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This study is aimed at evaluating antibody responses, viral loads, viral clearance and growth rate of Tanzanian free-range local chicken (FRLC) challenged with LaSota strain of Newcastle disease virus (NDV) as indicator traits for selection of chickens for breeding with enhanced resistance to the disease and economic value. Three popular free-range local chicken ecotypes: Kuchi, Ching’wekwe and Morogoro-medium from three ecological zones of Tanzania were used for the experiments. Progenies from the breeder chickens were challenged with 107 titer of 50% egg infectious dose (EID50) of the virus at 28 days of age. The viral loads and viral clearance rates evaluated by qRT-PCR from tear samples collected at 2- and 6-days post infection (dpi) showed that Kuchi could clear NDV better than Morogoro-medium and Ching’wekwe. Anti-NDV antibody levels determined from blood samples collected at 10 dpi using ELISA showed that Kuchi ecotype expressed higher mean anti-NDV antibodies compared to Morogoro-medium and Ching’wekwe. Growth rates determined from body weights collected for 38 days from day of hatch (D0) to 10 dpi showed higher growth rate for Kuchi than Morogoro-medium and Ching’wekwe chickens. Kuchi chickens were potentially more resistant to ND compared to Morogoro-medium and Ching’wekwe. Key words: Free-range local chickens, Newcastle disease, immune response, innate resistance.

Patients with Wiskott–Aldrich syndrome (WAS) lacking a human leukocyte antigen-matched donor may benefit from gene therapy through the provision of gene-corrected, autologous hematopoietic stem/progenitor cells. Here, we present comprehensive, long-term follow-up results (median follow-up, 7.6 years) (phase I/II trial no. NCT02333760) for eight patients with WAS having undergone phase I/II lentiviral vector-based gene therapy trials (nos. NCT01347346 and NCT01347242), with a focus on thrombocytopenia and autoimmunity. Primary outcomes of the long-term study were to establish clinical and biological safety, efficacy and tolerability by evaluating the incidence and type of serious adverse events and clinical status and biological parameters including lentiviral genomic integration sites in different cell subpopulations from 3 years to 15 years after gene therapy. Secondary outcomes included monitoring the need for additional treatment and T cell repertoire diversity. An interim analysis shows that the study meets the primary outcome criteria tested given that the gene-corrected cells engrafted stably, and no serious treatment-associated adverse events occurred. Overall, severe infections and eczema resolved. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. The results suggest that lentiviral gene therapy provides sustained clinical benefits for patients with WAS., Long-term monitoring of patients with Wiskott–Aldrich syndrome following lentiviral gene therapy shows a safe profile and a reduction in the frequency of autoimmune manifestations and bleeding events, despite incomplete platelet reconstitution.

The binding of both ethidium bromide (EtBr) and Hoechst 33258 (H33258) to calf thymus DNA differing by the mechanism at different ionic strengths of NaCl water solutions (2, 20 and 150[Formula: see text]mM) has been quantitatively studied by square wave voltammetry (SWV). It was revealed that EtBr binds to DNA by more than one mode: at the solution ionic strengths 2 and 150[Formula: see text]mM, two modes were revealed, at 20[Formula: see text]mM — three modes. Values of EtBr binding constant ([Formula: see text]) to DNA and the number of nucleotides per one binding site ([Formula: see text]) for respective binding modes were determined. For H33258 under the same conditions, two binding modes were found and for both these modes values of [Formula: see text] and [Formula: see text] were determined. Dependence of the binding types and parameters on the solution ionic strength by SWV method was revealed, which differs by the binding type of EtBr and H33258. The obtained data are in good accordance with the ones determined by spectroscopic (absorption and fluorescence) and differential pulse voltammetry (DPV) methods. The obtained data indicate the sensibility and high precision of SWV method which may be applied to studies on interaction of different ligands with DNA, which reveal some peculiarities of their binding to DNA that are hidden and are not found by other methods.

A Newcastle disease virus was isolated from a chicken from a live bird market in the Mbeya region of Tanzania. Complete genome characterization of the isolate identified it as a member of subgenotype Vd. This is the first complete genome sequence of this subgenotype.

Newcastle Disease (ND) is a continuing global threat to domestic poultry, especially in developing countries, where severe outbreaks of velogenic ND virus (NDV) often cause major economic losses to households. Local chickens are of great importance to rural family livelihoods through provision of high-quality protein. To investigate the genetic basis of host response to NDV, three popular Tanzanian chicken ecotypes (regional populations) were challenged with a lentogenic (vaccine) strain of NDV at 28 days of age. Various host response phenotypes, including anti-NDV antibody levels (pre-infection and 10 days post-infection, dpi), and viral load (2 and 6 dpi) were measured, in addition to growth rate. We estimated genetic parameters and conducted genome-wide association study analyses by genotyping 1399 chickens using the Affymetrix 600K chicken SNP chip. Estimates of heritability of the evaluated traits were moderate (0.18&ndash, 0.35). Five quantitative trait loci (QTL) associated with growth and/or response to NDV were identified by single-SNP analyses, with some regions explaining &ge, 1% of genetic variance based on the Bayes-B method. Immune related genes, such as ETS1, TIRAP, and KIRREL3, were located in regions associated with viral load at 6 dpi. The moderate estimates of heritability and identified QTL indicate that NDV response traits may be improved through selective breeding of chickens to enhance increased NDV resistance and vaccine efficacy in Tanzanian local ecotypes.

Chickens in live bird markets (LBMs) from six different regions of Tanzania were surveyed for Newcastle disease (ND) virus (NDV) and avian influenza virus in 2012. ELISA-based serology, virus isolation, and characterization, including pathotyping was conducted. Virulent NDV was isolated from almost 10% of the tested samples, with two distinct genotypes being detected. One genotype was similar to recent viruses circulating in Kenya and Uganda, which share a northern border with Tanzania. Several viruses of this genotype were also isolated from Tanzania in 1995, the last time surveillance for NDV was conducted in the country. The second genotype of virus from Tanzania was closely related to viruses from Mozambique, a southern neighbor, and more distantly to viruses from South Africa, Botswana, and several European countries. Partial fusion gene sequence from the isolated viruses showed identical fusion cleavage sites that were compatible with virulent viruses. Selected viruses were tested by the intracerebral pathogenicity index, and all viruses tested had scores of1.78, indicating highly virulent viruses. Serology showed only a third of the chickens had detectable antibody to NDV, suggesting that vaccination is not being commonly used in the country, despite the availability of vaccines in agricultural-related markets. All samples were taken from clinically healthy birds, and it is believed that the birds were sold or slaughtered before showing ND clinical signs. LBMs remain a biosecurity risk for farmers through the return of live infected birds to the farm or village or the movement of virus on fomites, such as uncleaned wooden cages.Aislamiento y caracterización de virus de la enfermedad de Newcastle de mercados de aves vivas en Tanzania. Se llevó a cabo un muestreo de pollos en mercados de aves vivas (LBM) de seis regiones diferentes de Tanzania para detectar al virus de la enfermedad de Newcastle (NDV) y el virus de la influenza aviar en el año 2012. Se llevaron a cabo la serología basada en la prueba de ELISA, el aislamiento viral y la caracterización, incluyendo la determinación del patotipo. Formas virulentas del virus de Newcastle se aislaron de casi el 10% de las muestras analizadas y se detectaron dos genotipos distintos. Un genotipo era similar a los virus recientes que circulan en Kenia y Uganda, países que comparten una frontera al norte de Tanzania. Varios virus de este genotipo también se aislaron de Tanzania en el año 1995, la última vez que se realizó la vigilancia del virus de Newcastle en el país. El segundo genotipo de virus de Tanzania estaba estrechamente relacionado con virus de Mozambique, país vecino al sur, y más distantemente con virus de Sudáfrica, Botswana y de varios países europeos. Una secuencia parcial del gene de fusión de los virus aislados mostró sitios de disociación en la proteína de fusión idénticos que eran compatibles con los virus virulentos. Los virus seleccionados fueron analizados mediante el índice de patogenicidad intracerebral y todos los virus analizados tuvieron puntajes mayores de 1.78, lo que indica que son virus altamente virulentos. La serología mostró que solo un tercio de los pollos tenían anticuerpos detectables contra el virus de Newcastle, lo que sugiere que la vacunación no se usa comúnmente en el país, a pesar de la disponibilidad de vacunas en los mercados agrícolas. Todas las muestras fueron recolectadas de aves clínicamente sanas y se cree que las aves fueron vendidas o sacrificadas antes de mostrar signos clínicos de la enfermedad de Newcastle. Los mercados de aves vivas siguen siendo un riesgo de bioseguridad para los agricultores mediante el regreso de aves vivas infectadas a la granja o a los pueblos o por el movimiento de virus en fómites, como las jaulas de madera sin limpiar.

Newcastle disease (ND) is one of the most challenging infectious diseases affecting poultry production in Africa, causing major economic losses. To date, Newcastle disease virus isolates from several African countries have been grouped into class II NDV genotypes I, IV, V, VI, VII, XI, XIII, XIV, XVII, XVIII and XXI. Although ND is endemic in many African countries, information on circulating genotypes is still scarce. In Tanzania, outbreaks with genotypes V and XIII have been reported. In West and Central Africa, genotypes XIV, XVII, and XVIII are the most predominant. To investigate other genotypes circulating in Tanzania and Ghana, we performed molecular genotyping on isolates from Tanzania and Ghana using the MinION, a third-generation portable sequencing device from Oxford Nanopore Technologies. Using the MinION, we successfully sequenced the NDV F gene hypervariable region of 24 isolates from Tanzania and four samples from Ghana. In Tanzania, genotypes V, VII and XIII were detected. All isolates from Ghana belonged to genotype XVIII. The data obtained in this study reflect the genetic diversity of NDV in Africa and highlight the importance of surveillance for monitoring the distribution of NDV genotypes and viral evolution.

© 2016 American Chemical Society.This chapter describes Generative Topographic Mapping (GTM) -A dimensionality reduction method which can be used both to data visualization, clustering and modeling. GTM is a probabilistic extension of Kohonen maps. Its probabilistic nature can be exploited in order to build regression or classification models, to define their applicability domain, to predict activity profiles of compounds, to compare large datasets, to screen for compounds of interest, and even to identify new molecules possessing desirable properties. Thus, GTM can be seen as a sort of a multi-purpose Swiss knife, each of its blades being able to shape an answer to a specific chemoinformatics question, based on a unique map.

© 2016 American Chemical Society.This chapter describes Generative Topographic Mapping (GTM) -A dimensionality reduction method which can be used both to data visualization, clustering and modeling. GTM is a probabilistic extension of Kohonen maps. Its probabilistic nature can be exploited in order to build regression or classification models, to define their applicability domain, to predict activity profiles of compounds, to compare large datasets, to screen for compounds of interest, and even to identify new molecules possessing desirable properties. Thus, GTM can be seen as a sort of a multi-purpose Swiss knife, each of its blades being able to shape an answer to a specific chemoinformatics question, based on a unique map.

© 2016 American Chemical Society.In this chapter, we review some concepts and techniques used to visualize chemical compounds represented as objects in a multidimensional descriptor space. Several modern dimensionality reduction techniques are compared with respect to their ability to visualize the data in 2D space, using as example a dataset of acetylcholinesterase inhibitors and their decoys.

© 2016 American Chemical Society.In this chapter, we review some concepts and techniques used to visualize chemical compounds represented as objects in a multidimensional descriptor space. Several modern dimensionality reduction techniques are compared with respect to their ability to visualize the data in 2D space, using as example a dataset of acetylcholinesterase inhibitors and their decoys.

© 2014 American Chemical Society. This paper is devoted to the analysis and visualization in 2-dimensional space of large data sets of millions of compounds using the incremental version of generative topographic mapping (iGTM). The iGTM algorithm implemented in the in-house ISIDA-GTM program was applied to a database of more than 2 million compounds combining data sets of 36 chemicals suppliers and the NCI collection, encoded either by MOE descriptors or by MACCS keys. Taking advantage of the probabilistic nature of GTM, several approaches to data analysis were proposed. The chemical space coverage was evaluated using the normalized Shannon entropy. Different views of the data (property landscapes) were obtained by mapping various physical and chemical properties (molecular weight, aqueous solubility, LogP, etc.) onto the iGTM map. The superposition of these views helped to identify the regions in the chemical space populated by compounds with desirable physicochemical profiles and the suppliers providing them. The data sets similarity in the latent space was assessed by applying several metrics (Euclidean distance, Tanimoto and Bhattacharyya coefficients) to data probability distributions based on cumulated responsibility vectors. As a complementary approach, data sets were compared by considering them as individual objects on a meta-GTM map, built on cumulated responsibility vectors or property landscapes produced with iGTM. We believe that the iGTM methodology described in this article represents a fast and reliable way to analyze and visualize large chemical databases.

© 2015 American Chemical Society. Predicting the activity profile of a molecule or discovering structures possessing a specific activity profile are two important goals in chemoinformatics, which could be achieved by bridging activity and molecular descriptor spaces. In this paper, we introduce the "Stargate"version of the Generative Topographic Mapping approach (S-GTM) in which two different multidimensional spaces (e.g., structural descriptor space and activity space) are linked through a common 2D latent space. In the S-GTM algorithm, the manifolds are trained simultaneously in two initial spaces using the probabilities in the 2D latent space calculated as a weighted geometric mean of probability distributions in both spaces. S-GTM has the following interesting features: (1) activities are involved during the training procedure; therefore, the method is supervised, unlike conventional GTM; (2) using molecular descriptors of a given compound as input, the model predicts a whole activity profile, and (3) using an activity profile as input, areas populated by relevant chemical structures can be detected. To assess the performance of S-GTM prediction models, a descriptor space (ISIDA descriptors) of a set of 1325 GPCR ligands was related to a B-dimensional (B = 1 or 8) activity space corresponding to pKi values for eight different targets. S-GTM outperforms conventional GTM for individual activities and performs similarly to the Lasso multitask learning algorithm, although it is still slightly less accurate than the Random Forest method.

© 2015 Springer International Publishing Switzerland. Intuitive, visual rendering - mapping - of high-dimensional chemical spaces (CS), is an important topic in chemoinformatics. Such maps were so far dedicated to specific compound collections - either limited series of known activities, or large, even exhaustive enumerations of molecules, but without associated property data. Typically, they were challenged to answer some classification problem with respect to those same molecules, admired for their aesthetical virtues and then forgotten - because they were set-specific constructs. This work wishes to address the question whether a general, compound set-independent map can be generated, and the claim of "universality" quantitatively justified, with respect to all the structure-activity information available so far - or, more realistically, an exploitable but significant fraction thereof. The "universal" CS map is expected to project molecules from the initial CS into a lower-dimensional space that is neighborhood behavior-compliant with respect to a large panel of ligand properties. Such map should be able to discriminate actives from inactives, or even support quantitative neighborhood-based, parameter-free property prediction (regression) models, for a wide panel of targets and target families. It should be polypharmacologically competent, without requiring any target-specific parameter fitting. This work describes an evolutionary growth procedure of such maps, based on generative topographic mapping, followed by the validation of their polypharmacological competence. Validation was achieved with respect to a maximum of exploitable structure-activity information, covering all of Homo sapiens proteins of the ChEMBL database, antiparasitic and antiviral data, etc. Five evolved maps satisfactorily solved hundreds of activity-based ligand classification challenges for targets, and even in vivo properties independent from training data. They also stood chemogenomics-related challenges, as cumulated responsibility vectors obtained by mapping of target-specific ligand collections were shown to represent validated target descriptors, complying with currently accepted target classification in biology. Therefore, they represent, in our opinion, a robust and well documented answer to the key question "What is a good CS map?

The origins of irregular satellites of the giant planets are an important piece of the giant "puzzle" that is the theory of Solar System formation. It is well established that they are not "in situ" formation objects, around the planet, as are believed to be the regular ones. Then, the most plausible hypothesis to explain their origins is that they formed elsewhere and were captured by the planet. However, captures under restricted three-body problem dynamics have temporary feature, which makes necessary the action of an auxiliary capture mechanism. Nevertheless, there not exist one well established capture mechanism. In this work, we tried to understand which aspects of a binary-asteroid capture mechanism could favor the permanent capture of one member of a binary asteroid. We performed more than eight thousand numerical simulations of capture trajectories considering the four-body dynamical system Sun, Jupiter, Binary-asteroid. We restricted the problem to the circular planar prograde case, and time of integration to 10^4 years. With respect to the binary features, we noted that 1) tighter binaries are much more susceptible to produce permanent captures than the large separation-ones. We also found that 2) the permanent capture probability of the minor member of the binary is much more expressive than the major body permanent capture probability. On the other hand, among the aspects of capture-disruption process, 4) a pseudo eastern-quadrature was noted to be a very likely capture angular configuration at the instant of binary disruptions. In addition, we also found that the 5) capture probability is higher for binary asteroids which disrupt in an inferior-conjunction with Jupiter. These results show that the Sun plays a very important role on the capture dynamic of binary asteroids., Comment: 12 pages, 11 figures

The optimal approach for stem cell transplantation in children with immunodeficiency has yet to be determined. Conditioning therapy is necessary for reliable engraftment and full immune reconstitution; however, the beneficial effect of cytoreductive conditioning is counterbalanced by increased short- and long-term treatment-related toxicity. Whether bone marrow transplantation with a nonmyeloablative preparative regimen was sufficient for the establishment of donor immune reconstitution, with the resultant correction of disease phenotype, was investigated. Eight patients with severe immunodeficiency states underwent T-cell replete bone marrow transplantation from a human leukocyte antigen-matched unrelated (n = 6) or sibling (n = 2) donor with nonmyeloablative conditioning using a fludarabine–melphalan–anti-lymphocyte globulin-based regimen. All patients had severe organ dysfunction that precluded transplantation with conventional conditioning. All patients were engrafted with predominantly donor hematopoiesis, and the duration of neutropenia was brief. Significant acute graft-versus-host disease (GVHD) did not develop, but one patient had limited chronic GVHD. One patient died of disease recurrence, and 3 have stable, mixed chimerism. At a median follow-up of 1 year, all patients have had good recovery of CD3+ T-cell numbers, and 6 of 7 evaluable patients have normal phytohemagglutinin stimulation indices. The rate of immune reconstitution is comparable with that of historical controls undergoing standard myeloablative protocols. Two patients with CD40 ligand deficiency now show significant expression, and a patient with adenosine deaminase deficiency has improved deoxy adenosine triphosphate metabolites. In summary, it has been demonstrated that nonmyeloablative stem cell transplantation permits rapid engraftment from both sibling and unrelated donors with minimal toxicity even in the presence of severe organ dysfunction. If long-term immune reconstitution of patients treated with this protocol is demonstrated, it is believed this approach might offer significant advantages compared with standard protocols by combining adequate immune reconstitution with reduced short- and long-term toxicity.

The findings of the 1996 Cardiac Catheterization Laboratory Survey of the Sociedad Mexicana de Cardiología are presented. There are 52 cardiac catheterization laboratory departments distributed in 16 cities of which Mexico City has 20, Guadalajara 6 and Monterrey 5. Ninety-six percent are in hospitals where heart surgery can be performed and 8 (17%) have a training program in cardiac catheterization. Only two (3.8%) are exclusively dedicated to pediatric cardiac catheterization. In 1995, 19,214 diagnostic procedures and 2,429 PTCAs were done. A total of 270 physicians were reported to have privileges to perform cardiac catheterization. The geographical distribution of the cath labs, procedure volumes and number of physicians performing catheterization are discussed.

Inherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunodeficiency (SCID) known as severe combined immune deficiency caused by adenosine deaminase defects (ADA-SCID). Most affected infants can receive a diagnosis while still asymptomatic by using an SCID newborn screening test, allowing early initiation of therapy. We review the evidence currently available and propose a consensus management strategy. In addition to treatment of the immune deficiency seen in patients with ADA-SCID, patients should be followed for specific noninfectious respiratory, neurological, and biochemical complications associated with ADA deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of 2 equal first-line options. If an HLA-matched sibling donor or HLA-matched family donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) should be pursued. The excellent safety and efficacy observed in more than 100 patients with ADA-SCID who received gammaretrovirus- or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If HLA-matched sibling donor/HLA-matched family donor HSCT or HSC-GT are not available or have failed, ERT can be continued or reinstituted, and HSCT with alternative donors should be considered. The outcomes of novel HSCT, ERT, and HSC-GT strategies should be evaluated prospectively in "real-life" conditions to further inform these management guidelines.