads to genetic tradeoff phenomena, where the selection of enhanced secondary traits might lead to sub-optimal primary fermentation traits. To circumvent this phenomenon, we applied a multi-step and strongly directed genetic improvement strategy aimed at combining a strong fermentative aptitude (primary trait) with an enhanced production of glutathione (secondary trait). We exploited the random genetic recombination associated to a library of 69 monosporic clones of strain UMCC 855 (Saccharomyces cerevisiae) to search for new candidates possessing both traits. This was achieved by consecutively applying three directional selective criteria: molybdate resistance (1), fermentative aptitude (2), and glutathione production (3). The strategy brought to the selection of strain 21T2-D58, which produces a high concentration of glutathione, comparable to that of other glutathione high-producers, still with a much greater fermentative aptitude. [ABSTRACT FROM AUTHOR]

Bisphenol A, used in the production of plastic, is able to leach from containers into food and cause multidirectional adverse effects in living organisms, including neurodegeneration and metabolic disorders. Knowledge of the impact of BPA on enteric neurons is practically non-existent. The destination of this study was to investigate the influence of BPA at a specific dose (0.05 mg/kg body weight/day) and at a dose ten times higher (0.5 mg/kg body weight/day), given for 28 days, on the porcine ileum. The influence of BPA on enteric neuron immunoreactive to selected neuronal active substances, including substance P (SP), vasoactive intestinal polypeptide (VIP), galanin (GAL), vesicular acetylcholine transporter (VAChT--used here as a marker of cholinergic neurons), and cocaine- and amphetamine-regulated transcript peptide (CART), was studied by the double immunofluorescence method. Both doses of BPA affected the neurochemical characterization of the enteric neurons. The observed changes depended on the type of enteric plexus but were generally characterized by an increase in the number of cells immunoreactive to the particular substances. More visible fluctuations were observed after treatment with higher doses of BPA. The results confirm that even low doses of BPA may influence the neurochemical characterization of the enteric neurons and are not neutral for living organisms. [ABSTRACT FROM AUTHOR]

Background: Translocations of the IGH locus on 14q32.3 are present in about 8% of patients with chronic lymphocytic leukemia (CLL) and contribute to leukemogenesis by deregulating the expression of the IGH-partner genes. Identification of these genes and investigation of the downstream effects of their deregulation can reveal disease-causing mechanisms. Case presentation: We report on the molecular characterization of a novel t(12;14)(q23.2;q32.3) in CLL. As a consequence of the rearrangement ASCL1 was brought into proximity of the IGHJ-Cμ enhancer and was highly overexpressed in the aberrant B-cells of the patient, as shown by qPCR and immunohistochemistry. ASCL1 encodes for a transcription factor acting as a master regulator of neurogenesis, is overexpressed in neuroendocrine tumors and a promising therapeutic target in small cell lung cancer (SCLC). Its overexpression has also been recently reported in acute adult T-cell leukemia/lymphoma. To examine possible downstream effects of the ASCL1 upregulation in CLL, we compared the gene expression of sorted CD5+ cells of the translocation patient to that of CD19+ B-cells from seven healthy donors and detected 176 significantly deregulated genes (Fold Change ≥2, FDR p ≤ 0.01). Deregulation of 55 genes in our gene set was concordant with at least two studies comparing gene expression of normal and CLL B-lymphocytes. INSM1, a well-established ASCL1 target in the nervous system and SCLC, was the gene with the strongest upregulation (Fold Change = 209.4, FDR p = 1.37E-4). INSM1 encodes for a transcriptional repressor with extranuclear functions, implicated in neuroendocrine differentiation and overexpressed in the majority of neuroendocrine tumors. It was previously shown to be induced in CLL cells but not in normal B-cells upon treatment with IL-4 and to be overexpressed in CLL cells with unmutated versus mutated IGHV genes. Its role in CLL is still unexplored. Conclusion: We identified ASCL1 as a novel IGH-partner gene in CLL. The neural transcription factor was strongly overexpressed in the patient's CLL cells. Microarray gene expression analysis revealed the strong upregulation of INSM1, a prominent ASCL1 target, which was previously shown to be induced in CLL cells upon IL-4 treatment. We propose further investigation of the expression and potential role of INSM1 in CLL. [ABSTRACT FROM AUTHOR]

Vesivirus 2117 was first discovered as a contaminant in Chinese hamster ovary (CHO) cell cultures used for human drug production. Similar vesiviruses (VeVs) have been detected recently in dogs. In order to address the hypothesis that cats may also be exposed to 2117-like VeVs, in this study, we screened 236 feline sera using an enzyme-linked immunosorbent assay (ELISA) based on a recombinant VP1 protein from the canine VeV Bari/212/07/ITA. IgG antibodies against the 2117-like VeV were detected in 37.3% of the sera tested. Also, by screening cat faecal specimens, the RNA of a 2117-like VeV was detected in a clinically healthy cat. [ABSTRACT FROM AUTHOR]

Purpose: We describe our experience using a modified suture fistula technique for addressing tension in longer gap esophageal atresia (EA). Esophagoesophagopexy (EEP) is the tacking of the proximal and distal ends of esophageal pouches without formal anastomosis. In this retrospective cohort, we review the outcomes of patients with EA after EEP.Methods: We reviewed the operative reports of EA cases treated at our institution from 1997 to 2016 and identified all patients described as having EEP.Results: Of 129 EA cases, five patients underwent EEP. Formal anastomosis was not done due to patient's instability, prematurity, or long gap. Median birth weight was 1.4 kg (0.6-2.2 kg), and median gestational age at birth was 29 weeks (25-34 weeks). Age at time of EEP ranged 0-5 months. Esophagoesophageal fistula was confirmed in three patients. All three had strictures requiring weekly dilations. One of these patients died. The two surviving patients underwent fundoplication.Conclusion: We describe an alternative technique for esophageal anastomosis in patients for whom a standard anastomosis is not possible. EEP can lead to a functional anastomosis through fistulization and avoid the morbidity of multiple thoracotomies and lengthening procedures. Families should be educated on the potential need for dilations and antireflux procedures. [ABSTRACT FROM AUTHOR]

The direct flux reconstruction (DFR) scheme is a high-order numerical method which is an alternative realization of the flux reconstruction (FR) approach. In 1D, the DFR scheme has been shown to be equivalent to the FR variant of the nodal discontinuous Galerkin scheme. In this article, the DFR approach is extended to triangular elements for advection and advection-diffusion problems. This was accomplished by combining aspects of the SD-RT variant of the spectral difference (SD) scheme for triangles, with modifications motivated by characteristics of the DFR scheme in one dimension. Von Neumann analysis is applied to the new scheme and linear stability is found to be dependent on the location of internal collocation points. This is in contrast to the standard FR scheme. This analysis indicates certain internal point sets can result in schemes which exhibit weak stability; however, stable and accurate solutions to a number of linear and nonlinear benchmark problems are readily obtained. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a movement disorder characterized by dopaminergic nigrostriatal neuron degeneration and the formation of Lewy bodies (LB), pathological inclusions containing fibrils that are mainly composed of α-synuclein. Dopaminergic neurons, for their intrinsic characteristics, have a high energy demand that relies on the efficiency of the mitochondria respiratory chain. Dysregulations of mitochondria, deriving from alterations of complex I protein or oxidative DNA damage, change the trafficking, size and morphology of these organelles. Of note, these mitochondrial bioenergetics defects have been related to PD. A series of experimental evidence supports that α-synuclein physiological action is relevant for mitochondrial homeostasis, while its pathological aggregation can negatively impinge on mitochondrial function. It thus appears that imbalances in the equilibrium between the reciprocal modulatory action of mitochondria and α-synuclein can contribute to PD onset by inducing neuronal impairment. This review will try to highlight the role of physiological and pathological α-synuclein in the modulation of mitochondrial functions. [ABSTRACT FROM AUTHOR]

Genitalia are among the most studied phenotypes because they exhibit high anatomical diversity, experience fast evolutionary rates and may be shaped by several evolutionary mechanisms. A key element to uncover the mechanisms behind such impressive diversity is their copulatory function. This topic has been overlooked, especially concerning structures not directly involved in sperm transfer and reception. Here, we conduct a hypothesis-driven experimental study to elucidate the operation of various external genital parts in five species of stink bugs with differing levels of phylogenetic relatedness. These insects are unique because their male and female genitalia are externally well developed, rigid and composed of multiple components. In contrast with their anatomical complexity and diversity, we show that genital structures work jointly to perform a single function of mechanical stabilization during copula. However, distinct lineages have evolved alternative strategies to clasp different parts of the opposite sex. In spite of a high functional correspondence between male and female traits, the overall pattern of our data does not clearly support an intersexual coevolutionary scenario. We propose that the extraordinary male genital diversity in the family is probably a result of a process of natural selection enhancing morphological accommodation, but we consider alternative mechanisms. [ABSTRACT FROM AUTHOR]

The use of spanwise waviness in wings has been proposed in the literature as a possible mechanism for obtaining improved aerodynamic characteristics, motivated by the tubercles that cover the leading edge of the pectoral flippers of the humpback whale. We investigate the effect of this type of waviness on the incompressible flow around infinite wings with a NACA0012 profile, using direct numerical simulations employing the spectral/hp method. Simulations were performed for Reynolds numbers of Re = 10 000 and Re = 50 000, considering different angles of attack in both the pre-stall and post-stall regimes. The results show that the waviness can either increase or decrease the lift coefficient, depending on the particular Re and flow regime. We observe that the flow around the wavy wing exhibits a tendency to remain attached behind the waviness peak, with separation restricted to the troughs, which is consistent with results from the literature. Then, we identify three important physical mechanisms in this flow. The first mechanism is the weakening of the suction peak on the sections corresponding to the waviness peaks. This characteristic had been observed in a previous investigation for a very low Reynolds number of Re=1000, and we show that this is still important even at Re=50 000. As a second mechanism, the waviness has a significant effect on the stability of the separated shear layers, with transition occurring earlier for the wavy wing. In the pre-stall regime, for Re=10 000, the flow around the baseline wing is completely laminar, and the earlier transition leads to a large increase in the lift coefficient, while for Re = 50 000, the earlier transition leads to a shortening of the separation bubble which does not lead to an increased lift coefficient. The last mechanism corresponds to a sub-harmonic behaviour, with the flow being notably different between subsequent wavelengths. This allows the wing to maintain higher lift coefficients in some portions of the span. [ABSTRACT FROM AUTHOR]

Background: Thrombolysis is still used when primary angioplasty is delayed for a long time, but 25%-30% of patients require rescue angioplasty (RA). There are no established recommendations for antithrombotic management in RA. This registry analyzes regimens for antithrombotic management.Methods: A retrospective, multicenter, observational registry of consecutive patients treated with RA at 8 hospitals. All variables were collected and follow-up took place at 6 months.Results: The study included 417 patients. Antithrombotic therapy in RA was: no additional drugs 22.3%, unfractionated heparin (UFH) 36.6%, abciximab 15.5%, abciximab plus UFH 10.5%, bivalirudin 5.7%, enoxaparin 4.3%, and others 4.7%. Outcomes at 6 months were: mortality 9.1%, infarction 3.3%, definite or probable stent thrombosis 4.3%, revascularization 1.9%, and stroke 0.5%. Mortality was related to cardiogenic shock, age > 75 years, and anterior location. The stent thrombosis rate was highest with bivalirudin (12.5% at 6 months). The incidence of bleeding at admission was high (14.8%), but most cases were not severe (82% BARC ≤2). Variables independently associated with bleeding were: femoral access (OR 3.30; 95% CI 1.3-8.3: p = 0.004) and post-RA abciximab infusion (OR 2.26; 95% CI 1.02-5: p = 0.04).Conclusions: Antithrombotic treatment regimens in RA vary greatly, predominant strategies consisting of no additional drugs or UFH 70 U/kg. No regimen proved predictive of mortality, but bivalirudin was related to more stent thrombosis. There was a high incidence of bleeding, associated with post-RA abciximab infusion and femoral access. [ABSTRACT FROM AUTHOR]

Flow in a channel with corrugated walls has been studied, with the primary goal of establishing channel geometries that enhance achievable mixing at possibly low drag increase. The wall corrugation has the form of a sinusoidal wave oriented transversely, i.e., the lines of constant elevation (or phase) are parallel to the direction of the flow. The analysis is performed up to the Reynolds numbers resulting in the formation of secondary states. The first part of the analysis is focused on the properties of the two-dimensional, base flow. Mainly, the dependence of the drag on the channel's geometry is characterized. The second part of the analysis discusses the onset of the three-dimensional traveling wave instability. Linear stability is investigated by the Direct Numerical Simulation of the Navier-Stokes equations. Critical conditions for the onset of instabilities at a range of geometric parameters are determined. Finally, nonlinear saturation of the unstable modes and the resulting secondary flows is examined. It is shown that the drag reduction property of the base flow can be maintained in the state resulting from non-linear saturation of the disturbance. [ABSTRACT FROM AUTHOR]

Contour trees are extensively used in scalar field analysis. The contour tree is a data structure that tracks the evolution of level set topology in a scalar field. Scalar fields are typically available as samples at vertices of a mesh and are linearly interpolated within each cell of the mesh. A more suitable way of representing scalar fields, especially when a smoother function needs to be modeled, is via higher order interpolants. We propose an algorithm to compute the contour tree for such functions. The algorithm computes a local structure by connecting critical points using a numerically stable monotone path tracing procedure. Such structures are computed for each cell and are stitched together to obtain the contour tree of the function. The algorithm is scalable to higher degree interpolants whereas previous methods were restricted to quadratic or linear interpolants. The algorithm is intrinsically parallelizable and has potential applications to isosurface extraction. [ABSTRACT FROM AUTHOR]

Rationale: Administration of tuberculosis (TB) vaccines in participants with previous or current pulmonary TB may have the potential for causing harmful postvaccination immunologic (Koch-type) reactions.Objectives: To assess the safety and immunogenicity of three dose levels of the AERAS-402 live, replication-deficient adenovirus 35-vectored TB candidate vaccine, containing three mycobacterial antigens, in individuals with current or previous pulmonary TB.Methods: We performed a phase II randomized, placebo-controlled, double-blinded dose-escalation study in an HIV-negative adult South African cohort (n = 72) with active pulmonary TB (on treatment for 1-4 mo) or pulmonary TB treated at least 12 months before study entry and considered cured. Safety endpoints included clinical assessment, flow volume curves, diffusing capacity of the lung for carbon monoxide, pulse oximetry, chest radiograph, and high-resolution thoracic computerized tomography scans. Cytokine expression by CD4 and CD8 T cells, after stimulation with Ag85A, Ag85B, and TB10.4 peptide pools, was examined by intracellular cytokine staining.Measurements and Main Results: No apparent temporal or dose-related changes in clinical status (specifically acute, Koch phenomenon-like reactions), lung function, or radiology attributable to vaccine were observed. Injection site reactions were mild or moderate. Hematuria (by dipstick only) occurred in 25 (41%) of 61 AERAS-402 recipients and 3 (27%) of 11 placebo recipients, although no gross hematuria was reported. AERAS-402 induced robust CD8+ and moderate CD4+ T-cell responses, mainly to Ag85B in both vaccine groups.Conclusions: Administration of the AERAS-402 candidate TB vaccine to participants with current or previous pulmonary TB induced a robust immune response and is not associated with clinically significant pulmonary complications. Clinical trial registered with www.clinicaltrials.gov (NCT 02414828) and in the South African National Clinical Trials Register ( www.sanctr.gov.za DOH 27-0808-2060). [ABSTRACT FROM AUTHOR]

We consider a smooth, spanwise-uniform forward-facing step defined by a Gauss error function of height 4%-30% and four times the width of the local boundary layer thickness δ99. The boundary layer flow over a smooth forward-facing stepped plate is studied with particular emphasis on stabilisation and destabilisation of the twodimensional Tollmien-Schlichting (TS) waves and subsequently on three-dimensional disturbances at transition. The interaction between TS waves at a range of frequencies and a base flow over a single or two forward-facing smooth steps is conducted by linear analysis. The results indicate that for a TS wave with a frequency F ε[140,160] (F=wv/U²∏ × 106, where w and U²∏ denote the perturbation angle frequency and free-stream velocity magnitude, respectively, and denotes kinematic viscosity), the amplitude of the TS wave is attenuated in the unstable regime of the neutral stability curve corresponding to a flat plate boundary layer. Furthermore, it is observed that two smooth forward-facing steps lead to a more acute reduction of the amplitude of the TS wave. When the height of a step is increased to more than 20% of the local boundary layer thickness for a fixed width parameter, the TS wave is amplified, and thereby a destabilisation effect is introduced. Therefore, the stabilisation or destabilisation effect of a smooth step is typically dependent on its shape parameters. To validate the results of the linear stability analysis, where a TS wave is damped by the forward-facing smooth steps direct numerical simulation (DNS) is performed. The results of the DNS correlate favourably with the linear analysis and show that for the investigated frequency of the TS wave, the K-type transition process is altered whereas the onset of the H-type transition is delayed. The results of the DNS suggest that for the perturbation with the non-dimensional frequency parameter F D 150 and in the absence of other external perturbations, two forward-facing smooth steps of height 5% and 12% of the boundary layer thickness delayed the H-type transition scenario and completely suppressed for the K-type transition. By considering Gaussian white noise with both fixed and random phase shifts, it is demonstrated by DNS that transition is postponed in time and space by two forward-facing smooth steps. [ABSTRACT FROM AUTHOR]

Nowadays, there is an increase in the application of natural products for the prevention of different disorders or adjuvant substances next to pharmacological treatment. Phytochemicals include different chromone derivatives, which possess a wide spectrum of biological activity. The aim of the present study was the investigation of the antioxidant activity, cytotoxicity and oxidative transformation of nine chromone derivatives. First we investigated the radical scavenging activity (ABTS), the oxygen radical absorption capacity (ORAC) and the ferric reducing antioxidant power (FRAP) of the investigated molecules. The cytotoxic effects of the compounds were tested on H9c2 cell cultures by the MTT assay. Each compound showed a significant ORAC value compared to the reference. However, the compound 865 possess significantly higher FRAP and ABTS activity in comparison with the reference and other tested molecules, respectively. Based on these assays, the compound 865 was selected for further analysis. In these experiments, we investigated the oxidative metabolism of the compound in vitro. The molecule was oxidized by the Fenton reaction, artificial porphyrin and electrochemistry; then, the formed products were identified by mass spectrometry. Four possible metabolites were detected. The results revealed the compound 865 to possess good antioxidant properties and to be stable metabolically; hence, it is worth investigating its effects in vivo. [ABSTRACT FROM AUTHOR]

Wake of two side-by-side square cylinders was investigated through direct numerical simulation at low Reynolds numbers (16-200). The gap between the two cylinders varied from 0 to 10D, where D is the dimension of the square cylinder (edge length). 9 different wake patterns and their dependency on both the Reynolds number and gap spacing were identified and analysed. A system classification map, demarcated by the Reynolds number and gap ratio g* (g/D, where g is the gap spacing between 2 cylinders), was derived for these 9 wake modes. Steady-state wake (mode I) was observed when the Reynolds number is lower than the critical Reynolds number, which depends on g*. For the gap ratio less than 0.7, only single vortex street was observed. The single vortex street wake can be either symmetric and periodic (mode II), or asymmetric and periodic (mode III), or irregular (mode IV). In this gap ratio range (less than 0.7), shedding frequency decreases with the gap ratio due to the damping role of the gap flow. For the gap ratio larger than 0.7, two vortex streets were also observed. For the gap ratio larger than 1, only two vortex streets were observed. Vortex shedding can be either synchronized and in-phase (mode V), synchronized and anti-phase (mode VI), in-phase dominated with low frequency modulation (mode VII), anti-phase dominated with low frequency modulation (mode VIII), asymmetric synchronized anti-phase (mode IX), or irregular (mode IV). For the gap ratio larger than 4, only synchronized anti-phase mode was observed under the conditions of this study. In the two vortex streets regime, shedding frequency is higher than that of a single cylinder, due to a stronger gap flow than that in the freestream side. The impact of gap ratio and Reynolds number on the drag and lift forces was also studied. [ABSTRACT FROM AUTHOR]

Lessonia spicata is a key dominant species along the Pacific coast of South America, providing a habitat for many organisms. However, this role can be affected by abiotic stress, such as metals. To counteract the toxic effect, L. spicata, among other seaweeds, releases exudates that bind metals. In this study, tolerances to copper of organisms related to the kelp forest (spores of Ulva lactuca (Chlorophyceae) and L. spicata (Phaeophyceae) and Zoea I of Taliepus dentatus (Milne-Edwards, Crustacea)) were studied; then, exudates are assessed by their protective effect. Exudates increase the 48-h 50% effective concentration (EC) of the germination of spores from 8 to 23 μg Cu L for U. lactuca and from 119 to 213 μg Cu L for L. spicata and the survival of the larvae Zoea I 48-h 50% of lethal concentration (LC) from 144 to 249 μg Cu L. Results indicated that exudates had a protective effect. Each species is specifically sensitive to copper. Crab larvae Zoea I were able to support higher doses, and exposure before hatching increased their tolerance. [ABSTRACT FROM AUTHOR]

Irreversible neuron loss caused by central nervous system injuries usually leads to persistent neurological dysfunction. Reactive astrocytes, because of their high proliferative capacity, proximity to neuronal lineage, and significant involvement in glial scarring, are ideal starting cells for neuronal regeneration. Having previously identified several small molecules as important regulators of astrocyte-to-neuron reprogramming, we established herein that miR-124, ruxolitinib, SB203580, and forskolin could co-regulate rat cortical reactive astrocyte-to-neuron conversion. The induced cells had reduced astroglial properties, displayed typical neuronal morphologies, and expressed neuronal markers, reflecting 25.9% of cholinergic neurons and 22.3% of glutamatergic neurons. Gene analysis revealed that induced neuron gene expression patterns were more similar to that of primary neurons than of initial reactive astrocytes. On the molecular level, miR-124-driven neuronal differentiation of reactive astrocytes was via targeting of the SOX9-NFIA-HES1 axis to inhibit HES1 expression. In conclusion, we present a novel approach to inducing endogenous rat cortical reactive astrocytes into neurons through co-regulation involving miR-124 and three small molecules. Thus, our research has potential implications for inhibiting glial scar formation and promoting neuronal regeneration after central nervous system injury or disease.

Many repetitive sequences in the human genome can adopt conformations that differ from the canonical B-DNA double helix (i.e., non-B DNA), and can impact important biological processes such as DNA replication, transcription, recombination, telomere maintenance, viral integration, transposome activation, DNA damage and repair. Thus, non-B DNA-forming sequences have been implicated in genetic instability and disease development. In this article, we discuss the interactions of non-B DNA with the replication and/or transcription machinery, particularly in disease states (e.g., tumors) that can lead to an abnormal cellular environment, and how such interactions may alter DNA replication and transcription, leading to potential conflicts at non-B DNA regions, and eventually result in genetic stability and human disease. [ABSTRACT FROM AUTHOR]

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An analysis of flows in converging-diverging channels has been carried out with the primary goal of identifying geometries which result in increased mixing. The model geometry consists of a channel whose walls are fitted with spanwise grooves of moderate amplitudes (up to 10% of the mean channel opening) and of sinusoidal shape. The groove systems on each wall are shifted by half of a wavelength with respect to each other, resulting in the formation of a converging-diverging conduit. The analysis is carried out up to Reynolds numbers resulting in the formation of secondary states. The first part of the analysis is based on a two-dimensional model and demonstrates that increasing the corrugation wavelength results in the appearance of an unsteady separation whose onset correlates with the onset of the travelling wave instability. The second part of the analysis is based on a three-dimensional model and demonstrates that the flow dynamics is dominated by the centrifugal instability over a large range of geometric parameters, resulting in the formation of streamwise vortices. It is shown that the onset of the vortices may lead to the elimination of the unsteady separation. The critical Reynolds number for the vortex onset initially decreases as the corrugation amplitude increases but an excessive increase leads to the stream lift up, reduction of the centrifugal forces and flow stabilization. The flow dynamics under such conditions is again dominated by the travelling wave instability. Conditions leading to the formation of streamwise vortices without interference from the travelling wave instability have been identified. The structure and the mixing properties of the saturated states are discussed. [ABSTRACT FROM AUTHOR]

Pituitary adenylate cyclase activating polypeptide (PACAP) belongs to the vasoactive intestinal peptide-secretin-glucagon peptide family, isolated first from ovine hypothalamus. The diverse physiological effects of PACAP are known mainly from animal experiments, including several actions in endocrine glands. Alteration of PACAP expression has been shown in several tumors, but changes in expression of PACAP and its specific PAC1 receptor in human thyroid gland pathologies have not yet been investigated. Therefore, the aim of the present study was to investigate expression of PACAP and its PAC1 receptor in human thyroid papillary carcinoma, the most common endocrine malignant tumor. PACAP and PAC1 receptor expressions were investigated from thyroid gland samples of patients with papillary carcinomas. The staining intensity of follicular epithelial cells and thyroid colloid of tumor tissue was compared to that of tumor-free tissue in the same thyroid glands in a semi-quantitative way. Our results reveal that both PACAP(-like) and PAC1 receptor(-like) immunoreactivities are altered in papillary carcinoma. Stronger PACAP immunoreactivity was observed in active follicles. Colloidal PACAP immunostaining was either lacking or very weak, and more tumorous cells displayed strong apical immunoreactivity. Regarding PAC1 receptor, cells of the normal thyroid tissue showed strong granular expression, which was lacking in the tumor cells. The cytoplasm of tumor cells displayed weak, minimal staining, while in a few tumor cells we observed strong PAC1 receptor expression. This pattern was similar to that observed in the PACAP expression, but fewer in number. In summary, we showed alteration of PACAP and PAC1 receptor expression in human thyroid papillary carcinoma, indicating that PACAP regulation is disturbed in tumorous tissue of the thyroid gland. The exact role of PACAP in thyroid tumor growth should be further explored. [ABSTRACT FROM AUTHOR]

Sequences that can adopt alternative DNA structures (i.e., non-B DNA) are very abundant in mammalian genomes, and recent studies have revealed many important biological functions of non-B DNA structures in chromatin remodeling, DNA replication, transcription, and genetic instability. Here, we provide results from an in silico webbased search engine coupled with cell-based experiments to characterize the roles of non-B DNA conformations in genetic instability in eukaryotes. The purpose of this article is to illustrate strategies that can be used to identify and interrogate the biological roles of non-B DNA structures, particularly on genetic instability. We have included unpublished data using a short H-DNA-forming sequence from the human c-MYC promoter region as an example, and identified two different mechanisms of H-DNAinduced genetic instability in yeast and mammalian cells: a DNA replication-related model of mutagenesis; and a replication-independent cleavage model. Further, we identified candidate proteins involved in H-DNA-induced genetic instability by using a yeast genetic screen. A combination of in silico and cellular methods, as described here, should provide further insight into the contributions of non-B DNA structures in biological functions, genetic evolution, and disease development. [ABSTRACT FROM AUTHOR]

The immunopathology of chronic obstructive pulmonary disease (COPD) is based on the innate and adaptive inflammatory immune responses to the chronic inhalation of cigarette smoking. In the last quarter of the century, the analysis of specimens obtained from the lower airways of COPD patients compared with those from a control group of age-matched smokers with normal lung function has provided novel insights on the potential pathogenetic role of the different cells of the innate and acquired immune responses and their pro/anti-inflammatory mediators and intracellular signalling pathways, contributing to a better knowledge of the immunopathology of COPD both during its stable phase and during its exacerbations. This also has provided a scientific rationale for new drugs discovery and targeting to the lower airways. This review summarises and discusses the immunopathology of COPD patients, of different severity, compared with control smokers with normal lung function. [ABSTRACT FROM AUTHOR]

Helicobacter pylori infection is acquired mainly during childhood and causes various diseases such as gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphoma, and iron deficiency anemia. Although H. pylori infection in children differs from adults in many ways, this is often overlooked in clinical practice. Unlike adults, nodular gastritis may be a pathognomonic endoscopic finding of childhood H. pylori infection. Histopathological findings of gastric tissues are also different in children due to predominance of lymphocytes and plasma cells and the formation of gastric MALT. Although endoscopy is recommended for the initial diagnosis of H. pylori infection, several non-invasive diagnostic tests such as the urea breath test (UBT) and the H. pylori stool antigen test (HpSA) are available and well validated even in children. According to recent data, both the 13C-UBT and HpSA using enzyme-linked immunosorbent assay are reliable non-invasive tests to determine H. pylori status after eradication therapy, although children younger than 6 years are known to have high false positives. When invasive or noninvasive tests are applied to children to detect H. pylori infection, it should be noted that there are differences between children and adults in diagnosing H. pylori infection. [ABSTRACT FROM AUTHOR]