gebhart/patrepeval huggingface dataset:
The MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation (2008)

There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich's ataxia (FA). The identification of potentially toxic mitochondrial (MIT) iron (Fe) deposits in FA suggests that Fe plays a role in its pathogenesis. This study used the muscle creatine kinase conditional frataxin (Fxn) knockout (mutant) mouse model that reproduces the classical traits associated with cardiomyopathy in FA. We examined the mechanisms responsible for the increased cardiac MIT Fe loading in mutants. Moreover, we explored the effect of Fe chelation on the pathogenesis of the cardiomyopathy. Our investigation showed that increased MIT Fe in the myocardium of mutants was due to marked transferrin Fe uptake, which was the result of enhanced transferrin receptor 1 expression. In contrast to the mitochondrion, cytosolic ferritin expression and the proportion of cytosolic Fe were decreased in mutant mice, indicating cytosolic Fe deprivation and markedly increased MIT Fe targeting. These studies demonstrated that loss of Fxn alters cardiac Fe metabolism due to pronounced changes in Fe trafficking away from the cytosol to the mitochondrion. Further work showed that combining the MIT-permeable ligand pyridoxal isonicotinoyl hydrazone with the hydrophilic chelator desferrioxamine prevented cardiac Fe loading and limited cardiac hypertrophy in mutants but did not lead to overt cardiac Fe depletion or toxicity. Fe chelation did not prevent decreased succinate dehydrogenase expression in the mutants or loss of cardiac function. In summary, we show that loss of Fxn markedly alters cellular Fe trafficking and that Fe chelation limits myocardial hypertrophy in the mutant.
Dose-ranging study of Indole-3-Carbinol for breast cancer prevention (1997)

Sixty women at increased risk for breast cancer were enrolled in a placebo-controlled, double-blind dose-ranging chemoprevention study of indole-3-carbinol (I3C). Fifty-seven of these women with a mean age of 47 years (range 22-74) completed the study. Each woman took a placebo capsule or an I3C capsule daily for a total of 4 weeks; none of the women experienced any significant toxicity effects. The urinary estrogen metabolite ratio of 2-hydroxyestrone to 16 alpha-hydroxyestrone, as determined by an ELISA assay, served as the surrogate endpoint biomarker (SEB). Perturbation in the levels of SEB from baseline was comparable among women in the control (C) group and the 50, 100, and 200 mg low-dose (LD) group. Similarly, it was comparable among women in the 300 and 400 mg high-dose (HD) group. Regression analysis showed that peak relative change of SEB for women in the HD group was significantly greater than that for women in the C and LD groups by an amount that was inversely related to baseline ratio; the difference at the median baseline ratio was 0.48 with 95% confidence interval (0.30, 0.67). No other factors, such as age and menopausal status, were found to be significant in the regression analysis. The results in this study suggest that I3C at a minimum effective dose schedule of 300 mg per day is a promising chemopreventive agent for breast cancer prevention. A larger study to validate these results and to identify an optimal effective dose schedule of I3C for long-term breast cancer chemoprevention will be necessary.
Basic and Clinical Aspects of Non-neuronal Acetylcholine: Biological and Clinical Significance of Non-canonical Ligands of Epithelial Nicotinic Acetylcholine Receptors (2008)

Mucocutaneous keratinocytes and bronchial epithelial cells express nicotinic acetylcholine receptors (nAChRs). Emerging evidence indicates that nAChRs can be stimulated also by the tobacco-derived nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) that can induce tumors in laboratory animals. Nitrosamines may disturb the delicate balance between cell proliferation, growth arrest, and apoptosis. A novel paradigm of cell regulation via nAChR has been discovered in studies of SLURP (secreted mammalian Ly-6/urokinase plasminogen activator receptor-related protein)-1 and -2. Experimental results suggest that SLURP-1 and -2 regulate keratinocyte proliferation, apoptosis, and differentiation. Most importantly, SLURPs and professional nicotinic antagonists can abolish, in part, the abilities of NNK and NNN to cause tumorigenic transformation of immortalized keratinocytes. Learning the pharmacology of the nitrosamine vs. SLURP action on epithelial cells may help develop an effective anti-cancer treatment and prevention programs wherein hazardous effects of tobacco products are anticipated, or even abolished, by a pharmacologic ligand of the specific nicotinic receptor acting as an antidote.
Developments in Rail Simulators and Computer Based Training to Increase Training (2000)

Recent advances in computer software and hardware has allowed development of new methods of computer and simulator based training. Sydac Pty Ltd has recently upgraded and developed a number of simulators that provide new capabilities designed to increase training efficiency and effectiveness. This has been done in conjunction with QR who have extensive experience in the use of Train Driving Simulators and Part Task Trainers for their competency based training and action learning programs. The underlying training effectiveness and efficiency goals, the new capabilities and functionality plus an outline of how these have been implemented in upgraded 3000 class electric locomotives console simulators and the new 4000 class diesel locomotives full cab mobile simulator are presented. A discussion of the success achieved since their introduction is included. New capabilities introduced to meet the QR training objectives are explained. These include the trainee only operation, swipe card access and training performance logging system and the facility for remote access via the QR network provide through the use of 'web enabled' software. New training features such as the provision of automatic expert driver, a fully configurable lesson option menu definable for a specific user or group of users and a graphical train building tool are discussed.
Dissociation of Synchronization and Excitability in Furosemide Blockade of Epileptiform Activity (1995)

Furosemide, a chloride cotransport inhibitor, reversibly blocked synchronized burst discharges in hippocampal slices without reducing the pyramidal cell response to single electrical stimuli. Images of the intrinsic optical signal acquired during these slice experiments indicated that furosemide coincidentally blocked changes in extracellular space. In urethane-anesthetized rats, systemically injected furosemide blocked kainic acid-induced electrical discharges recorded from cortex. These results suggest that (i) neuronal synchronization involved in epileptiform activity can be dissociated from synaptic excitability; (ii) nonsynaptic mechanisms, possibly associated with furosemide-sensitive cell volume regulation, may be critical for synchronization of neuronal activity; and (iii) agents that affect extracellular volume may have clinical utility as antiepileptic drugs.
Thermal analysis and NMR study of a poly(ethylene oxide) complex electrolyte : PEO(LiCF3SO3)x (1984)

We have determined the equilibrium diagram between the different phases which coexist in the complexes between the poly(ethylene oxide) PEO and the salt LiCF3SO 3, by using DSC and NMR techniques. We have also measured the variation of the glass transition temperature as a function of the salt concentration dTg/dx = 280 K/(mole of salt per mole of monomer unit). We show that in the temperature range 340-420 K the ionic conduction σ only takes place in the amorphous phase. The thermal dependence of σ, previously interpreted in term of Arrhenius law, indeed results from that of three terms : the salt concentration in the amorphous phase (number of carriers), the local dynamics of the polymer chains (diffusion coefficient) and the respective amounts of crystalline and amorphous phases. The temperature dependence of each of these parameters has been estimated from experiments in the sample x-1 = 8 and they combine to give a fair description of σ(T). A striking result is the small temperature dependence of the diffusion coefficient (Dσ ≅ 6 x 10 -8 cm2 s-1 at 375 K). Taking into account these parameters also provides a satisfactory interpretation of the ionic conductivity behaviour in most of complexes formed between PEO and the alkali metals salts.
Sulfate Moieties in the Subendothelial Extracellular Matrix Are Involved in Basic Fibroblast Growth Factor Sequestration, Dimerization, and Stimulation of Cell Proliferation (1996)

The growth promoting activity of the subendothelial extracellular matrix (ECM) is attributed to sequestration of basic fibroblast growth factor (bFGF) by heparan sulfate proteoglycans and its regulated release by heparin-like molecules and heparan sulfate (HS) degrading enzymes. HS is also involved in bFGF receptor binding and activation. The present study focuses on the growth promoting activity and bFGF binding capacity of sulfate-depleted ECM. Corneal endothelial cells (EC) maintained in the presence of chlorate, an inhibitor of phosphoadenosine phosphosulfate synthesis, produced ECM containing 10-15% of the sulfate normally present in ECM. Incorporation of sulfate into HS was reduced by more than 90%. Binding of 125I-bFGF to sulfate-depleted ECM was reduced by 50-60% and only about 10% of the ECM-bound bFGF was accessible to release by heparin. Incubation of 125I-bFGF on top of native ECM resulted in dimerization of the ECM-bound bFGF, but there was a markedly reduced binding and dimerization of bFGF on sulfate-depleted ECM. ECM produced in the presence of chlorate contained a nearly 10-fold less endogenous bFGF as compared to native ECM and exerted little or no mitogenic activity toward vascular EC and 3T3 fibroblasts. In other studies, we investigated the interaction between chlorate-treated vascular EC and either native or sulfate-depleted ECM. Exogenous heparin stimulated the proliferation of chlorate-treated EC seeded on native ECM, suggesting its interaction with ECM-bound bFGF and subsequent presentation to high affinity cell surface receptors. On the other hand, heparin had no effect on chlorate-treated cells seeded in contact with sulfate-depleted ECM or regular tissue culture plastic. Altogether, the present experiments indicate that heparan sulfate proteoglycans associated with the cell surface and ECM act in concert to regulate the bioavailability and growth promoting activity of bFGF. While HS in the subendothelial ECM functions primarily in sequestration of bFGF in the vicinity of responsive cells, HS on cell surfaces is playing a more active role in displacing the ECM-bound bFGF and its subsequent presentation to high affinity signal transducing receptors.
Exploiting VLIW schedule slacks for dynamic and leakage energy reduction (2001)

The mobile computing device market is projected to grow to 16.8 million units in 2004, representing an average annual growth rate of 28% over the five year forecast period. This brings the technologies that optimize system energy to the forefront. As circuits continue to scale in future, it would be important to optimize both leakage and dynamic energy. Effective optimization of leakage and dynamic energy consumption requires a vertical integration of techniques spanning from circuit to software levels. Schedule stacks in codes executing in VLIW architectures present an opportunity for such an integration. In this paper, we present compiler-directed techniques that take advantage of schedule slacks to optimize leakage and dynamic energy consumption. The proposed techniques have been incorporated into a cycle accurate simulator using parameters extracted from circuit level simulation. Our results show that a unified scheme that uses both dynamic and leakage energy reduction techniques is effective in reducing energy consumption.
Interface capacitance in metal-semiconductor junctions (1989)

A new theory of the interface capacitance at metal-semiconductor junctions is presented. The diode capacitance is attributed to the modulation of the effective Schottky barrier height by interface charge. Relations between the measured capacitance and the physical properties of the interface states are formulated by using Shockley–Read statistics and taking into account the electron relaxation-time dispersion. This theory is applied to NiSi2-nSi diodes with both epitaxial and nonepitaxial interfaces. Spectra of density distribution, as well as other interface parameters, are obtained, indicating that interface states in these diodes are most probably defect related.
Antitumor effect of implanted ethylene-vinyl alcohol copolymer matrices containing anticancer agents on Ehrlich ascites carcinoma and P388 leukemia in mice. (1985)

Ethylene-vinyl alcohol (EVAI) copolymer was evaluated as a vehicle for controlled or sustained release of 5-fluorouracil (5-FU) and adriamycin. The variation of initial drug concentration and, to an even greater extent, the variation in comonomer ratio affected the drug release rate as well as the cumulative amount of the drug released. An increase in the ethylene content of the EVAI copolymer decreased drug release. It appears that EVAI copolymer can be used as a membrane for controlling the release of 5-FU or adriamycin. The antitumor activity of EVAI copolymer matrices containing these anticancer agents was evaluated against Ehrlich ascites carcinoma (EAC) in mice on the basis of changes in body weight and animal survival data. Tumor cell injections were performed on day 0 and matrix implantations on day 3, both intraperitoneally. The suppressive effect of matrices containing anticancer agents on the increase in body weight was higher than that of the free drugs. A prolongation of the life span of tumor-bearing mice following implantation of therapeutic matrices was also noted. Implantation of the EVAI copolymer matrix containing an anticancer agent was less effective against the P388 leukemia than the EAC. These results suggest that EVAI copolymer matrices containing anticancer agents may be effective in cancer chemotherapy. Matrices composed of EVAI copolymer could be useful vehicles for implanted delivery systems for anticancer agents.
Herpesvirus Entry Mediator Ligand (HVEM-L), a Novel Ligand for HVEM/TR2, Stimulates Proliferation of T Cells and Inhibits HT29 Cell Growth (1998)

Herpesvirus entry mediator (HVEM), a member of the tumor necrosis factor (TNF) receptor family, mediates herpesvirus entry into cells during infection. Upon overexpression, HVEM activates NF-kappaB and AP-1 through a TNF receptor-associated factor (TRAF)-mediated mechanism. Using an HVEM-Fc fusion protein, we screened soluble forms of novel TNF-related proteins derived from an expressed sequence tag data base. One of these, which we designated HVEM-L, specifically bound to HVEM-Fc with an affinity of 44 nM. This association was confirmed with soluble and membrane forms of both receptor and ligand. HVEM-L mRNA is expressed in spleen, lymph nodes, macrophages, and T cells and encodes a 240-amino acid protein. A soluble, secreted form of the protein stimulates proliferation of T lymphocytes during allogeneic responses, inhibits HT-29 cell growth, and weakly stimulates NF-kappaB-dependent transcription.
The RIFLE and AKIN classifications for acute kidney injury: a critical and comprehensive review (2013)

In May 2004, a new classification, the RIFLE (Risk, Injury, Failure, Loss of kidney function, and Endstage kidney disease) classification, was proposed in order to define and stratify the severity of acute kidney injury (AKI). This system relies on changes in the serum creatinine (SCr) or glomerular filtration rates and/or urine output, and it has been largely demonstrated that the RIFLE criteria allows the identification of a significant proportion of AKI patients hospitalized in numerous settings, enables monitoring of AKI severity, and is a good predictor of patient outcome. Three years later (March 2007), the Acute Kidney Injury Network (AKIN) classification, a modified version of the RIFLE, was released in order to increase the sensitivity and specificity of AKI diagnosis. Until now, the benefit of these modifications for clinical practice has not been clearly demonstrated.
Expression and localisation of matrix metalloproteinases and their natural inhibitors in fistulae of patients with Crohn’s disease (2004)

Background: Fistulae are a troublesome complication of Crohn’s disease but little is known of the final effector molecules responsible for matrix degradation. Although matrix metalloproteinases (MMPs) have been strongly implicated in tissue injury in Crohn’s disease, their role in fistula formation is unknown. Aim: To determine the expression pattern of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in fistulae of patients with Crohn’s disease. Patients and methods: Resected fistula specimens were obtained from patients with Crohn’s disease (n = 11) and classified according to the predominant histological features—that is, acute versus chronic inflammation. Patients with fistulae due to other diseases (n = 9) and normal colon (n = 5) served as controls. MMP and TIMP protein expression was measured by single or double labelled immunohistochemistry, and mRNA expression by in situ hybridisation. MMP activity was measured by gelatin zymography. Results: Compared with normal colon, strong MMP-3 expression was consistently observed in fistulae in Crohn’s disease, irrespective of the stage of inflammatory activity. MMP-3 transcripts and protein were localised in large mononuclear cells and fibroblasts. MMP-9 transcripts and protein were expressed in granulocytes and only in fistulae with acute inflammation. Staining for MMP-1 and MMP-7 was weak and negative for MMP-10, whereas MMP-2 was equally expressed in normal colon and fistulae. TIMP-1, TIMP-2, and TIMP-3 expression was low in all samples. Similar expression patterns were found in fistulae of the disease control group. Fistulae also expressed active MMP-2 and MMP-9, as measured by gelatin zymography. Conclusion: MMP-3 and MMP-9 are markedly upregulated in intestinal fistulae and may contribute to fistula formation through degradation of the extracellular matrix, irrespective of the underlying disease process.
Response of lightly and highly pigmented porcine skin (Sus scrofa domestica) to single 3.8-microm laser radiation pulses. (2006)

The purpose of this study was to determine the effect of melanin on skin response to single 3.8-microm, 8-micros laser pulses and the difference in lesion formation thresholds. Our hypothesis was that pigmentation would play a significant role in skin energy absorption at 3.8 microm. Previous studies comparing pigmented and lightly pigmented porcine skin with human skin found that compared with Yorkshire pigs, Yucatan minipigs were a superior model for laser skin exposure because of their higher pigmentation levels. In the current study, 10 pigs under general anesthesia were exposed to 3.8-microm laser pulses ranging from 0.01 J/cm2 to 93 J/cm2. Gross examinations and skin biopsies were done 24 h after laser exposure, and histologic examinations were conducted on these tissue samples. The 24-h effective dose (ED50) was determined to be 4.5 J/cm2 for Yucatan mini-pigs and 2.6 J/cm2 for Yorkshire pigs. As deposited energy was increased, the lesion presentation progressed from desiccation of the superficial layer of epidermis (4 J/cm2) to desiccation with inflammatory centers (14 J/cm2), and finally to replacement of inflammatory areas with an epidermal ulcerated central area (=21 J/cm2). Therefore we found no statistical difference between the 24-h ED50 of the 2 breeds of pigs, nor was there any difference in histologic presentation at 24 h postexposure.
High expression of human beta S- and alpha-globins in transgenic mice: erythrocyte abnormalities, organ damage, and the effect of hypoxia. (1992)

A line of transgenic mice with two cointegrated transgenes, the human beta S- and alpha 2-globin genes, linked to the beta-globin locus control region was produced and bred with mice carrying a deletion of the mouse beta major-globin gene. In transgenic mice homozygous for the beta major deletion (alpha H beta S[beta MDD]; where alpha H is human alpha-globin and MD is mouse deletion), 72.5 +/- 2.4% (mean +/- SD) of the beta-chains are beta S and the ratio of alpha H- to beta S-globin was 0.73. Introduction of a heterozygous mouse alpha-globin deletion into mice homozygous for the beta major deletion (alpha H beta S[alpha MD beta MDD]) resulted in 65.1 +/- 8.5% beta S and a human alpha/beta ratio of 0.89 +/- 0.2. Sickling occurs in 95% of erythrocytes from alpha H beta S[beta MDD] mice after slow deoxygenation. Transmission electron microscopy revealed polymer fiber formation but not fascicles of fiber. Increased organ weight was noted in lung, spleen, and kidney of transgenic mice vs. controls that may be due to hypertrophy or increased blood volume in the lungs and/or increased tissue water content. The hemoglobin content of lung, spleen, and kidney was also elevated in transgenic animals due to trapped hemoglobin and/or increased blood volume. When transgenic and control mice were examined by magnetic resonance imaging at 9.4 tesla, some transgenic animals had enlarged kidneys with prolonged relaxation time, consistent with increased organ weight and water content. The glomerular filtration rate was elevated in transgenic animals, which is characteristic of young sickle cell patients. Furthermore, exposure to hypoxia resulted in significantly decreased hematocrit, increased erythrocyte density, and induced a urine-concentrating defect. We conclude that the transgenic mouse line reported here has chronic organ damage and further hematological and organ dysfunction can be induced by hypoxia.
Genetic algorithm based quantum circuit synthesis with adaptive parameters control (2009)

Genetic algorithms were among the early choices for quantum circuit synthesis, because of their ability to evolve a given starting circuit towards one of the possible solutions. The synthesis method presented here is the first GA-based approach that dynamically adjusts its control parameters. The adaptive parameter control takes into account the analysis performed on each genetic operator, in order to automatically find an acceptable tradeoff between runtime and appropriate exploration. The experimental results prove that this method improves the synthesis runtime and the size of the circuit to be handled up to 7 qubits (previous GA-based techniques are effective only for 3-4 qubit circuits).
Exploiting microRNA regulation for genetic engineering (2012)

RNA interference (RNAi) has been a landmark discovery in science. A typical application is to knock down the expression of endogenous genes by delivering small interfering RNA (siRNA) into cells triggering the degradation of complementary mRNA. However, RNAi can also be exploited the other way round: making use of the huge diversity of endogenous microRNAs (miRNA), the expression of exogenously introduced genes tagged with artificial miRNA target sequences can be negatively regulated according to the activity of a given miRNA which can be tissue-, lineage-, activation- or differentiation stage specific. This has significantly expanded the regulatory potential of gene transfer vectors and will benefit both basic science and therapeutic applications. This review briefly introduces the reader to the technical basis for exploiting miRNA regulation, followed by a discussion of specific applications for miRNA-regulated vectors/viruses in basic research, gene- and virotherapy.