Fundamental Research Studies Research Articles

Aspirin Discontinuation Syndromes: Clinical Implications of Basic Research Studies

Abrupt discontinuation of many drugs used in medicine causes withdrawal syndromes, some of which can be fatal. Discontinuation of a number of cardiovascular drugs can increase the risk of cardiovascular events. Whereas aspirin administration is known to decrease the risk of vascular ischemic problems, aspirin withdrawal may temporarily increase the risk of thrombotic events. Indeed, aspirin withdrawal has been associated with an increased risk of thrombosis both in clinical and fundamental research studies. Such complications occur within the first month after interrupting aspirin therapy and their mechanism remains unexplained. We have previously demonstrated that aspirin, when injected as a single high dose (100mg/kg), induces a prothrombotic state in the rat, similar to that described above, 8 and 10days after administration. This effect in the rat may be reproduced 1 hour after a single injection of ultra-low-dose aspirin. Caution is therefore required regarding the possibility of drug discontinuation effects within the framework of drug safety evaluation.

Heavy Liquid Metal Corrosion of Structural Materials in Advanced Nuclear Systems

Interest in advanced nuclear concepts using liquid metal coolant has increased in the past few years. Liquid metal coolants have been proposed for the next generation of small-sized nuclear reactors, which offer exceptional safety and reliability, sustainability, nonproliferation, and economic competitiveness. Heavy liquid metal coolants are investigated for advanced fast reactors that operate at high temperatures, reaching high efficiencies. Lead and lead-bismuth eutectic (LBE) coolants are also proposed as coolants and targets of accelerator driven systems. High temperature, corrosive environment, high fast neutron flux, high fluence, and radiation damage, among other physical phenomena, challenge the integrity of materials in these advanced systems. Excellent compatibility with the liquid coolant is recognized as a key factor in the selection of structural materials for advanced concepts. In this article, we review materials requirements for heavy metal cooled systems with emphasis on lead and LBE materials corrosion properties. We describe experimental corrosion tests currently ongoing at the Los Alamos National Laboratory (LANL) Development of Lead Alloy Technical Applications (DELTA) loop. DELTA is a facility designed to study the long-term corrosive effects of LBE on structural materials under relevant conditions of chemistry, flow, and temperature. The research studies will provide data of corrosion rates and corrosion mechanisms in selected steel exposed to high velocity (above 2 m/s) in flowing LBE at 500°C. Fundamental research studies will help support conceptual design efforts and further the development of heavy liquid metals technology.

Translational research on esophageal adenocarcinoma: from cell line to clinic

Human esophageal adenocarcinoma (EAC) cell lines have made a substantial contribution to elucidating mechanisms of carcinogenesis and drug discovery. Model research on EAC relies almost entirely on a relatively small set of established tumor cell lines because appropriate animal models are lacking. Nowadays, more than 20% of all fundamental translational research studies regarding EAC are partially or entirely based on these cell lines. The ready availability of these cell lines to investigators worldwide have resulted in more than 250 publications, including many examples of important biomedical discoveries. The high genomic similarities (but certainly not completely identical) between the EAC cell lines and their original tumors provide rational for their use. Recently, in a collaborative effort all available EAC cell lines have been verified resulting in the establishment of a reliable panel of 10 EAC cell lines. It could be expected that the value of these cell lines increases as unlimited source of tumor material because new biomedical techniques require more tumor cells and the supply of viable tumor cells is diminishing because of neoadjuvant chemo(radio)therapy of patients with EAC. Here, we review the history of the EAC cell lines and their utility in translational research and biomedical discovery.

Analysis of an Image-Based Method to Quantify the Size and Shape of Sand Particles

Sand response depends on particle morphology (size and shape). In geotechnical research and practice, size is typically assessed by sieve analysis and particle shapes are qualitatively described. Technological developments mean that digital images of sand particles can easily be obtained, enabling shape to be quantified. The complexity associated with many digital image analysis algorithms seems to have restricted their use to fundamental research studies. This study introduces a pragmatic approach for quantitative shape analysis that has the potential to be broadly adopted in geotechnical engineering research and practice. The approach generates three shape measures (convexity, sphericity, and aspect ratio) that can easily be calculated from digital images. Following an analysis of these shape measures and the imaging method used here, a database of 36 sands, including many of the sands commonly used in geotechnical research, is presented. The subjective nature of qualitative description is clear from the discrepancies that were found in published shape assessments of these sands. Convexity, sphericity, and aspect ratio data for each of the 36 sands are presented. The relevance of these parameters to geotechnical engineering is established by comparing them with widely used qualitative descriptions.

Proteomics to Unravel Platelet-Related Diseases and Identify Novel Anti-Platelet Drugs

Blood platelets play a fundamental role in primary haemostasis and wound repair, but are also involved in several thrombotic and bleeding disorders for which the underlying mechanisms are still largely unknown. Elucidating platelet biology would help in finding novel disease biomarkers and drug targets in complex and/or genetically unknown platelet-related disorders. Proteomics, which allows studying thousands of gene products at once, represents an efficient tool to quali-quantitatively analyze and compare the platelet protein patterns of different samples (i.e. control/patient, treated/untreated, drug sensitive/resistant), to investigate post-translation modifications, protein-protein interactions and the underlying molecular pathways. This review gives an overview of the applications of proteomic strategies to study platelet biology and function, as well as to unravel differences in protein expression according to specific platelet conditions (i.e. basic versus activated), compartments (i.e. membrane or granules) and fractions (i.e. phosphoproteins and glycoproteins). The use of innovative powerful proteomic technologies can lead to the identification of proteins whose expression is altered in pathological conditions, allowing the identification of candidate biomarkers for: i) understanding the molecular defects underlying platelet disorders, ii) obtaining novel insights in more complex diseases that involve platelets, iii) unraveling the drug mode of action or identifying the mechanisms of drug resistance and iv) detecting novel therapeutic antiplatelet targets based on fundamental platelet research studies. Several studies on how proteomics proved to be useful in our understanding of platelet function and its diseases are discussed. Eventually, this could result in the discovery of novel drug targets for antiplatelet therapy.

Fluorescence imaging beyond the ballistic regime by ultrasound pulse guided digital phase conjugation.

Fluorescence imaging has revolutionized biomedical research over the past three decades. Its high molecular specificity and unrivaled single molecule level sensitivity have enabled breakthroughs in a variety of research fields. For in vivo applications, its major limitation is the superficial imaging depth as random scattering in biological tissues causes exponential attenuation of the ballistic component of a light wave. Here we present fluorescence imaging beyond the ballistic regime by combining single cycle pulsed ultrasound modulation and digital optical phase conjugation. We demonstrate a near isotropic 3D localized sound-light interaction zone. With the exceptionally high optical gain provided by the digital optical phase conjugation system, we can deliver sufficient optical power to a focus inside highly scattering media for not only fluorescence imaging but also a variety of linear and nonlinear spectroscopy measurements. This technology paves the way for many important applications in both fundamental biology research and clinical studies.

Fundamental research study regarding the flow in turbine journal bearings: the flow in a confusor with a single moving wall

Die Stromungsverhaltnisse in einem schlanken Konfusor mit einseitig bewegter ebener Wand werden experimentell und numerisch fur eine turbulente Reynolds-Zahl von 9,95×103 untersucht. Die Resultate konnen zum grundlegenden Verstandnis fur die Stromungen, die in Gleitlagertaschen fur hochtourige Turbomaschinen in Schwerbauweise auftreten, verwendet werden. Hierbei zeigt sich, dass sich in unmittelbarer Nahe der bewegten Wand (Wellenzapfen) eine dunne turbulente Grenzschicht ausbildet, wahrend die ubrige Kanalgeometrie (Lagertasche) von einem turbulenten Totwasser mit nur sehr geringen Sekundarstromungen (Rezirkulationen) erfullt ist. Durch den Vergleich mit detaillierten LDA-Messungen zeigte sich, dass das Realizable k–e-Modell gut geeignet fur die numerische Simulation solcher Stromungen ist.

Detrimental impact of hyperlipidemia on the peripheral nervous system: A novel target of medical epidemiological and fundamental research study.

Recently, epidemiological studies on the etiology of peripheral neuropathies have revealed that hyperlipidemia is a novel risk factor. Plasma lipid levels were confirmed to be associated with the incidence of many peripheral neuropathies including axonal distal polyneuropathy, vision and hearing loss, motor nerve system lesions and sympathetic nerve system dysfunction. Moreover, different lipid components such as cholesterol, triacylglycerols and lipoprotein are involved in the pathogenesis of these neuropathies. This review aimed to discuss the effect of hyperlipidemia on the peripheral nervous system and its association with peripheral neuropathies. Furthermore, a detailed discussion focusing on the explicit mechanisms related to hyperlipidemia-induced peripheral neuropathies is presented here. These mechanisms, including intracellular oxidative stress, inflammatory lesions, ischemia and dysregulation of local lipid metabolism, share pathways and interact mutually. In addition, we examined current information on clinical trials to prevent and treat peripheral neuropathies caused by hyperlipidemia, with a predictive discussion regarding the orientation of future investigations.

The pedagogical university of the future

In the article is regarded the question concerning the reasonability of school teachers' training in profilepedagogical Universities on the bases of the fundamental research studies, done by the staff of the University.

Current status and future plans of Advanced ORIENT Cycle strategy

For minimization of the ecological risks inherent in nuclear fuel recycling, a new fuel cycle paradigm was proposed and its key technology developments have been carried out as a part of the Advanced Optimization by Recycling Instructive Elements (Adv.-ORIENT) Cycle strategy. The basic concept of the Adv.-ORIENT Cycle uses a three-pronged approach, separation, transmutation and utilization of nuclides and elements, based on the FBR fuel cycle. Fundamental research studies done in Adv.-OEIENT Cycle [Phase-1: 2006–2010] have led to the following findings. 1. Cs and Sr separation and its utilization: Silica gel loaded with ammonium molybdophosphate (AMP) and hybrid organic microcapsules with crown ether D18C6 were investigated to chromatographically separate Cs and Sr, respectively. In particular, uptake experiments of Cs from solution simulating the spent fuel solution obtained were carried out by a batch method, and the uptake rates achieved were more than 90%. 2. Minor actinide (MA)/lanthanide/fission product (FP) separation: A tertiary pyridine type resin (TPR) can be used to recover Am, Cm and lantanide elements with a high separation factor by a chromatographic method from spent fuel solution. The TPR can be used with hydrochloric acid (HCl) as well as nitric acid (HNO 3). 3. Ru, Ph, Pd and Tc separation: A catalytic electrolytic extraction (CEE) method can effectively separate Ru, Ph, Pd and Tc. High recovery ratios of Ru, Rh, Pd, Tc, Se, etc. were achieved using HCl solutions. Rh co-deposition significantly accelerated reduction of Ru, Tc and Re using HNO 3 solutions. 4. Ru, Ph, Pd and Tc utilization: Based on the mixed deposit obtained from the CEE experiments, Ru/Rh/Pd/Tc(Re)-Pt electrodes provided the highest catalytic reactivity in the electrolytic production of hydrogen in an alkali solution. 5. Basic engineering research: Results of corrosion experiments showed that Hastelloy-B and Ta had a good anti-corrosive property in a wide range of HCl concentrations. The basic thermo-chemical stability of TPR and tri-butyl phosphorous (TBP, as a reference) was also experimentally studied, and the process safety conditions to be specified for practical use of TPR could be identified.

Multi-sample acoustic biosensing microsystem for protein interaction analysis

The current work describes a novel setup for multi-sample biomolecular analysis. It is based on the assembly of a dual acoustic device chip with a four-channel microfluidic module, forming an array of eight available domains for experiments. Initially, multiple detection was demonstrated via the specific interaction of neutravidin with four different biotinylated proteins, namely protein G, protein A, bovine serum albumin, and immunoglobulin G; results revealed a reproducibility between the microchannel domains better than 90%. Real-time analysis of the binding interactions was used to calculate the affinity and kinetic constants of the four biotinylated molecules binding to surface-immobilized neutravidin; this was the first time that this information was derived using a biosensing device and four biotinylated molecules. Interestingly, all calculated kinetic and affinity constants resemble those typical of antibody-antigen interactions, although the investigated specific binding was of avidin–biotin nature. Finally, under device pre-functionalization conditions, it was possible to probe eight interactions all together, exploiting the full capacity of the microsystem and reducing significantly the analysis time, contrary to the use of the standard acoustic device configuration. The outcome of this full-scale validation opens the way for the integrated acoustic platform to be implemented in even higher throughput detection for future diagnostic/biomedical applications, as well as in fundamental research studies regarding biomolecular interaction investigation and characterization.

Comparison between Nickel‐Sulfur Fire Assay Te Co‐precipitation and Isotope Dilution with High‐Pressure Asher Acid Digestion for the Determination of Platinum‐Group Elements, Rhenium and Gold

The accurate determination of platinum‐group elements (PGE), rhenium and gold is important in both fundamental research and ore deposit studies. Questions have been raised by some authors as to whether the nickel‐sulfur fire assay technique (NiS‐FA) efficiently collects all the PGE. On the other hand, most isotope dilution (ID) techniques can only treat small test portion masses (2 g was used for high‐pressure asher digestion; HPA) and this makes them more vulnerable to nugget effects. We determined PGE concentrations in ten reference materials with the aim of comparing the performance characteristics of the two methods. Both methods determine Ru, Pd, Os, Ir and Pt and we found that there were no significant systematic differences in the recovery. The advantages of NiS‐FA were that: (a) it is capable of determining Rh and Au; (b) the relatively large test portion mass (15 g) reduces the nugget effect and (c) it is faster and less expensive than HPA‐ID. The advantages of HPA‐ID were that: (a) it determined Re and (b) it had low level blanks, lower detection limits and hence better precision in low‐level homogeneous samples. Each technique had advantages and limitations; they should be considered as complementary rather than competing techniques.

Neue therapeutische Ansätze bei speziellen Erkrankungen des Dünndarms

Numerous reports on fundamental research and clinical studies have appeared in the past 1-2 decades which have contributed decisively to understanding inflammatory diseases of the small intestine. Illustrated by the examples of Crohn's disease, celiac disease, refractory sprue, and Whipple's disease, the rationale and evidence for treatment approaches are presented that are based on these pathophysiological findings. Emphasis is placed on modulation of the intestinal flora with antibiotics and probiotics as well as immunomodulatory/immunosuppressive measures with so-called biological agents. Future treatment options that directly intervene in the disease process are discussed.

Coal chemical industry and its sustainable development in China

China is rich in coal resource, which is vital for energy security in this country. In early 21st century, the coal chemical industry in China will be oriented to the development of high efficiency, safety, cleanliness, and optimum utilization. In this review, the authors present an introduction to the utilization status of primary energy production and consumption in China. Since 2005, fundamental research studies, supported by the Ministry of Science and Technology of Chinese National Basic Research Program, have been carried out at Taiyuan University of Technology. The Ministry stresses that the new coal chemical industry should be developed in a sustainable manner to realize effective utilization of energy. Moreover, upgrading the high technology to improve actively the recycling processes of coal chemical engineering is of strategic importance to realize the modern coal chemical engineering.

RECENT ADVANCES IN THE GENETICS OF PHAEOCHROMOCYTOMA AND FUNCTIONAL PARAGANGLIOMA

1. Recent clinical and fundamental research studies have revolutionized our understanding of the genetics of phaeochromocytoma (PH) and functional paraganglioma (FPGL). It was widely thought that only 10% of PH patients had familial disease and that the malignant phenotype of PH could not be diagnosed before occurrence of the first metastasis. 2. Human genetic studies have now shown that 25-30% of patients have hereditary PH due to a germline mutation in the SDHB, SDHD, VHL, RET or NF1 gene and that the identification of a germline SDHB mutation is associated with a high risk of malignancy and a poor prognosis in PH/PGL patients. 3. Fundamental research studies have shown that SDH genes are tumour suppressor genes and that succinate dehydrogenase inactivation induces abnormal stimulation of the hypoxia-angiogenesis pathway. 4. Finally various fundamental research studies, conducted through the Cortico and Medullo-surrenale: les Tumeurs Endocrines (COMETE) network in France and by other groups worldwide, have produced new recommendations for genetic counselling and testing and for the management of PH patients. They have also improved our understanding of the molecular mechanisms involved in PH tumorigenesis.

A biologically active angiogenesis inhibitor, human serum albumin–TIMP-2 fusion protein, secreted from Saccharomyces cerevisiae

Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an endogenous and bi-functional inhibitor of angiogenesis. TIMP-2 is expressed in an insoluble form in Escherichia coli and secreted at a very low level from yeast. Here, we report on a high level of secretion of TIMP-2 fused with human serum albumin (HSA) from the yeast Saccharomyces cerevisiae. The secreted HSA–TIMP-2 fusion protein (87kDa) was purified to greater than 95% homogeneity. The HSA–TIMP-2 protein inhibited approximately 81% of tube formation of human umbilical vein endothelial cells (HUVECs) when studied at a concentration of 187μM. The systemic administration of HSA–TIMP-2 at 40mg/kg to the C57B1/6 mouse inhibited the growth of B16BL6 tumors. Furthermore, a combination treatment of HSA–TIMP-2 with 5-fluorouracil (50mg/kg) showed significant effects on tumor growth in this model. The high level of secretion of the biologically active angiogenesis inhibitor from S. cerevisiae should facilitate fundamental research and application studies of HSA–TIMP-2, as an attractive candidate for therapeutic agents treating angiogenesis-related diseases.

Recombinant protein production by large-scale transient gene expression in mammalian cells: state of the art and future perspectives

The expansion of the biologics pipeline depends on the identification of candidate proteins for clinical trials. Speed is one of the critical issues, and the rapid production of high quality, research-grade material for preclinical studies by transient gene expression (TGE) is addressing this factor in an impressive way: following DNA transfection, the production phase for TGE is usually 2-10 days. Recombinant proteins (r-proteins) produced by TGE can therefore enter the drug development and screening process in a very short time--weeks. With "classical" approaches to protein expression from mammalian cells, it takes months to establish a productive host cell line. This article summarizes efforts in industry and academia to use TGE to produce tens to hundreds of milligrams of r-proteins for either fundamental research or preclinical studies.

Development of high power VRLA batteries using novel materials and processes

Nowadays UPS manufacturers demand batteries with very high specific power and relatively low specific energy, because most mains failures can be defined as “microfailures”, usually of the order of seconds. Due to this fact, it is not necessary to provide energy but power. Within a 3-year EU funded project, a new AGM valve-regulated lead–acid battery with weight and volume substantially reduced, as well as a substantial improvement in its reliability, is under development. These aspects can provide the achievement of a more efficient, safe and economic energy supply.Battery specific power is practically related to electrode area, so that its increase, and therefore an electrode thickness reduction, appear essential to achieve the project objectives. Furthermore, it is necessary to achieve a similar reduction in the conventional glass microfibre separator. But such thin material should have improved mechanical properties and can make the battery more prone to develop short circuits across the separator. In order to avoid this problem, a new microporous polyethylene membrane has been developed and tested, with excellent mechanical properties, high porosity and low pore size. For these reasons, the final separator configuration includes a combination of both materials, improved non-woven glass microfibre and the polyethylene membrane.Batteries are designed and assembled by Tudor (Exide Technologies) as battery manufacturer and will be tested in real conditions by MGE UPS Systems as end user. Daramic for the membrane and Bernard Dumas for the glass microfibre mat, have developed and supplied the separators, while the Inorganic Chemistry Department of Córdoba University carries out fundamental research studies on very thin electrodes.

A Concentric Flow Conical Nozzle Burner for Highly Stabilized Partially Premixed Flames

A new burner design is presented in this work for highly stabilized partially premixed flames using gaseous fuel. The partially premixed flow is created in a concentric flow tube and the flames are stabilized by a relatively large diverging conical nozzle. The concentric flow conical nozzle burner (CFCN) creates highly stabilized flames at high Reynolds number, up to 60000. Three versions of the burner have been investigated and a maximum load of about 250 kW with 20 mm diameter nozzle has been achieved in partially premixed flame. Higher load is expected for larger burner size. The stability characteristics of the CFCN burner show that it is suitable for industrial applications. The burner turndown ratio is between 15 and 20. Fundamental research studies and modeling of the flames in CFCN are feasible because of the simple flow geometry of the burner. Therefore, four flames have been selected in the present work for detailed thermal reaction zone structure investigation and OH radical distribution using simultaneous two-dimensional imaging of Rayleigh scattering and Laser Induced Predissoeiation Fluorescence (LIPF). The reaction zone structure is relatively thin and may be classified in the thin reaction zones regime. The OH signal correlates well with temperature at the reaction zone. More fine structure in the preheat zone can be observed from the temperature images as compared with those of the OH radical. Stable flame structure with continuous reaction zone at high stretch conditions has been observed.

Influence of cations vacancies on the K and LIII Zn edges of spinel-related compounds.

Compounds having oxygen vacancies exhibit particular physico-chemical properties. For example, in the ease of the perovskite type cubic system, disordered oxygen vacancies are intimately linked to ionic conductivity (Mori et al, 1994). Here we conduct a fundamental research study dedicated to spinel related compounds in order to discuss the information which can be extracted from the XANES part of the absorption spectra. In order to achieve this goal, we first recall the structural characteristics of the ZnAI204 reference compound and the structural parameters derived from the numerical simulations of the EXAFS modulations collected at the Zn K edge on a set of original materials coming from soft chemistry (Bazin et al, 1998). Then, we will discuss the XANES data obtained at the Zn K and Lm edges as well as the numerical simulations performed us ing the FeFF program and corresponding to several structural hypothesis (essentially influence of Zn or O vacancies).