Miracle-dz/UniFAR-FTUs huggingface dataset:
Enhanced anti‐angiogenic effect of a deletion mutant of plasminogen kringle 5 on neovascularization

Kringle 5 (K5), a proteolytic fragment of plasminogen, has been proved to be an angiogenic inhibitor. Previously, we have evaluated the effect of K5 on the vascular leakage and neovascularization in a rat model of oxygen‐induced retinopathy. In this study, we expressed K5 and a deletion mutant of K5 (K5 mutant) in a prokaryocyte expression system and purified them by affinity chromatography. K5 mutant was generated by deleting 11 amino acids from K5 while retaining the three disulfide bonds. The anti‐angiogenic activity of intact K5 and K5 mutant were compared in endothelial cells and retinal neovascularization rat model. K5 mutant inhibited the proliferation of primary human retinal capillary endothelial cells (HRCEC) in a concentration‐dependent manner, with an apparent EC50 of approximate 35 nmol/L, which is twofold more potent than intact K5. In the even higher concentration range, K5 mutant did not inhibit pericytes from the same origin of HRCEC, which suggested an endothelial cell‐specific inhibition. K5 mutant had no effect on normal liver cells and Bel7402 hepatoma cells even at high concentration range either. Intravitreal injection of the K5 and mutant in the oxygen‐induced retinopathy rat model both resulted in significantly fewer neovascular tufts and nonperfusion area than controls with PBS injection, as shown by fluorescein angiography. Furthermore, K5 mutant exhibited more strong inhibition effect on neovascularization than intact K5 by quantification of vascular cells. These results suggest that this K5 deletion mutant is a more potent angiogenic inhibitor than intact K5 and may have therapeutic potential in the treatment of those disorders with neovascularization, such as solid tumor, diabetic retinopathy, age‐related macular degeneration, rheumatoid arthritis, and hyperplasia of prostate. J. Cell. Biochem. © 2005 Wiley‐Liss, Inc.
The Effect of Sedation on Intracranial Pressure in Patients with an Intracranial Space-Occupying Lesion: Remifentanil Versus Propofol

BACKGROUND: In this study, we compared the effect of light sedation with remifentanil versus propofol on intracranial (ICP) and cerebral perfusion pressure (CPP) of patients undergoing stereotactic brain tumor biopsy under regional anesthesia. METHODS: This was a prospective, open-label, randomized, and controlled study. Forty patients undergoing stereotactic brain tumor biopsy under regional anesthesia were randomized into two groups to receive remifentanil or propofol titrated to a level of four on the modified Assessment of Alertness/Sedation Scale. ICP was measured via the biopsy needle. RESULTS: At the targeted level of sedation, the rates of infusion for remifentanil and propofol were, respectively, 4.2 ± 1.8 &mgr;g · kg−1 · h−1 and 4.3 ± 2.5 mg · kg−1 · h−1. At the time of ICP measurement, patients in the remifentanil group had a slower respiratory rate (11/min ± 3 vs 15 per min ± 3, P = 0.0001) and a higher Pco2 (48.3 ± 6.2 mm Hg vs 43.1 ± 5.5 mm Hg, P = 0.009) than patients in the propofol group. The mean was similar for both groups, 19.0 ± 11.9 mm Hg vs 16.4 ± 11.1 mm Hg for remifentanil and propofol, respectively (P = 0.48). Higher mean arterial blood pressure in the remifentanil group (101.1 ± 13.7 mm Hg vs 85.8 ± 12.7 mm Hg, P = 0.0008) resulted in a higher CPP than the propofol group: 82.0 ± 19.0 mm Hg vs 69.5 ± 17.0 ± 19.0 mm Hg (P = 0.03). CONCLUSION: Light sedation with remifentanil does not result in a higher ICP than propofol in patients undergoing stereotactic brain tumor biopsy. CPP might be better preserved with remifentanil.
Negotiating the Foundations of European Law, 1950–57: The Legal History of the Treaties of Paris and Rome

Abstract This article analyses how the seeds for the development of European law from the 1960s onwards were sown in the foundational treaties. It argues that despite the fact that both European treaties embodied a conscious choice by the majority of the governments not to establish the European Communities on a constitutional basis, a small number of politicians and jurists managed nonetheless to insert the potential for the constitutional practice. Following a chronological account of each set of negotiations, the article untangles the complex ideas and decisions, which crafted both the legal shape of the treaties and the jurisdiction of the new European Court of Justice. Les négotiations sur les fondations du droit européen: l'histoire juridique des traités de Paris et de Rome L'article analyse la façon dont les bases pour le développement du droit européen ont originellement été implantées dans les traités fondateurs. Il fait valoir que, malgré un choix délibéré de la majorité des gouvernements de ne pas établir les communautés européennes sur une base constitutionnelle, un nombre réduit de politiciens et de juristes ont néanmoins réussi à insérer dans les traités de Paris et de Rome le potentiel d'une pratique constitutionnelle. En suivant la trame chronologique des négociations, l'article démêle les idées et les décisions complexes qui ont façonné la nature juridique de chaque traité et la Cour de Justice Européenne. Aushandeln der Grundfesten des europäischen Rechts, 1950–1957: Die Rechtsgeschichte der Pariser und der Römischen Verträge Dieser Artikel analysiert, wie in den Gründungsverträgen der Boden für die Entwicklung des europäischen Rechts ab den 1960er Jahren bereitet wurde. Er argumentiert, obwohl beide europäischen Vertragswerke eine bewusste Entscheidung der Mehrheit der Regierungen verkörperten, die Europäische Gemeinschaft nicht auf eine Verfassungsbasis zu stellen, schaffte es eine kleine Zahl von Politikern und Juristen trotzdem, das Potenzial für die Verfassungspraxis einzuführen. Der Artikel wirft in einer chronologischen Darstellung jedes Verhandlungsabschnitts ein Schlaglicht auf die komplexen Gedanken und Entscheidungen, die sowohl die rechtliche Gestalt der Verträge als auch die Gerichtsgewalt des neuen Europäischen Gerichtshofs prägten.
Inhibition of the integrin signal constitutes a mouse iPS cell niche

Stem cells are regulated by their surrounding microenvironments, called niche, such as cell–cell interaction and extracellular matrix. Classically, feeder cells as a niche have been used in the culture of iPS cells from both the mouse and the human. However, the regulation mechanism of stem cells by feeder cells as a niche still have been partially unclear. In this study, we used three murine iPS cell lines, iPS‐MEF‐Ng‐20D‐17, iPS‐MEF‐Ng‐178B‐5 and iPS‐MEF‐Fb/Ng‐440A‐3, which were generated by different reprogramming methods. In general, these cell lines commonly need the feeder cells as a niche to culture. Recently, the effect of substrate stiffness is known in stem cell study. First, we focused on the mechanical properties of feeder cells, and then we speculated that feeder‐less culture might be made possible by using molecules in place of the mechanical properties of the niche. Finally, we found that the combination of disintegrin (echistatin) and 2i (GSK3 inhibitor and MEK inhibitor) is a sufficient condition for three murine iPS culture. This novel method of mimicking the murine iPS cell niche may be useful to understand signaling pathways to maintain the pluripotency of stem cells.
Multidrug Resistance Is Common in Escherichia coli Associated with Ileal Crohn's Disease

Background:Escherichia coli is increasingly implicated in the pathogenesis of ileal Crohn's disease (ICD), offering a potential therapeutic target for disease management. Empirical antimicrobial targeting of ileal E. coli has advantages of economy and speed of implementation, but relies on uniform susceptibility of E. coli to routinely selected antimicrobials to avoid apparent treatment failure. Therefore, we examined the susceptibility of ileal E. coli to such antimicrobials. Methods:E. coli from 32 patients with ICD and 28 with normal ileum (NI) were characterized by phylogroup, pathotype, antimicrobial susceptibility, and presence of antimicrobial resistance genes. Results:In all, 17/32 ICD and 12/28 NI patients harbored ≥1 E. coli strain; 10/24 E. coli strains from ICD and 2/14 from NI were nonsuscepti-ble to ≥1 antimicrobial in ≥3 categories (multidrug-resistant). Resistance to amoxicillin/clavulanic-acid, cefoxitin, chloramphenicol, ciprofloxa-cin, gentamicin, and rifaximin was restricted to ICD, with 10/24 strains from 8/17 patients resistant to ciprofloxacin or rifaximin (P < 0.01). Adherent-invasive E. coli (AIEC) were isolated from 8/32 ICD and 5/28 NI, and accounted for 54% and 43% of E. coli strains in these groups. In all, 8/13 AIEC strains from ICD (6/8 patients) versus 2/6 NI (2/5 patients) showed resistance to the macrophage-penetrating antimicrobials ciprofloxacin, clarithromycin, rifampicin, tetracycline, and trimethoprim/sulfamethoxazole. Resistance was associated with tetA, tetB, tetC, bla-TEM, blaoxa-1, sulI, sulII, dhfrI, dhfrVII, ant(3″)-Ia, and catI genes and prior use of rifaximin (P < 0.01). Conclusions:ICD-associated E. coli frequently manifest resistance to commonly used antimicrobials. Clinical trials of antimicrobials against E. coli in ICD that are informed by susceptibility testing, rather than empirical selection, are more likely to demonstrate valid outcomes of such therapy.
High CD46 Receptor Density Determines Preferential Killing of Tumor Cells by Oncolytic Measles Virus

Live attenuated Edmonston B strain of measles virus (MV-Edm) is a potent and specific oncolytic agent, but the mechanism underlying its tumor selectivity is unknown. The virus causes cytopathic effects (CPEs) of extensive syncytial formation in tumor cells but minimal damage or cell killing in normal cells. The CPE is dependent on expression of viral proteins and the presence of CD46, the major cellular receptor of MV-Edm. Using a virally encoded soluble marker peptide to provide a quantitative readout of the level of viral gene expression, we determined that tumor cells and normal cells expressed comparable levels of viral proteins. CD46 mediates virus attachment, entry, and virus-induced cell-to-cell fusion. Using engineered cells expressing a range of CD46 densities, we determined that whereas virus entry increased progressively with CD46 density, cell fusion was minimal at low receptor densities but increased dramatically above a threshold density of CD46 receptors. It is well established that tumor cells express abundant CD46 receptors on their surfaces compared with their normal counterparts. Thus, at low CD46 densities typical of normal cells, infection occurs, but intercellular fusion is negligible. At higher densities typical of tumor cells, infection leads to extensive cell fusion. Intercellular fusion also results in enhancement of viral gene expression through recruitment of neighboring uninfected cells into the syncytium, further amplifying the CPE. Discrimination between high and low CD46 receptor density provides a compelling basis for the oncolytic specificity of MV-Edm and establishes MV-Edm as a promising CD46-targeted cancer therapeutic agent.
Generalization of the extended transmission disequilibrium test to two unlinked disease loci

The extended transmission disequilibrium test (ETDT) of Sham and Curtis [1995] is a powerful test of the null hypothesis of no linkage between a multi‐allelic marker locus and a disease susceptibility locus of unknown location in the presence of association between alleles at the two loci. We propose a generalization of the ETDT to test simultaneously for linkage of markers to two unlinked disease loci. Analysis of the simulated data for Problem 2 would suggest improvements in power to detect linkage to pairs of disease loci over single locus tests. This is as a result of the two locus model taking account of epistasis between the disease loci.
Adaptation of Haemophilus influenzae to acquired and innate humoral immunity based on phase variation of lipopolysaccharide

Phase variation in colony morphology has been associated with the pathogenesis of infection caused by Haemophilus influenzae. This study shows that differences in colony opacity in non‐typeable H. influenzae (NTHi) strain H233 involve phase changes in the lipopolysaccharide (LPS) and depend on the expression of lic1 and lic2, which contain translational switches based on intragenic tandem repeats of 5′‐CAAT‐3′. Genetic analysis showed that opaque organisms have an out‐of‐frame number of repeats in both lic1, required for the expression of phosphorylcholine (ChoP), and lic2, a putative galactosyl transferase that adds the terminal galactose on Galα1‐4Gal. Defined variants in these loci were used to examine the contribution of individual LPS structures to resistance to serum bactericidal activity mediated by antibody and C‐reactive protein (CRP). The addition of ChoP by lic1 was the only factor in serum killing involving CRP and complement. The terminal galactose moiety, in contrast, conferred resistance to killing by naturally acquired antibody and complement present in human serum. As Galα1‐4Gal is also found on human glycolipids, it appears that decoration of the cell surface with this host‐like antigen blocks antibody‐mediated serum bactericidal activity. Genetic analysis of NTHi within the human respiratory tract demonstrated that Galα1‐4Gal may not be expressed during carriage but may be advantageous for the organism in inflammatory states such as pneumonia.
Forkhead Transcription Factors Are Critical Effectors of Cell Death and Cell Cycle Arrest Downstream of PTEN

ABSTRACT PTEN acts as a tumor suppressor, at least in part, by antagonizing phosphoinositide 3-kinase (PI3K)/Akt signaling. Here we show that Forkhead transcription factors FKHRL1 and FKHR, substrates of the Akt kinase, are aberrantly localized to the cytoplasm and cannot activate transcription in PTEN-deficient cells. Restoration of PTEN function restores FKHR to the nucleus and restores transcriptional activation. Expression of a constitutively active form of FKHR that cannot be phosphorylated by Akt produces the same effect as reconstitution of PTEN on PTEN-deficient tumor cells. Specifically, activated FKHR induces apoptosis in cells that undergo PTEN-mediated cell death and induces G1 arrest in cells that undergo PTEN-mediated cell cycle arrest. Furthermore, both PTEN and constitutively active FKHR induce p27KIP1 protein but not p21. These data suggest that Forkhead transcription factors are critical effectors of PTEN-mediated tumor suppression.
Efficacy of Antimicrobials against Biofilms of Achromobacter and Pseudomonas

Purpose Achromobacter xylosoxidans and Pseudomonas aeruginosa biofilms can develop in ophthalmic products and accessories such as contact lens cases, leading to the development of ocular infections. This study evaluated the efficacy of the antimicrobials polyaminopropyl biguanide (PAPB) and benzalkonium chloride (BAK) against A. xylosoxidans and P. aeruginosa biofilms. Methods Biofilms of A. xylosoxidans and P. aeruginosa used as a comparative control were formed by incubating the bacteria on contact lens cases and on coverslips in phosphate-buffered saline. The biofilms were then exposed to PAPB and BAK for 5 minutes and 4 hours. After exposure, alginate swabs were used to remove the biofilms from the lens cases and the bacteria were plated on tryptic soy agar for determination of survivors. Also, after exposure to these disinfectants, the A. xylosoxidans and P. aeruginosa biofilms were stained with SYTO 9 and propidium iodide. Using a confocal microscope with a 488-nm laser, the number of cells with damaged cell membranes was determined. Results After 5 minutes of exposure to BAK or PAPB, A. xylosoxidans biofilms were more resistant to the antimicrobial effects of these disinfectants than P. aeruginosa biofilms. After 4 hours, both organisms were reduced by more than 3 logs after exposure to either BAK or PAPB. Confocal microscopy studies revealed that BAK was more effective at damaging A. xylosoxidans and P. aeruginosa cell membranes than PAPB at the concentrations used in ophthalmic products. Conclusions Biofilms of the emerging pathogen A. xylosoxidans were more resistant to the disinfectants PAPB and BAK than biofilms of P. aeruginosa. Because of the emergence of A. xylosoxidans and the demonstrated greater resistance to the common ophthalmic preservatives BAK and PAPB than the standard Gram-negative organism P. aeruginosa, A. xylosoxidans biofilms should be assessed in antimicrobial challenge tests to assure the safety of multiuse ophthalmic products.
Changes in lower limb kinematics, kinetics, and muscle activity in subjects with functional instability of the ankle joint during a single leg drop jump

The purpose of this study was to identify differences in 3D kinematics, kinetics, and ankle joint muscle activity in subjects with functional instability (FI) of the ankle joint during a drop jump. Twenty‐four subjects with the subjective complaint of FI of the ankle joint and 24 noninjured control subjects performed 10 single leg drop jumps onto a force‐plate. Timing and magnitude of kinetic data, timing of kinematic data, and integrated EMG (IEMG) activity of the rectus femoris, peroneus longus, tibialis anterior, and soleus muscles during two 200‐ms time periods either side of initial contact (IC) with the ground were analyzed and compared between groups. Subjects with FI demonstrated a significant decrease in pre‐IC peroneus longus IEMG activity, which was accompanied by a change in frontal plane movement at the ankle joint during the same time period. Following IC, FI subjects were less efficient than control group subjects in reaching the closed packed position of the ankle joint. Significant differences were seen between the groups' time‐averaged and peak vertical and sagittal components of ground reaction force. The altered pre‐IC peroneus longus IEMG and increased inversion of the ankle joint observed in FI subjects could help to explain why subjects with FI may suffer from inversion injury to their ankle joint when subjected to an unanticipated ground contact. The kinematic and kinetic differences observed in subjects with FI may lead to repeated injury and damage to the supporting structures of the ankle joint. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:1991–2000, 2006
Fat Digestion and Absorption in the Proximal Intestine of the Dog.∗

Summary Two jejunal fistula dogs were fed a mixed test meal containing cottonseed oil triglycerides as the source of fat. Quantitative collection of material not absorbed during the complete transit of chyme to the fistulous opening revealed that cottonseed oil triglycerides were efficiently absorbed (69.9% and 55.0%) in the proximal intestine. Analysis of unabsorbed fat for free fatty acids and monoglycerides showed this lipid to be moderately well digested. Although absorption was increased when digestion was more complete, both the extent of digestion and absorption of fat could have depended primarily on variations in other gastrointestinal processes. Consequently, it cannot be concluded from these experiments that fat absorption is enhanced by increased lipolysis. The importance of soap formation in fat absorption is minimized by the fact that intestinal contents were almost always acid during the course of collection.
Comparing software design for testability to hardware DFT and BIST

Software is replacing hardware whenever possible, and this trend is increasing. Software faults are every bit as pervasive and difficult to deal with as hardware faults. Debugging software faults is manual, time consuming, often elusive and since they affect all systems deployed, most often they are critical. Design for Debugging would ensure that a software package can be readily debugged for any software fault. A comprehensive software test, however, is intended to eliminate the need for ad hoc debugging and ideally all “bugs” (we call software faults) would be caught and identified by the software test. Thus, it is imperative that the software community adopt means to ensure that software components are designed in a way that will detect and isolate software faults. This requirement is familiar to designers of hardware systems. Could the discipline of hardware design for testability (DFT) and Built-In [Self] Test (BIST) apply to software design for testability? The purpose of this paper is to discuss how many of the testability requirements and techniques for hardware DFT can be applied to software.
Modulation of graft-versus-tumor effects in a murine allogeneic bone marrow transplantation model by tumor-derived transforming growth factor-betaI.

Although graft-versus-leukemia effects in allogeneic bone marrow transplantation (alloBMT) are well documented, graft-versus-tumor (GVT) effects are poorly defined. To investigate the latter, we established a murine model of breast cancer using TS/A, a transforming growth factor (TGF)-beta1-secreting breast cancer cell line of BALB/c origin. In the setting of disparate (parent into F1) alloBMT, no appreciable GVT was identified. To assess whether TGF-beta1 secreted by the tumor might inhibit the antitumor response, TGF-beta1 antisense vector was transfected into the TS/A breast cancer cell line. Mice were inoculated with either TGF-beta1 antisense transfected or the mock transfected cell line and underwent syngeneic or alloBMT. No evidence of GVT was appreciated for the mock-transfected breast cancer cell line as assessed by an absence of a statistically significant difference in survival between syngeneic and alloBMT groups. However, there was a highly statistically significant survival difference between allogeneic versus syngeneic bone marrow transplantation groups inoculated with the TGF-beta1 antisense-transfected cell line (P = .00001) as well as when comparing the survival of mice that received alloBMT for TGF-beta1 antisense-transfected tumor versus mock-transfected tumor (P = .0008). These data suggest that (1) GVT exists against the antisense-transfected breast cancer cells in this experimental model and (2) TGF-beta1 may be involved in suppressing antitumor responses in the setting of alloBMT for breast cancer.