gebhart/patrepeval huggingface dataset:
Animal models in translational medicine: Validation and prediction (2014)

Despite large investments in drug development, the overall success rate of drugs during clinical development remains low. One prominent explanation is flawed preclinical research, in which the use and outcome of animal models is pivotal to bridge the translational gap to the clinic. Therefore, the selection of a validated and predictive animal model is essential to address the clinical question. In this review, the current challenges and limitations of animal models are discussed, with a focus on the fit-for-purpose validation. Moreover, guidance is provided on the selection, design and conduct of an animal model, including the recommendation of assessing both efficacy and safety endpoints. In order to improve the clinical translation, the use of humanized mouse models and preclinical applications of clinical features are discussed. On top, the translational value of animal models could be further enhanced when combined with emerging alternative translational approaches. Focal points: • Bedside Animal models are essential for translation of drug findings from bench to bedside. Hence, critical evaluation of the face and predictive validity of these models is important. Reversely, clinical bedside findings that were not predicted by animal testing should be back translated and used to refine the animal models. • Benchside Proper design, execution and reporting of animal model results help to make preclinical data more reproducible and translatable to the clinic. • Industry Design of an animal model strategy is part of the translational plan rather than (a) single experiment(s). Data from animal models are essential in predicting the clinical outcome for a specific drug in development. • Community Review, standardization and refinement of animal models by disease expert groups helps to improve rigor of animal model testing. It is important that the applied animal models are validated fit-for-purpose according to stringent criteria and reproducible. • Governments As during drug development fit-for-purpose animal models are key for success in clinical translation, financial investments and support from the government to develop, optimize, validate and run such translation tools are important. Over time, this will be of benefit for patients and healthcare institutions. • Regulatory agencies Preclinical testing of a drug in an animal model is not a prerequisite for regulatory agencies before entering clinical trials, but does unquestionably provide valuable data on the expected clinical performance of the drug. Hence, testing in animal models is largely recommended from both a business and patient perspective. In addition, inclusion of safety parameters in animal models will help to build the required safety data package of drugs in development.
IL-12 plays a pivotal role in LFA-1-mediated T cell adhesiveness by up-regulation of CCR5 expression (2001)

The chemokine receptor CCR5 has been implicated in the recruitment of T cells to inflammatory sites. However, the regulation of CCR5 induction on T cells and its contribution to T cell adhesiveness are poorly understood. Using a Th1 clone, 2D6, that can be maintained with interleukin (IL)-12 or IL-2 alone (designated 2D6(IL-12) or 2D6(IL-2), respectively), we investigated how CCR5 is induced on T cells and whether CCR5 is responsible for up-regulating the function of adhesion molecules. 2D6(IL-12) grew, forming cell aggregates, in culture containing IL-12. This was due to lymphocyte function-associated antigen (LFA)-1-intercellular adhesion molecule (ICAM)-1 interaction, because 2D6(IL-12) expressed both LFA-1 and ICAM-1 and cell aggregation was inhibited by anti-ICAM-1 monoclonal antibody. Despite comparable levels of LFA-1 and ICAM-1 expression, 2D6(IL-2) cells did not aggregate in culture with IL-2. It is important that there was a critical difference in CCR5 expression between 2D6(IL-12) and 2D6(IL-2); the former expressed high levels of CCR5, and the latter expressed only marginal levels. Both types of cells expressed detectable albeit low levels of RANTES (regulated on activation, normal T expressed and secreted) mRNA. Unlike IL-12 or IL-2, IL-18 induced high levels of RANTES mRNA expression without modulating CCR5 expression. Therefore, combined stimulation with IL-12 and IL-18 strikingly up-regulated 2D6 cell aggregation. Notably, LFA-1-mediated aggregation of 2D6(IL-12) cells was suppressed by anti-CCR5 antibody. These results indicate that IL-12 plays a critical role in CCR5 expression on Th1 cells and consequently contributes to CCR5-mediated activation of LFA-1 molecules.
美国的社会主义者丹尼爱尔·德·莱昂 (1986)

十九世纪末二十世纪初美国社会主义运动和革命工人运动的历史同丹尼爱尔·德·莱昂(1852～1914)的名字紧密地联系在一起.德·莱昂——美国社会主义工人党的领袖、社会主义工人党中央机关报《人民报》的常任主编、马克思和恩格斯以及德国和法国社会主义者著作的英译者、精通史学、哲学、法学和经济学的行家——所有这些结合于一个人的一生.作为美国马克思主义的宣传者,德·莱昂是无与伦比的.
Distributed Learning Environment Using Advanced Services over the Internet. (1999)

Multimedia and hypermedia had and still have a tremendous impact on the evolution of educational software. In this paper we propose an Integrated Distributed Learning Environment (IDLE) for the implementation of the services of an educational network over TCP/IP networks such as the Internet. Our proposal aims at providing an integrated communicational environment, which supplies the communicative needs of an educational community, using the latest telecommunication and multimedia information processing technology. The environment that we implemented can be used for virtual lectures, virtual conferences, collaborative work on projects, which are shared among institutions, exchange of useful material and experiences among teachers, and creation of educational material.
Synthesis of a series of compounds related to betaxolol, a new .beta.1-adrenoceptor antagonist with a pharmacological and pharmacokinetic profile optimized for the treatment of chronic cardiovascular diseases (1987)

A series of para-substituted phenoxypropanolamines has been synthesized and tested for beta-adrenoceptor blocking activity. Some derivatives (8, 11, 12, 20, 21) exhibited greater in vitro potency than the reference drugs metoprolol and propranolol. This series, in contrast to propranolol but similar to metoprolol, possesses cardioselectivity. The 3-[p-[(cycloalkylmethoxy)ethyl]phenoxy]-1-substituted-amino-2-prop anol derivatives 8 (cyclopropylmethoxyethyl: betaxolol) and 11 (cyclobutylmethoxyethyl) produced antihypertensive effects in spontaneously hypertensive rats. Betaxolol (Kerlon, 8) was found to exhibit an appropriate preclinical pharmacological and human pharmacokinetic profile (elevated oral bioavailability and prolonged plasma half-life) for the treatment of chronic cardiovascular diseases such as hypertension and angina.
The L protein of Rift Valley fever virus can rescue viral ribonucleoproteins and transcribe synthetic genome-like RNA molecules (1995)

Overlapping cDNAs representing the complete L segment of Rift Valley fever virus were assembled, and the L protein was expressed via a recombinant vaccinia virus. The transcriptase activity of the L protein was assayed with two types of templates: natural ribonucleoproteins (RNPs) and artificial genome-like RNAs. RNPs purified in a CsCl gradient did not retain the RNA polymerase function, but the activity was restored when the L cDNA was expressed in mammalian cells via a recombinant vaccinia virus. Indeed, after transfection of transcriptase-depleted RNPs in cells infected with the recombinant vaccinia virus expressing the L protein, the mRNAs coding for the N and NSs proteins and to a lesser extent, those coding for the glycoproteins were synthesized as well as the corresponding proteins. The transcriptase activity of the recombinant L protein was then investigated by using synthetic templates containing the reporter chloramphenicol acetyltransferase gene in the antisense orientation flanked by the 3' and 5' noncoding region of the S genomic segment. Our results indicate that after transfection of the RNA templates, transcription was achieved in cells coexpressing both the L and N proteins. Together, the experiments demonstrate that the two proteins N and L are absolutely required and sufficient to reconstitute the transcriptase activity.
The intelligent network and forward-looking technology (1988)

The authors discuss the Advanced Intelligent Network (AIN), an architecture that includes both IN/1+ and IN/2 and will be introduced in phases, with releases envisioned at two-year intervals. Phase 1 requirements will be released in 1989 and first applications are targeted for deployment in 1991/2. They examine some future technologies and their impact on the AIN. They describe an AIN system architecture that can respond to change, concentrating on the effect of switching-system evolution to narrowband and broadband ISDN.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Amylin found in amyloid deposits in human type 2 diabetes mellitus may be a hormone that regulates glycogen metabolism in skeletal muscle. (1988)

Diabetes-associated peptide has recently been isolated and characterized from the amyloid of the islets of Langerhans in type 2 (non-insulin-dependent) diabetics, and immunoreactivity with antibodies to the peptide has been demonstrated in islet B cells of both normal and type 2 diabetic subjects. In view of the evidence presented in this paper that this 37-amino acid peptide may be a hormone present in normal individuals, we now propose the name "amylin" to replace "diabetes-associated peptide." Because increased amylin, deposited as amyloid within the islets of Langerhans, is characteristic of type 2 diabetes, the study below was performed to examine the possible effects of amylin on peripheral glucose metabolism. Whole amylin was synthesized by using solid-phase techniques, with formation of the disulfide linkage by oxidation in dilute aqueous solution and recovery of the peptide by lyophilization. The effects of amylin on glucose metabolism were studied in two preparations in vitro, isolated rat soleus muscle strips and isolated rat adipocytes. In skeletal muscle exposed to 120 nM amylin for 1 hr, there was a marked decrease in both basal and submaximally insulin-stimulated rates of glycogen synthesis, which resulted in significant reduction in the rates of insulin-stimulated glucose uptake. In muscles treated with amylin there was no response at the concentration of insulin required to stimulate glucose uptake half-maximally in untreated (control) muscles. In marked contrast, amylin had no effect on either basal or insulin-stimulated rates of glucose incorporation into either CO2 or triacylglycerol in isolated adipocytes. Therefore, amylin may be a factor in the etiology of the insulin resistance in type 2 diabetes mellitus, as both deposition of the peptide in islet amyloid and decreased rates of glucose uptake and glycogen synthesis in skeletal muscle are characteristic of this condition.
Efficient Generation of Major Histocompatibility Complex Class I-Peptide Complexes Using Synthetic Peptide Libraries (1998)

The use of synthetic random peptide libraries is a powerful technology for the study of many aspects of antigen presentation and peptide selection by major histocompatibility complex (MHC) molecules. Here we have used them in conjunction with a recombinant system to determine the peptide binding motifs of three classical class I MHC molecules of the laboratory rat: RT1-Aa, RT1-Au, and RT1-A1c. Described is a method for producing large amounts of soluble class I heavy and light chains in bacteria. Refolding RT1-Aa heavy chain (HC) with rat beta2-microglobulin (beta2m) in the presence of a specific peptide and the subsequent purification of the complex yielded conformationally correct material. This was assessed by gel chromatography, SDS-polyacrylamide gel electrophoresis, isoelectric focussing gel electrophoresis, enzyme-linked immunosorbent assay, and fluorescence-activated cell sorter analysis employing a previously unreported method utilizing a His-Tag affinity silica. By refolding RT1-Aa HC and rat beta2m around a random nonapeptide library and subjecting the resulting complex to acid elution of the bound peptides and pool sequencing, the peptide binding motif for this MHC class I molecule was determined. Results corresponded well with those previously determined from naturally bound peptides and in addition gave a clear and unambiguous signal for the C-terminal anchor residue. This method was then applied to determine the previously undescribed binding motifs for RT1-Au and RT1-A1c. For both molecules, the whole motif was confirmed from naturally bound peptides. We propose this method as an alternative way to obtain the whole class I MHC peptide motif, particularly when a specific antibody is unavailable and/or natural expression of the class I molecule of interest is low.
Trifluoroacetic Acid-Mediated Hydroarylation:  Synthesis of Dihydrocoumarins and Dihydroquinolones (2005)

[reaction: see text] Trifluoroacetic acid mediates the hydroarylation of alkenes to afford dihydrocoumarins and dihydroquinolones in good yield. Intermolecular hydroarylation of cinnamic acids by phenols is particularly facile, which leads to the conclusion that previous reports of palladium-catalyzed hydroarylation of cinnamic acids in trifluoroacetic acid are erroneous.
RNA Folding Methods and Protocols (2014)

Focusing on in vitro and intracellular RNA structure formation, RNA Folding: Methods and Protocols provides a comprehensive collection of experimental protocols which are suitable to dissect RNA folding pathways and to characterize the structure of RNA folding intermediates at nucleotide or even atomic resolution. The presented techniques include powerful tools with a long tradition in RNA research as well as more advanced, novel methods, thus the methods span multiple disciplines, including molecular biology, biochemistry, biophysics, and computational biology. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Practical and authoritative, RNA Folding: Methods and Protocols serves as a vital reference for researchers attempting to gain insights into the secrets of this astounding macromolecule
Ubiquitin-Mediated Pathways for Intracellular Proteolysis (1987)

Ubiquitination is one of several ways in which cells modify their proteins. As for phosphorylation or acetylation, there are distinct enzymes for adding and removing Ub from the surfaces of protein substrates. The dynamic equilibration of Ub with cellular proteins is also typical of most posttranslational modifications. Ubiquitination differs, however, in that the added group is large compared to acetate or phosphate. Its size must provide great potential for recognition by other cellular proteins. Ub may be the cell's reversible cross-linking reagent, covalently bound to protein substrates at one end and noncovalently associated with various Ub binding proteins at the other. It is likely that one ubiquitin binding protein is a component of the 26S ATP-dependent protease. The presence of Ub on histones and on the lymphocyte homing receptor suggests that ubiquitination does not serve exclusively to mark proteins for degradation. There are probably various ubiquitin binding proteins since Ub appears to be a multifunctional protein that affects chromatin structure, intracellular proteolysis, cellular interactions, and the stress response. This abundant protein may serve as an intracellular barometer whose distribution among several pools regulates a variety of processes.
A Novel, Valveless Ventricular Assist Device: The FishTail Pump. First Experimental In Vivo Studies (2002)

This article presents the first in vivo experiments with a new type of valveless ventricular assist device, a wave-generating pump. Our goal was to evaluate the hemodynamic performance of the pump by comparing it with the Biomedicus BP-80 centrifugal pump and by sustaining a 3 h long left ventricular assistance. We connected the two pumps in parallel and switched between them. We increased the aspiration by increments of -10 mm Hg at the inlet and measured developed flow, right carotid and femoral pressure, left atrial pressure, and left carotid flow. Then, we let the FishTail perform a 3 h long left ventricular assistance. The mean developed flow on the outlet was higher with the FishTail, with statistical significance, but this difference was not clinically significant. However, we observed an important amount of hemolysis during the ventricular assistance period. Although promising, this novel pumping device needs further prototypes to be clinically applicable.
Cell cycle: Regulatory events in G1 → S transition of mammalian cells (1994)

A cell divides into two daughter cells by progressing serially through the precisely controlled G1, S, G2, and M phases of the cell cycle. The crossing of the G1/S border, which is marked by the initiation of DNA synthesis, represents commitment to division into two complete cells. Beyond this critical point no further external signals are required. We now have more comprehensive knowledge of the temporal sequence of systems at this key transition from G1 to S--growth factor responses, a cascade of kinase reactions, activation of cyclins and their associated kinases, and oncogene and tumor suppressor gene products. Furthermore, we know that the absolute requirement for calcium and the timing of events associated with calmodulin and the 68 kDa calmodulin-binding protein are consistent with overall Ca++/calmodulin control of all steps from the response to growth factors in G1 to DNA replication in S phase. We now have to sort out the inter-relationships of myriad control proteins and their relation to the Ca++/calmodulin-dependent controls--Which are causes? Which are effects? And which are parallel processes? The answers will be important, as they represent both a much deeper understanding of this key process of life and an important opportunity for improving therapeutic medicine.
Insulin Action and Glucose Metabolism in Nondiabetic Control and NIDDM Subjects: Comparison Using Human Skeletal Muscle Cell Cultures (1995)

Myoblasts from human skeletal muscle were isolated from needle biopsy samples of vastus lateralis and fused to differentiated multinucleated myotubes. Specific high-affinity insulin and insulin-like growth factor I (IGF-I) binding, glucose transporter proteins GLUT1 and GLUT4, glycogen synthase and pyruvate dehydrogenase proteins, and their specific mRNAs were identified in fused myotubes. Insulin and IGF-I stimulated 2-deoxyglucose uptake twofold with half-maximal stimulation by insulin at 0.98 +/- 0.12 nmol/l and maximal stimulation at 17.5 nmol/l. Acute insulin treatment (33 nmol/l) doubled glycogen synthase activity and glucose incorporation into glycogen while increasing pyruvate dehydrogenase approximately 30%. In cells cultured from NIDDM subjects, both basal (6.9 +/- 1.0 vs. 13.0 +/- 1.7 pmol.mg protein-1.min-1) and acute insulin-stimulated transport (13.5 +/- 2.0 vs. 22.4 +/- 1.3 pmol.mg protein-1.min-1) were significantly reduced compared with nondiabetic control subjects (both P < or = 0.005). GLUT1 protein content of total membranes from NIDDM subjects was decreased compared with control subjects, while GLUT4 levels were similar between groups. A significant correlation (r = 0.65, P < or = 0.05) was present when maximal rates of insulin-stimulated glucose transport in cell culture from subjects were compared with their corresponding in vivo glucose disposal determined by hyperinsulinemic glucose clamp. In summary, differentiated human skeletal muscle cultures exhibit biochemical and molecular features of insulin-stimulated glucose transport and intracellular enzyme activity comparable with the in vivo situation. Defective insulin-stimulated glucose transport persists in muscle cultures from NIDDM subjects and resembles the reduced insulin-mediated glucose uptake present in vivo. We conclude that this technique provides a relevant cellular model to study insulin action and glucose metabolism in normal subjects and determine the mechanisms of insulin resistance in NIDDM.
Characterization of Rotating Structures in Coast-down by means of Continuous Tracking Laser Doppler Vibrometer (2011)

In rotating machinery variations of modal parameters with rotation speed may be extremely important in particular if very light and undamped structures are taken into account, like helicopters rotors or wind turbines. The relation between natural frequencies and rotation speed is expressed in the form of Campbell diagrams. However it could be required to know also the deviation of operational or mode shapes. In several cases it is not possible to fully control the rotating speed of the machine and only coast-down tests can be performed. Such kind of tests is often fast due to the reduced inertia of rotors: for this reason, an experimental technique able to determine Operational Deflection Shapes (ODSs) in short time and with sufficient accuracy, appears very promising. Moreover coast-down processes are very difficult to be controlled, they causing unsteady vibrations. The need to obtain ODSs from coast-down experiments requires the measurement over a large number of points and therefore a very efficient approach for the rotation control and synchronous acquisition must be developed. In this paper a continuous scanning system operating on rotating structures has been developed, that allows to measure ODS and natural frequencies excited in rotating conditions at different rotation speed during a coast down. This techniques has been tested on a laboratory test bench and compared with traditional Experimental Modal Analysis (EMA) results obtained in non-rotating conditions and with data from Tracking Laser Doppler Vibrometry (TLDV) operating in coast down and at consecutive constant rotation speeds (i.e. each measurement was performed in steady conditions). EMA and TLDV have been performed over a grid of points in order to have ODSs with adequate spatial resolution, it requiring long measurement time. However these data has been used as reference to validate the continuous scanning approach.
Group B Streptococcus Type III Glycoconjugate Vaccines. (1992)

グループB連鎖状球菌 (GBS) はグラム陽性で細胞表層に莢膜をもつ細菌であり、ヒト、特に新生児に病気を起させる。GBSの病毒性は主に、GBSの細胞を覆う莢膜多糖による。稀な例を除き4種の血清型の莢膜多糖 (Ia、Ib、II、III) がGBS疾患の原因となり、新生児でのGBS感染の3分の2近くは、III型の多糖を持つ系統による。GBS疾患の幼児の母親の、莢膜多糖に対する抗体のレベルは低いか測定にかからない程低い。ヒトに精製した多糖を接種することにより、多糖に特異的な抗体のレベルを上げることは理論的には可能である。しかしながら、他の多くの細菌の多糖と同様に、成人ではGBSの多糖の免疫原性は低い。最近の研究は、III型の糖鎖をそのまま、或いは誘導体として、破傷風トキソイドと結合させ、III型多糖の免疫原性を高めることに集中している。III型の多糖やオリゴ糖と破傷風トキソイドを結合させた色々なデザインの結合ワクチンが造られ、それらの免疫原性が実験動物で試されている。結合のさせ方や多糖の大きさが異なるにもかかわらず、GBSのIII型の糖結合体は全て、結合させていないネイティブのIII型の多糖と比べて、免疫原性が高かった。
Gene mapping by microdissection and enzymatic amplification: Heterogeneity in leukaemia associated breakpoints on chromosome II (1991)

A new strategy for mapping chromosome translocation breakpoints in relation to known genes has been developed. This approach is based on the amplification by the polymerase chain reaction (PCR) of specific target sequences from small numbers of microdissected chromosome fragments. This method has been applied to leukaemia-associated translocations affecting the q23 region of chromosome 11. In two independent leukaemias, the t(6;11) translocation was distinguished from the t(9;11) and t(4;11) translocations by demonstrating that the former breakpoint on chromosome 11 lay proximal to the CD3D gene while the latter breakpoints lay distal to CD3D. All three translocation breakpoints were found to lie proximal to ETSI and THYI. The data suggest that although these leukaemia-associated breakpoints on chromosome 11 are cytogenetically identical they may involve disruption of different genes. This approach offers a rapid alternative to mapping by hybridisation of probes either in situ to chromosomes or to somatic cell hybrids containing the appropriate derivative chromosomes.