Integrative analysis of RUNX1 downstream pathways and target genes

BACKGROUND: The RUNX1 transcription factor gene is frequently mutated in sporadic myeloid and lymphoid leukemia through translocation, point mutation or amplification. It is also responsible for a familial platelet disorder with predisposition to acute myeloid leukemia (FPD-AML). The disruption of the largely unknown biological pathways controlled by RUNX1 is likely to be responsible for the development of leukemia. We have used multiple microarray platforms and bioinformatic techniques to help identify these biological pathways to aid in the understanding of why RUNX1 mutations lead to leukemia. RESULTS: Here we report genes regulated either directly or indirectly by RUNX1 based on the study of gene expression profiles generated from 3 different human and mouse platforms. The platforms used were global gene expression profiling of: 1) cell lines with RUNX1 mutations from FPD-AML patients, 2) over-expression of RUNX1 and CBFbeta, and 3) Runx1 knockout mouse embryos using either cDNA or Affymetrix microarrays. We observe that our datasets (lists of differentially expressed genes) significantly correlate with published microarray data from sporadic AML patients with mutations in either RUNX1 or its cofactor, CBFbeta. A number of biological processes were identified among the differentially expressed genes and functional assays suggest that heterozygous RUNX1 point mutations in patients with FPD-AML impair cell proliferation, microtubule dynamics and possibly genetic stability. In addition, analysis of the regulatory regions of the differentially expressed genes has for the first time systematically identified numerous potential novel RUNX1 target genes. CONCLUSION: This work is the first large-scale study attempting to identify the genetic networks regulated by RUNX1, a master regulator in the development of the hematopoietic system and leukemia. The biological pathways and target genes controlled by RUNX1 will have considerable importance in disease progression in both familial and sporadic leukemia as well as therapeutic implications.

The role of upper-level dynamics and surface processes for the Pakistan flood of July 2010

In July and August 2010 floods of unprecedented impact afflicted Pakistan. The floods resulted from a series of intense multi-day precipitation events in July and early August. At the same time a series of blocking anticyclones dominated the upper-level flow over western Russia and breaking waves i.e. equatorward extrusions of stratospheric high potential vorticity (PV) air formed along the downstream flank of the blocks. Previous studies suggested that these extratropical upper-level breaking waves were crucial for instigating the precipitation events in Pakistan. Here a detailed analysis is provided of the extratropical forcing of the precipitation. Piecewise PV inversion is used to quantify the extratropical upper-level forcing associated with the wave breaking and trajectories are calculated to study the pathways and source regions of the moisture that precipitated over Pakistan. Limited-area model simulations are carried out to complement the Lagrangian analysis. The precipitation events over Pakistan resulted from a combination of favourable boundary conditions with strong extratropical and monsoonal forcing factors. Above-normal sea-surface temperatures in the Indian Ocean led to an elevated lower-tropospheric moisture content. Surface monsoonal depressions ensured the transport of moist air from the ocean towards northeastern Pakistan. Along this pathway the air parcel humidity increased substantially (60–90% of precipitated moisture) via evapotranspiration from the land surface. Extratropical breaking waves influenced the surface wind field substantially by enhancing the wind component directed towards the mountains which reinforced the precipitation.

Clathrin heavy chain plays multiple roles in polarizing the Drosophila oocyte downstream of Bic-D

Bicaudal-D (Bic-D), Egalitarian (Egl), microtubules and their motors form a transport machinery that localizes a remarkable diversity of mRNAs to specific cellular regions during oogenesis and embryogenesis. Bic-D family proteins also promote dynein-dependent transport of Golgi vesicles, lipid droplets, synaptic vesicles and nuclei. However, the transport of these different cargoes is still poorly understood. We searched for novel proteins that either mediate Bic-Ddependent transport processes or are transported by them. Clathrin heavy chain (Chc) co-immunopurifies with Bic-D in embryos and ovaries, and a fraction of Chc colocalizes with Bic-D. Both proteins control posterior patterning of the Drosophila oocyte and endocytosis. Although the role of Chc in endocytosis is well established, our results show that Bic-D is also needed for the elevated endocytic activity at the posterior of the oocyte. Apart fromaffecting endocytosis indirectly by its role in osk mRNA localization, Bic-D is also required to transport Chc mRNA into the oocyte and for transport and proper localization of Chc protein to the oocyte cortex, pointing to an additional,more direct role of Bic-D in the endocytic pathway. Furthermore, similar to Bic-D, Chc also contributes to proper localization of osk mRNA and to oocyte growth. However, in contrast to other endocytic components and factors of the endocytic recycling pathway, such as Rabenosyn-5 (Rbsn-5) and Rab11, Chc is needed during early stages of oogenesis (from stage 6 onwards) to localize oskmRNA correctly.Moreover,we also uncovered a novel, presumably endocytosis-independent, role of Chc in the establishment of microtubule polarity in stage 6 oocytes.

Physical oceanography, current meter data, and microstructure measurements 180 km downstream of Denmark Strait sill during Maria S. Merian cruise MSM21/1b

The main objectives of the cruise MSM21/1b were to characterize the spatio-temporal variability of the Denmark Strait overflow and to identify processes responsible for the exchange of the overflow plume with ambient water downstream of Denmark Strait. A multi-platform approach was taken to achieve the goals, based on moorings, an autonomous underwater vehicle (AUV), as well as lowered and vessel-mounted observations. From these platforms, measurements of temperature, salinity, dissolved oxygen, current velocity, dissipation of turbulent kinetic energy, and bottom pressure were obtained.

Chapter 3 Knowledge Exchanges and Innovation in Connected Firms: Evidence from Upstream-Downstream Relationships

This paper proposes evidences for linking innovation and knowledge exchanges in developing economies towards a comprehensive theory of new economic geography in the knowledge based spatial economy. Firms which dispatched engineers to customers achieved more innovations than firms which did not. Mutual sharing of knowledge also stimulates innovations. A just-in-time relationship is effective for dealing with upgrading production process. But such strong complementarities with partners are not effective for product innovation.. These evidences support the hypothesis that face-to-face communication and complementarities among production linkages have different roles in knowledge creation.

Hybrid simulation-optimization based approach for the optimal design of single-product biotechnological processes

In this work, we present a systematic method for the optimal development of bioprocesses that relies on the combined use of simulation packages and optimization tools. One of the main advantages of our method is that it allows for the simultaneous optimization of all the individual components of a bioprocess, including the main upstream and downstream units. The design task is mathematically formulated as a mixed-integer dynamic optimization (MIDO) problem, which is solved by a decomposition method that iterates between primal and master sub-problems. The primal dynamic optimization problem optimizes the operating conditions, bioreactor kinetics and equipment sizes, whereas the master levels entails the solution of a tailored mixed-integer linear programming (MILP) model that decides on the values of the integer variables (i.e., number of equipments in parallel and topological decisions). The dynamic optimization primal sub-problems are solved via a sequential approach that integrates the process simulator SuperPro Designer® with an external NLP solver implemented in Matlab®. The capabilities of the proposed methodology are illustrated through its application to a typical fermentation process and to the production of the amino acid L-lysine.

A synthesis of dominant ecological processes in intensive shrimp ponds and adjacent coastal environments in NE Australia

One of the key environmental concerns about shrimp farming is the discharge of waters with high levels of nutrients and suspended solids into adjacent waterways. In this paper we synthesize the results of our multidisciplinary research linking ecological processes in intensive shrimp ponds with their downstream impacts in tidal, mangrove-lined creeks. The incorporation of process measurements and bioindicators, in addition to water quality measurements, improved our understanding of the effect of shrimp farm discharges on the ecological health of the receiving water bodies. Changes in water quality parameters were an oversimplification of the ecological effects of water discharges, and use of key measures including primary production rates, phytoplankton responses to nutrients, community shifts in zooplankton and delta(15)N ratios in marine plants have the potential to provide more integrated and robust measures. Ultimately, reduction in nutrient discharges is most likely to ensure the future sustainability of the industry. (C) 2003 Elsevier Ltd. All rights reserved.

Flow processes in a radiant tube burner: isothermal flow

This paper presents the first part of a study of the combustion processes in an industrial radiant tube burner (RTB). The RTB is used typically in heat-treating furnaces. The work was initiated because of the need for improvements in burner lifetime and performance. The present paper is concerned with the flow of combustion air; a future paper will address the combusting flow. A detailed three-dimensional computational fluid dynamics model of the burner was developed, validated with experimental air flow velocity measurements using a split-film probe. Satisfactory agreement was achieved using the k-e turbulence model. Various features along the air inlet passage were subsequently analysed. The effectiveness of the air recuperator swirler was found to be significantly compromised by the need for a generous assembly tolerance. Also, a substantial circumferential flow maldistribution introduced by the swirler is effectively removed by the positioning of a constriction in the downstream passage.

Influence of downstream processing on the breakage of whey protein precipitates

Whey proteins may be fractionated by isoelectric precipitation followed by centrifugal recovery of the precipitate phase. Transport and processing of protein precipitates may alter the precipitate particle properties, which may affect how they behave in subsequent processes. For example, the transport of precipitate solution through pumps, pipes and valves and into a centrifugal separator may cause changes in particle size and density, which may affect the performance of the separator. This work investigates the effect of fluid flow intensity, flow geometry and exposure time on the breakage of whey protein precipitates: Computational fluid dynamics (CFD) was used to quantify the flow intensity in different geometries. Flow geometry can have a critical impact on particle breakage. Sharp geometrical transitions induce large increases in turbulence that can result in substantial particle breakage. As protein precipitate particles break, they tend to form denser more compact structures. The reduction in particle size and increase in compaction is due to breakage. This makes the particles become more resistant to further breakage as particle compactness increases. The effect of flow intensity on particle breakage is coupled to exposure time, with greater exposure time producing more breakage. However, it is expected that the particles will attain an equilibrium particle size and density after prolonged exposure in a constant flow field where no further breakage will occur with exposure time. © 2005 Institution of Chemical Engineers.

Biogeochemical Processes on Tree Islands in the Greater Everglades: Initiating a New Paradigm

Scientists’ understanding of the role of tree islands in the Everglades has evolved from a plant community of minor biogeochemical importance to a plant community recognized as the driving force for localized phosphorus accumulation within the landscape. Results from this review suggest that tree transpiration, nutrient infiltration from the soil surface, and groundwater flow create a soil zone of confluence where nutrients and salts accumulate under the head of a tree island during dry periods. Results also suggest accumulated salts and nutrients are flushed downstream by regional water flows during wet periods. That trees modulate their environment to create biogeochemical hot spots and strong nutrient gradients is a significant ecological paradigm shift in the understanding of the biogeochemical processes in the Everglades. In terms of island sustainability, this new paradigm suggests the need for distinct dry-wet cycles as well as a hydrologic regime that supports tree survival. Restoration of historic tree islands needs further investigation but the creation of functional tree islands is promising.

Physical modeling of processes of sediment transport in inlets

During the transformation of the low tide to the high tide, an exactly inverse phenomenon is occurred and the high tidal delta is formed at the mouth upstream. Increasing the tidal range does not affect the nature of this phenomenon and just change its intensity. In this situation, the inlet will be balance over time. A new relationship between equilibrium cross section and tidal prism for different tidal levels as well as sediment grading has been provided which its results are corresponded with results of numerical modeling. In the combination state, the wave height significantly affects the current and sedimentary pattern such that the wave height dimensionless index (Hw/Ht) determines the dominant parameter (the short period wave or tide) in the inlet. It is notable that in this state, the inlet will be balanced over the time. In order to calculate sedimentary phenomena, each of which are individually determined under solely wave and only tide conditions and then they are added. Estimated values are similar to numerical modeling results of the combination state considering nonlinear terms. Also, it is clear that the wave and tide performance is of meaning in the direct relationship with the water level. The water level change causes variations of the position of the breaking line and sedimentary active area. It changes the current and sedimentary pattern coastward while does not change anything seaward. Based on modeling results of sediment transport due to the wave, tide and their combination, it could be said that the erosion at the mouth due to the wave is less than that due to the wave and tide combination. In these situations, tide and wave-tide combination increase the low tidal and high tidal delta volume, respectively. Hence, tide plays an effective role in changing sedimentary phenomena at the channel and mouth downstream. Whereas, short period and combined waves have a crucial role in varying the morphology and sediment transport coast ward.

Geochemistry Of Acid Mine Drainage From A Coal Mining Area And Processes Controlling Metal Attenuation In Stream Waters, Southern Brazil.

Acid drainage influence on the water and sediment quality was investigated in a coal mining area (southern Brazil). Mine drainage showed pH between 3.2 and 4.6 and elevated concentrations of sulfate, As and metals, of which, Fe, Mn and Zn exceeded the limits for the emission of effluents stated in the Brazilian legislation. Arsenic also exceeded the limit, but only slightly. Groundwater monitoring wells from active mines and tailings piles showed pH interval and chemical concentrations similar to those of mine drainage. However, the river and ground water samples of municipal public water supplies revealed a pH range from 7.2 to 7.5 and low chemical concentrations, although Cd concentration slightly exceeded the limit adopted by Brazilian legislation for groundwater. In general, surface waters showed large pH range (6 to 10.8), and changes caused by acid drainage in the chemical composition of these waters were not very significant. Locally, acid drainage seemed to have dissolved carbonate rocks present in the local stratigraphic sequence, attenuating the dispersion of metals and As. Stream sediments presented anomalies of these elements, which were strongly dependent on the proximity of tailings piles and abandoned mines. We found that precipitation processes in sediments and the dilution of dissolved phases were responsible for the attenuation of the concentrations of the metals and As in the acid drainage and river water mixing zone. In general, a larger influence of mining activities on the chemical composition of the surface waters and sediments was observed when enrichment factors in relation to regional background levels were used.

Construction Of A Manual Of Work Processes And Techniques From Centro De Dispensação De Medicamentos De Alto Custo (cedmac), Hospital De Clínicas, Unicamp.

The Centers for High Cost Medication (Centros de Medicação de Alto Custo, CEDMAC), Health Department, São Paulo were instituted by project in partnership with the Clinical Hospital of the Faculty of Medicine, USP, sponsored by the Foundation for Research Support of the State of São Paulo (Fundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP) aimed at the formation of a statewide network for comprehensive care of patients referred for use of immunobiological agents in rheumatological diseases. The CEDMAC of Hospital de Clínicas, Universidade Estadual de Campinas (HC-Unicamp), implemented by the Division of Rheumatology, Faculty of Medical Sciences, identified the need for standardization of the multidisciplinary team conducts, in face of the specificity of care conducts, verifying the importance of describing, in manual format, their operational and technical processes. The aim of this study is to present the methodology applied to the elaboration of the CEDMAC/HC-Unicamp Manual as an institutional tool, with the aim of offering the best assistance and administrative quality. In the methodology for preparing the manuals at HC-Unicamp since 2008, the premise was to obtain a document that is participatory, multidisciplinary, focused on work processes integrated with institutional rules, with objective and didactic descriptions, in a standardized format and with electronic dissemination. The CEDMAC/HC-Unicamp Manual was elaborated in 10 months, with involvement of the entire multidisciplinary team, with 19 chapters on work processes and techniques, in addition to those concerning the organizational structure and its annexes. Published in the electronic portal of HC Manuals in July 2012 as an e-Book (ISBN 978-85-63274-17-5), the manual has been a valuable instrument in guiding professionals in healthcare, teaching and research activities.

Agrin And Perlecan Mediate Tumorigenic Processes In Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma is the most common type of cancer in the oral cavity, representing more than 90% of all oral cancers. The characterization of altered molecules in oral cancer is essential to understand molecular mechanisms underlying tumor progression as well as to contribute to cancer biomarker and therapeutic target discovery. Proteoglycans are key molecular effectors of cell surface and pericellular microenvironments, performing multiple functions in cancer. Two of the major basement membrane proteoglycans, agrin and perlecan, were investigated in this study regarding their role in oral cancer. Using real time quantitative PCR (qRT-PCR), we showed that agrin and perlecan are highly expressed in oral squamous cell carcinoma. Interestingly, cell lines originated from distinct sites showed different expression of agrin and perlecan. Enzymatically targeting chondroitin sulfate modification by chondroitinase, oral squamous carcinoma cell line had a reduced ability to adhere to extracellular matrix proteins and increased sensibility to cisplatin. Additionally, knockdown of agrin and perlecan promoted a decrease on cell migration and adhesion, and on resistance of cells to cisplatin. Our study showed, for the first time, a negative regulation on oral cancer-associated events by either targeting chondroitin sulfate content or agrin and perlecan levels.

In vitro Microfluidic Model For The Study Of Vaso-occlusive Processes.

Vaso-occlusion, responsible for much of the morbidity of sickle-cell disease, is a complex multicellular process, apparently triggered by leukocyte adhesion to the vessel wall. The microcirculation represents a major site of leukocyte-endothelial interactions and vaso-occlusive processes. We have developed a biochip with subdividing interconnecting microchannels that decrease in size (40 μm to 10 μm in width), for use in conjunction with a precise microfluidic device, to mimic cell flow and adhesion through channels of sizes that approach those of the microcirculation. The biochips were utilized to observe the dynamics of the passage of neutrophils and red blood cells, isolated from healthy and sickle-cell anemia (SCA) individuals, through laminin or endothelial adhesion molecule-coated microchannels at physiologically relevant rates of flow and shear stress. Obstruction of E-selectin/intercellular adhesion molecule 1-coated biochip microchannels by SCA neutrophils was significantly greater than that observed for healthy neutrophils, particularly in the microchannels of 40-15 μm in width. Whereas SCA red blood cells alone did not significantly adhere to, or obstruct, microchannels, mixed suspensions of SCA neutrophils and red blood cells significantly adhered to and obstructed laminin-coated channels. Results from this in vitro microfluidic model support a primary role for leukocytes in the initiation of SCA occlusive processes in the microcirculation. This assay represents an easy-to-use and reproducible in vitro technique for understanding molecular mechanisms and cellular interactions occurring in subdividing microchannels of widths approaching those observed in the microvasculature. The assay could hold potential for testing drugs developed to inhibit occlusive mechanisms such as those observed in SCA and thrombotic diseases.