Primate adult brain cell autotransplantation produces behavioral and biological recovery in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian St. Kitts monkeys.

The potential for "replacement cells" to restore function in Parkinson's disease has been widely reported over the past 3 decades, rejuvenating the central nervous system rather than just relieving symptoms. Most such experiments have used fetal or embryonic sources that may induce immunological rejection and generate ethical concerns. Autologous sources, in which the cells to be implanted are derived from recipients' own cells after reprogramming to stem cells, direct genetic modifications, or epigenetic modifications in culture, could eliminate many of these problems. In a previous study on autologous brain cell transplantation, we demonstrated that adult monkey brain cells, obtained from cortical biopsies and kept in culture for 7 weeks, exhibited potential as a method of brain repair after low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused dopaminergic cell death. The present study exposed monkeys to higher MPTP doses to produce significant parkinsonism and behavioral impairments. Cerebral cortical cells were biopsied from the animals, held in culture for 7 weeks to create an autologous neural cell "ecosystem" and reimplanted bilaterally into the striatum of the same six donor monkeys. These cells expressed neuroectodermal and progenitor markers such as nestin, doublecortin, GFAP, neurofilament, and vimentin. Five to six months after reimplantation, histological analysis with the dye PKH67 and unbiased stereology showed that reimplanted cells survived, migrated bilaterally throughout the striatum, and seemed to exert a neurorestorative effect. More tyrosine hydroxylase-immunoreactive neurons and significant behavioral improvement followed reimplantation of cultured autologous neural cells as a result of unknown trophic factors released by the grafts. J. Comp. Neurol. 522:2729-2740, 2014. © 2014 Wiley Periodicals, Inc.

Carbon and oxygen isotope study of hydrothermal carbonates in the zinc-lead deposits of the San Vicente district, central Peru: A quantitative modeling on mixing processes and CO2 degassing

Carbon and oxygen isotope studies of the host and gangue carbonates of Mississippi Valley-type zinc-lead deposits in the San Vicente District hosted in the Upper Triassic to Lower Jurassic dolostones of the Pucara basin (central Peru) were used to constrain models of the ore formation. A mixing model between an incoming hot saline slightly acidic radiogenic (Pb, Sr) fluid and the native formation water explains the overall isotopic variation (delta(13)C = - 11.5 to + 2.5 parts per thousand relative to PDB and delta(18)O = + 18.0 to + 24.3 parts per thousand relative to SMOW) of the carbonate generations. The dolomites formed during the main ore stage show a narrower range (delta(13)C = - 0.1 to + 1.7 parts per thousand and delta(18)O = + 18.7 to + 23.4 parts per thousand) which is explained by exchange between the mineralizing fluids and the host carbonates combined with changes in temperature and pressure. This model of fluid-rock interaction explains the pervasive alteration of the host dolomite I and precipitation of sphalerite I. The open-space filling hydrothermal white sparry dolomite and the coexisting sphalerite II formed by prolonged fluid-host dolomite interaction and limited CO2 degassing. Late void-filling dolomite III (or calcite) and the associated sphalerite III formed as the consequence of CO2 degassing and concomitant pH increase of a slightly acidic ore fluid. Widespread brecciation is associated to CO2 outgassing. Consequently, pressure variability plays a major role in the ore precipitation during the late hydrothermal events in San Vicente. The presence of native sulfur associated with extremely carbon-light calcites replacing evaporitic sulfates (e.g., delta(13)C = - 11.5 parts per thousand), altered native organic matter and heavier hydrothermal bitumen (from - 27.0 to - 23.0 parts per thousand delta(13)C) points to thermochemical reduction of sulfate and/or thiosulfate. The delta(13)C- and delta(18)O-values of the altered host dolostone and hydrothermal carbonates, and the carbon isotope composition of the associated organic matter show a strong regional homogeneity. These results coupled with the strong mineralogical and petrographic similarities of the different MVT occurrences perhaps reflects the fact that the mineralizing processes were similar in the whole San Vicente belt, suggesting the existence of a common regional mineralizing hydrothermal system with interconnected plumbing.

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function.

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

Spatial variability of the chemical, physical and biological properties in lowland cultivated with irrigated rice

In the areas where irrigated rice is grown in the south of Brazil, few studies have been carried out to investigate the spatial variability structure of soil properties and to establish new forms of soil management as well as determine soil corrective and fertilizer applications. In this sense, this study had the objective of evaluating the spatial variability of chemical, physical and biological soil properties in a lowland area under irrigated rice cultivation in the conventional till system. For this purpose, a 10 x 10 m grid of 100 points was established, in an experimental field of the Embrapa Clima Temperado, in the County of Capão do Leão, State of Rio Grande do Sul. The spatial variability structure was evaluated by geostatistical tools and the number of subsamples required to represent each soil property in future studies was calculated using classical statistics. Results showed that the spatial variability structure of sand, silt, SMP index, cation exchange capacity (pH 7.0), Al3+ and total N properties could be detected by geostatistical analysis. A pure nugget effect was observed for the nutrients K, S and B, as well as macroporosity, mean weighted diameter of aggregates, and soil water storage. The cross validation procedure, based on linear regression and the determination coefficient, was more efficient to evaluate the quality of the adjusted mathematical model than the degree of spatial dependence. It was also concluded that the combination of classical with geostatistics can in many cases simplify the soil sampling process without losing information quality.

The wound watch: an objective staging system for wounds in the diabetic (db/db) mouse model.

As in cancer biology, in wound healing there is a need for objective staging systems to decide for the best treatment and predictors of outcome. We developed in the diabetic (db/db) wound healing model, a staging system, the "wound watch," based on the quantification of angiogenesis and cell proliferation in open wounds. In chronic wounds, there is often a lack of cellular proliferation and angiogenesis that leads to impaired healing. The wound watch addresses this by quantifying the proliferative phase of wound healing in two dimensions (cellular division and angiogenesis). The results are plotted in a two-dimensional graph to monitor the course of healing and compare the response to different treatments.

Microbial biomass and soil fauna during the decomposition of cover crops in no-tillage system

The decomposition of plant residues is a biological process mediated by soil fauna, but few studies have been done evaluating its dynamics in time during the process of disappearance of straw. This study was carried out in Chapecó, in southern Brazil, with the objective of monitoring modifications in soil fauna populations and the C content in the soil microbial biomass (C SMB) during the decomposition of winter cover crop residues in a no-till system. The following treatments were tested: 1) Black oat straw (Avena strigosa Schreb.); 2) Rye straw (Secale cereale L.); 3) Common vetch straw (Vicia sativa L.). The cover crops were grown until full flowering and then cut mechanically with a rolling stalk chopper. The soil fauna and C content in soil microbial biomass (C SMB) were assessed during the period of straw decomposition, from October 2006 to February 2007. To evaluate C SMB by the irradiation-extraction method, soil samples from the 0-10 cm layer were used, collected on eight dates, from before until 100 days after residue chopping. The soil fauna was collected with pitfall traps on seven dates up to 85 days after residue chopping. The phytomass decomposition of common vetch was faster than of black oat and rye residues. The C SMB decreased during the process of straw decomposition, fastest in the treatment with common vetch. In the common vetch treatment, the diversity of the soil fauna was reduced at the end of the decomposition process.

Sex differences in urinary levels of several biological indicators of exposure: a simulation study using a compartmental based toxicokinetic model

Toxicokinetic modeling is a useful tool to describe or predict the behavior of a chemical agent in the human or animal organism. A general model based on four compartments was developed in a previous study in order to quantify the effect of human variability on a wide range of biological exposure indicators. The aim of this study was to adapt this existing general toxicokinetic model to three organic solvents, which were methyl ethyl ketone, 1-methoxy-2-propanol and 1,1,1,-trichloroethane, and to take into account sex differences. We assessed in a previous human volunteer study the impact of sex on different biomarkers of exposure corresponding to the three organic solvents mentioned above. Results from that study suggested that not only physiological differences between men and women but also differences due to sex hormones levels could influence the toxicokinetics of the solvents. In fact the use of hormonal contraceptive had an effect on the urinary levels of several biomarkers, suggesting that exogenous sex hormones could influence CYP2E1 enzyme activity. These experimental data were used to calibrate the toxicokinetic models developed in this study. Our results showed that it was possible to use an existing general toxicokinetic model for other compounds. In fact, most of the simulation results showed good agreement with the experimental data obtained for the studied solvents, with a percentage of model predictions that lies within the 95% confidence interval varying from 44.4 to 90%. Results pointed out that for same exposure conditions, men and women can show important differences in urinary levels of biological indicators of exposure. Moreover, when running the models by simulating industrial working conditions, these differences could even be more pronounced. In conclusion, a general and simple toxicokinetic model, adapted for three well known organic solvents, allowed us to show that metabolic parameters can have an important impact on the urinary levels of the corresponding biomarkers. These observations give evidence of an interindividual variablity, an aspect that should have its place in the approaches for setting limits of occupational exposure.

Structural sustainability of cambisol under different land use system

Incongruous management techniques have been associated with some significant loss of agricultural land to degradation in many parts of the world. Land degradation results in the alteration of physical, chemical and biological properties of the soil, thereby posing a serious threat to sustainable agricultural development. In this study, our objective is to evaluate the changes in a Cambisol structure under six land use systems using the load bearing capacity model. Sampling was conducted in Amazonas Region, Brazil, in the following land use: a) young secondary forest; b) old secondary forest; c) forest; d) pasture; e) cropping, and f) agroforestry. To obtain the load bearing capacity models the undisturbed soil samples were collected in those land use systems and subjected to the uniaxial compression test. These models were used to evaluate which land use system preserved or degraded the Cambisol structure. The results of the bulk density and total porosity of the soil samples were not adequate to quantify structural degradation in Cambisol. Using the forest topsoil level (0-0.03 m) as a reference, it was observed that pasture land use system was most severe in the degradation of the soil structure while the structure were most preserved under old secondary forest, cropping system and forest. At the subsoil level (0.10-0.13 m depth), the soil structure was most degraded in the cropping land use system while it was most preserved in young secondary forest and pasture. At the 0.20-0.23 m depth, soil structure degradation was most severe in the old secondary forest system and well preserved in young secondary forest, cropping and agroforestry.

High-precision satellite positioning system as a new tool to study the biomechanics of human locomotion.

New Global Positioning System (GPS) receivers allow now to measure a location on earth at high frequency (5Hz) with a centimetric precision using phase differential positioning method. We studied whether such technique was accurate enough to retrieve basic parameters of human locomotion. Eight subjects walked on an athletics track at four different imposed step frequencies (70-130steps/min) plus a run at free pace. Differential carrier phase localization between a fixed base station and the mobile antenna mounted on the walking person was calculated. In parallel, a triaxial accelerometer, attached to the low back, recorded body accelerations. The different parameters were averaged for 150 consecutive steps of each run for each subject (total of 6000 steps analyzed). We observed a perfect correlation between average step duration measured by accelerometer and by GPS (r=0.9998, N=40). Two important parameters for the calculation of the external work of walking were also analyzed, namely the vertical lift of the trunk and the velocity variation per step. For an average walking speed of 4.0km/h, average vertical lift and velocity variation were, respectively, 4.8cm and 0.60km/h. The average intra-individual step-to-step variability at a constant speed, which includes GPS errors and the biological gait style variation, were found to be 24. 5% (coefficient of variation) for vertical lift and 44.5% for velocity variation. It is concluded that GPS technique can provide useful biomechanical parameters for the analysis of an unlimited number of strides in an unconstrained free-living environment.

Estimating dormant and active hematopoietic stem cell kinetics through extensive modeling of bromodeoxyuridine label-retaining cell dynamics.

Bone marrow hematopoietic stem cells (HSCs) are responsible for both lifelong daily maintenance of all blood cells and for repair after cell loss. Until recently the cellular mechanisms by which HSCs accomplish these two very different tasks remained an open question. Biological evidence has now been found for the existence of two related mouse HSC populations. First, a dormant HSC (d-HSC) population which harbors the highest self-renewal potential of all blood cells but is only induced into active self-renewal in response to hematopoietic stress. And second, an active HSC (a-HSC) subset that by and large produces the progenitors and mature cells required for maintenance of day-to-day hematopoiesis. Here we present computational analyses further supporting the d-HSC concept through extensive modeling of experimental DNA label-retaining cell (LRC) data. Our conclusion that the presence of a slowly dividing subpopulation of HSCs is the most likely explanation (amongst the various possible causes including stochastic cellular variation) of the observed long term Bromodeoxyuridine (BrdU) retention, is confirmed by the deterministic and stochastic models presented here. Moreover, modeling both HSC BrdU uptake and dilution in three stages and careful treatment of the BrdU detection sensitivity permitted improved estimates of HSC turnover rates. This analysis predicts that d-HSCs cycle about once every 149-193 days and a-HSCs about once every 28-36 days. We further predict that, using LRC assays, a 75%-92.5% purification of d-HSCs can be achieved after 59-130 days of chase. Interestingly, the d-HSC proportion is now estimated to be around 30-45% of total HSCs - more than twice that of our previous estimate.

Fuzzy logic applied to the modeling of water dynamics in an Oxisol in northeastern Brazil

Modeling of water movement in non-saturated soil usually requires a large number of parameters and variables, such as initial soil water content, saturated water content and saturated hydraulic conductivity, which can be assessed relatively easily. Dimensional flow of water in the soil is usually modeled by a nonlinear partial differential equation, known as the Richards equation. Since this equation cannot be solved analytically in certain cases, one way to approach its solution is by numerical algorithms. The success of numerical models in describing the dynamics of water in the soil is closely related to the accuracy with which the water-physical parameters are determined. That has been a big challenge in the use of numerical models because these parameters are generally difficult to determine since they present great spatial variability in the soil. Therefore, it is necessary to develop and use methods that properly incorporate the uncertainties inherent to water displacement in soils. In this paper, a model based on fuzzy logic is used as an alternative to describe water flow in the vadose zone. This fuzzy model was developed to simulate the displacement of water in a non-vegetated crop soil during the period called the emergency phase. The principle of this model consists of a Mamdani fuzzy rule-based system in which the rules are based on the moisture content of adjacent soil layers. The performances of the results modeled by the fuzzy system were evaluated by the evolution of moisture profiles over time as compared to those obtained in the field. The results obtained through use of the fuzzy model provided satisfactory reproduction of soil moisture profiles.

MORM--a Petri net based model for assessing OH&S risks in industrial processes: modeling qualitative aspects.

Because of the increase in workplace automation and the diversification of industrial processes, workplaces have become more and more complex. The classical approaches used to address workplace hazard concerns, such as checklists or sequence models, are, therefore, of limited use in such complex systems. Moreover, because of the multifaceted nature of workplaces, the use of single-oriented methods, such as AEA (man oriented), FMEA (system oriented), or HAZOP (process oriented), is not satisfactory. The use of a dynamic modeling approach in order to allow multiple-oriented analyses may constitute an alternative to overcome this limitation. The qualitative modeling aspects of the MORM (man-machine occupational risk modeling) model are discussed in this article. The model, realized on an object-oriented Petri net tool (CO-OPN), has been developed to simulate and analyze industrial processes in an OH&S perspective. The industrial process is modeled as a set of interconnected subnets (state spaces), which describe its constitutive machines. Process-related factors are introduced, in an explicit way, through machine interconnections and flow properties. While man-machine interactions are modeled as triggering events for the state spaces of the machines, the CREAM cognitive behavior model is used in order to establish the relevant triggering events. In the CO-OPN formalism, the model is expressed as a set of interconnected CO-OPN objects defined over data types expressing the measure attached to the flow of entities transiting through the machines. Constraints on the measures assigned to these entities are used to determine the state changes in each machine. Interconnecting machines implies the composition of such flow and consequently the interconnection of the measure constraints. This is reflected by the construction of constraint enrichment hierarchies, which can be used for simulation and analysis optimization in a clear mathematical framework. The use of Petri nets to perform multiple-oriented analysis opens perspectives in the field of industrial risk management. It may significantly reduce the duration of the assessment process. But, most of all, it opens perspectives in the field of risk comparisons and integrated risk management. Moreover, because of the generic nature of the model and tool used, the same concepts and patterns may be used to model a wide range of systems and application fields.

Budgeting rockfall and modeling sedimentary delivery in torrent systems

This thesis is a compilation of projects to study sediment processes recharging debris flow channels. These works, conducted during my stay at the University of Lausanne, focus in the geological and morphological implications of torrent catchments to characterize debris supply, a fundamental element to predict debris flows. Other aspects of sediment dynamics are considered, e.g. the coupling headwaters - torrent, as well as the development of a modeling software that simulates sediment transfer in torrent systems. The sediment activity at Manival, an active torrent system of the northern French Alps, was investigated using terrestrial laser scanning and supplemented with geostructural investigations and a survey of sediment transferred in the main torrent. A full year of sediment flux could be observed, which coincided with two debris flows and several bedload transport events. This study revealed that both debris flows generated in the torrent and were preceded in time by recharge of material from the headwaters. Debris production occurred mostly during winter - early spring time and was caused by large slope failures. Sediment transfers were more puzzling, occurring almost exclusively in early spring subordinated to runoffconditions and in autumn during long rainfall. Intense rainstorms in summer did not affect debris storage that seems to rely on the stability of debris deposits. The morpho-geological implication in debris supply was evaluated using DEM and field surveys. A slope angle-based classification of topography could characterize the mode of debris production and transfer. A slope stability analysis derived from the structures in rock mass could assess susceptibility to failure. The modeled rockfall source areas included more than 97% of the recorded events and the sediment budgets appeared to be correlated to the density of potential slope failure. This work showed that the analysis of process-related terrain morphology and of susceptibility to slope failure document the sediment dynamics to quantitatively assess erosion zones leading to debris flow activity. The development of erosional landforms was evaluated by analyzing their geometry with the orientations of potential rock slope failure and with the direction of the maximum joint frequency. Structure in rock mass, but in particular wedge failure and the dominant discontinuities, appear as a first-order control of erosional mechanisms affecting bedrock- dominated catchment. They represent some weaknesses that are exploited primarily by mass wasting processes and erosion, promoting not only the initiation of rock couloirs and gullies, but also their propagation. Incorporating the geological control in geomorphic processes contributes to better understand the landscape evolution of active catchments. A sediment flux algorithm was implemented in a sediment cascade model that discretizes the torrent catchment in channel reaches and individual process-response systems. Each conceptual element includes in simple manner geomorphological and sediment flux information derived from GIS complemented with field mapping. This tool enables to simulate sediment transfers in channels considering evolving debris supply and conveyance, and helps reducing the uncertainty inherent to sediment budget prediction in torrent systems. Cette thèse est un recueil de projets d'études des processus de recharges sédimentaires des chenaux torrentiels. Ces travaux, réalisés lorsque j'étais employé à l'Université de Lausanne, se concentrent sur les implications géologiques et morphologiques des bassins dans l'apport de sédiments, élément fondamental dans la prédiction de laves torrentielles. D'autres aspects de dynamique sédimentaire ont été abordés, p. ex. le couplage torrent - bassin, ainsi qu'un modèle de simulation du transfert sédimentaire en milieu torrentiel. L'activité sédimentaire du Manival, un système torrentiel actif des Alpes françaises, a été étudiée par relevés au laser scanner terrestre et complétée par une étude géostructurale ainsi qu'un suivi du transfert en sédiments du torrent. Une année de flux sédimentaire a pu être observée, coïncidant avec deux laves torrentielles et plusieurs phénomènes de charriages. Cette étude a révélé que les laves s'étaient générées dans le torrent et étaient précédées par une recharge de débris depuis les versants. La production de débris s'est passée principalement en l'hiver - début du printemps, causée par de grandes ruptures de pentes. Le transfert était plus étrange, se produisant presque exclusivement au début du printemps subordonné aux conditions d'écoulement et en automne lors de longues pluies. Les orages d'été n'affectèrent guère les dépôts, qui semblent dépendre de leur stabilité. Les implications morpho-géologiques dans l'apport sédimentaire ont été évaluées à l'aide de MNT et études de terrain. Une classification de la topographie basée sur la pente a permis de charactériser le mode de production et transfert. Une analyse de stabilité de pente à partir des structures de roches a permis d'estimer la susceptibilité à la rupture. Les zones sources modélisées comprennent plus de 97% des chutes de blocs observées et les bilans sédimentaires sont corrélés à la densité de ruptures potentielles. Ce travail d'analyses des morphologies du terrain et de susceptibilité à la rupture documente la dynamique sédimentaire pour l'estimation quantitative des zones érosives induisant l'activité torrentielle. Le développement des formes d'érosion a été évalué par l'analyse de leur géométrie avec celle des ruptures potentielles et avec la direction de la fréquence maximale des joints. Les structures de roches, mais en particulier les dièdres et les discontinuités dominantes, semblent être très influents dans les mécanismes d'érosion affectant les bassins rocheux. Ils représentent des zones de faiblesse exploitées en priorité par les processus de démantèlement et d'érosion, encourageant l'initiation de ravines et couloirs, mais aussi leur propagation. L'incorporation du control géologique dans les processus de surface contribue à une meilleure compréhension de l'évolution topographique de bassins actifs. Un algorithme de flux sédimentaire a été implémenté dans un modèle en cascade, lequel divise le bassin en biefs et en systèmes individuels répondant aux processus. Chaque unité inclut de façon simple les informations géomorpologiques et celles du flux sédimentaire dérivées à partir de SIG et de cartographie de terrain. Cet outil permet la simulation des transferts de masse dans les chenaux, considérants la variabilité de l'apport et son transport, et aide à réduire l'incertitude liée à la prédiction de bilans sédimentaires torrentiels. Ce travail vise très humblement d'éclairer quelques aspects de la dynamique sédimentaire en milieu torrentiel.