gebhart/patrepeval huggingface dataset:
New horizons in the pathogenesis, diagnosis and management of sarcopenia (2013)

Sarcopenia is the age-related loss of skeletal muscle mass and function. It is now recognised as a major clinical problem for older people and research in the area is expanding exponentially. One of the most important recent developments has been convergence in the operational definition of sarcopenia combining measures of muscle mass and strength or physical performance. This has been accompanied by considerable progress in understanding of pathogenesis from animal models of sarcopenia. Well-described risk factors include age, gender and levels of physical activity and this knowledge is now being translated into effective management strategies including resistance exercise with recent interest in the additional role of nutritional intervention. Sarcopenia is currently a major focus for drug discovery and development although there remains debate about the best primary outcome measure for trials, and various promising avenues to date have proved unsatisfactory. The concept of 'new tricks for old drugs' is, however, promising, for example, there is some evidence that the angiotensin-converting enzyme inhibitors may improve physical performance. Future directions will include a deeper understanding of the molecular and cellular mechanisms of sarcopenia and the application of a lifecourse approach to understanding aetiology as well as to informing the optimal timing of interventions.
Quantification of picogram levels of specific DNA immobilized in microtiter wells (1985)

A non-radioisotopic and sensitive method for quantification of specific DNA immobilized in microtiter wells has been developed. This method is based upon the immobilization of DNA in microtiter wells and hybridization with biotinylated DNA probe which is followed by complexing with avidin-beta-galactosidase. By measuring fluorescence emitted from the hydrolyzed product by beta-galactosidase of 4-methylumbelliferyl-beta-D-galactoside, it has become possible to quantify a few picograms of specific DNA in DNA samples immobilized in plastic microtiter wells.
Mouse Model of Colonic Adenoma-Carcinoma Progression Based on Somatic Apc Inactivation (2007)

Mutations in the adenomatous polyposis coli (APC) gene are pivotal in colorectal tumorigenesis. Existing mouse intestinal tumor models display mainly small intestinal lesions and carcinomas are rare. We defined human CDX2 sequences conferring colon epithelium-preferential transgene expression in the adult mouse. Mice carrying a CDX2P-NLS Cre recombinase transgene and a loxP-targeted Apc allele developed mainly colorectal tumors, with carcinomas seen in 6 of 36 (17%) of mice followed for 300 days. Like human colorectal lesions, the mouse tumors showed biallelic Apc inactivation, beta-catenin dysregulation, global DNA hypomethylation, and aneuploidy. The predominantly distal colon and rectal distribution of tumors seen in mice where one Apc allele was inactivated in epithelial cells from distal ileum to rectum suggests that regional differences in the intestinal tract in the frequency and nature of secondary genetic and epigenetic events associated with adenoma outgrowth have a contributing role in determining where adenomas develop. The presence of large numbers of small intestine tumors seemed to inhibit colorectal tumor development in the mouse, and gender-specific effects on tumor multiplicity in the distal mouse colon and rectum mimic the situation in humans where males have a larger number of advanced adenomas and carcinomas in the distal colon and rectum than females. The mouse model of colon-preferential gene targeting described here should facilitate efforts to define novel factors and mechanisms contributing to human colon tumor pathogenesis, as well as work on tumor-promoting environmental factors and agents and strategies for cancer prevention and treatment.
Antidote-Controlled Platelet Inhibition Targeting von Willebrand Factor with Aptamers (2007)

Thrombus formation is initiated by platelets and leads to cardiovascular, cerebrovascular, and peripheral vascular disease, the leading causes of morbidity and mortality in the Western world. A number of antiplatelet drugs have improved clinical outcomes for thrombosis patients. However, their expanded use, especially in surgery, is limited by hemorrhage. Here, we describe an antiplatelet agent that can have its activity controlled by a matched antidote. We demonstrate that an RNA aptamer targeting von Willebrand factor (VWF) can potently inhibit VWF-mediated platelet adhesion and aggregation. By targeting this important adhesion step, we show that the aptamer molecule can inhibit platelet aggregation in PFA-100 and ristocetin-induced platelet aggregation assays. Furthermore, we show that a rationally designed antidote molecule can reverse the effects of the aptamer molecule, restoring platelet function quickly and effectively over a clinically relevant period. This aptamer-antidote pair represents a reversible antiplatelet agent inhibiting a platelet specific pathway. Furthermore, it is an important step towards creating safer drugs in clinics through the utilization of an antidote molecule.
JNK or IKK, AP-1 or NF-κB, which are the targets for MEK kinase 1 action? (1998)

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans the biological, physical, and social sciences.
Kinetics of p53 Binding to Promoter Sites In Vivo (2001)

Downstream target genes of p53 are thought to mediate its tumor-suppressive activity, but it is unknown whether differential transactivation of these genes is regulated at the level of p53 binding to their promoters. To address this issue, p53 binding in vivo to consensus sites in the p21(Waf1), MDM2, and PIG3 promoters was investigated in cells exposed to adriamycin (ADR) or ionizing radiation as well as in an inducible p53 cell line. p53-DNA complexes were cross-linked in vivo by treating the cells with formaldehyde and processed by chromatin immunoprecipitation-PCR. This methodology allowed for the analysis of relevant p53-DNA complexes by preventing redistribution of cellular components upon collection of cell extracts. Increased p53 binding to the p21(Waf1), MDM2, and PIG3 promoters occurred within 2 h after p53 activation; however, significant increases in PIG3 transcription did not occur until 15 h after p53 binding. Gel shift analyses indicated that p53 had lower affinity for the consensus binding site in the PIG3 promoters compared to its consensus sites in the p21 and MDM2 genes, which suggests that additional factors may be required to stabilize the interaction of p53 with the PIG3 promoter. Further, acetylated p53 (Lys382) was found in chemically cross-linked complexes at all promoter sites examined after treatment of cells with ADR. In summary, the kinetics of p53 binding in vivo to target gene regulatory regions does not uniformly correlate with target gene mRNA expression for the p53 target genes examined. Our results suggest that target genes with low-affinity p53 binding sites may require additional events and will have delayed kinetics of induction compared to those with high-affinity binding sites.
Active Immunization Against the Vascular Endothelial Growth Factor Receptor flk1 Inhibits Tumor Angiogenesis and Metastasis (2002)

The vascular endothelial growth factor (VEGF) receptor fetal liver kinase 1 (flk1; VEGFR-2, KDR) is an endothelial cell-specific receptor tyrosine kinase that mediates physiological and pathological angiogenesis. We hypothesized that an active immunotherapy approach targeting flk1 may inhibit tumor angiogenesis and metastasis. To test this hypothesis, we first evaluated whether immune responses to flk1 could be elicited in mice by immunization with dendritic cells pulsed with a soluble flk1 protein (DC-flk1). This immunization generated flk1-specific neutralizing antibody and CD8+ cytotoxic T cell responses, breaking tolerance to self-flk1 antigen. Tumor-induced angiogenesis was suppressed in immunized mice as measured in an alginate bead assay. Development of pulmonary metastases was strongly inhibited in DC-flk1-immunized mice challenged with B16 melanoma or Lewis lung carcinoma cells. DC-flk1 immunization also significantly prolonged the survival of mice challenged with Lewis lung tumors. Thus, an active immunization strategy that targets an angiogenesis-related antigen on endothelium can inhibit angiogenesis and may be a useful approach for treating angiogenesis-related diseases.
Synthesis and Structure–Activity Relationships ofN-Benzyl Phenethylamines as 5-HT2A/2CAgonists (2014)

N-Benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting subnanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1- to 40-fold) for the 5-HT2A receptor in the binding assays, although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay, selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor.
Clinical observations on enzyme replacement therapy in patients with Fabry disease and the switch from agalsidase beta to agalsidase alfa (2014)

The switch of ERT from agalsidase beta to agalsidase alfa appears to be safe after 1 year of follow-up for Taiwanese patients with Fabry disease.
Vitamin E Supplementation in Patients With Carotid Atherosclerosis (2003)

An imbalance between oxidative stress and antioxidant status is present in patients with advanced atherosclerosis. Vitamin E supplementation improves this imbalance in plasma but not in plaques.
Cold denaturation of a repressor-operator complex: the role of entropy in protein-DNA recognition. (1994)

The mechanisms by which regulatory proteins recognize specific DNA sequences are not fully understood. Here we examine the basis for the stability of a protein-DNA complex, using hydrostatic pressure and low temperature. Pressure converts the DNA-binding Arc repressor protein from a native state to a denatured, molten-globule state. Our data show that the folding and dimerization of Arc repressor in the temperature range 0-20 degrees C are favored by a large positive entropy value, so that the reaction proceeds in spite of an unfavorable positive enthalpy. On binding operator DNA, Arc repressor becomes extremely stable against denaturation. However, the Arc repressor-operator DNA complex is cold-denatured at subzero temperatures under pressure, demonstrating that the favorable entropy increases greatly when Arc repressor binds tightly to its operator sequence but not a nonspecific sequence. We show how an increase in entropy may operate to provide the protein with a mechanism to distinguish between a specific and a nonspecific DNA sequence. It is postulated that the formation of the Arc-operator DNA complex is followed by an increase in apolar interactions and release of solvent which would explain its entropy-driven character, whereas this solvent would not be displaced in nonspecific complexes.
The Impact of Application and Architecture Properties on Real-Time Multiprocessor Scheduling (1997)

Guaranteeing the temporal correctness of a real-time system is a very challenging problem since application and architecture properties may be hard to model accurately. For example, modern computer architectures are typically equipped with mechanisms, such as cache memories and instruction pipelines, whose behavior are by nature stochastic. For hard real-time system with strict timing requirements, the worst-case performance of these mechanisms must be accounted for, which typically yields too low a resource utilization in the system. Also, many applications contain program loops whose termination conditions are a function of dynamic parameters such as input data. As a consequence, the predicted worst-case execution time of the application may have to be overly pessimistic to fit into a hard real-time context. Because the contemporary approach to designing real-time systems is very much based on design practices that assume fairly simple and "well-behaved" applications and architectures, there exists a gap between real-time scheduling theory and the models used for the application and architecture properties. Current trends indicate that applications and architectures are becoming more complex, which means that there is a risk that this gap will widen in the years to come. This motivates the evaluation of existing real-time scheduling techniques to study what application and architecture properties are critical from a real-time scheduling viewpoint. To achieve this, a flexible evaluation methodology is needed to provide for an objective evaluation of current and new real-time scheduling techniques. This thesis contributes towards fulfilling this need by developing an evaluation framework that allows for extensive studies of the impact of application and architecture properties on the quality of real-time multiprocessor schedules. This framework is an important part of a comprehensive methodology which has been successfully used for finding solutions for a set of problems related to real-time scheduling. The problems addressed in this thesis concern (i) time-deterministic communication in point-to-point networks, (ii) deadline assignment for precedence-constrained applications, (iii) objective function selection in list scheduling algorithms, and (iv) parameter selection in a branch-and-bound strategy for multiprocessor scheduling. The results in this thesis indicate that the impact of application and architecture properties cannot be ignored in the design of real-time scheduling techniques, be they direct properties such as application timing constraints or resource availability, or indirect properties such as application parallelism or execution time distribution. We have performed extensive simulation experiments that demonstrate fundamental phenomena for which we find the remedy in either new techniques, improvements of existing techniques, or recommendations in terms of parameter choices for existing techniques.
Chronic Motor Cortex Stimulation for Phantom Limb Pain: A Functional Magnetic Resonance Imaging Study: Technical Case Report (2001)

Chronic motor cortex stimulation can be used to relieve phantom limb pain and phantom limb phenomena. Integrated by an infrared-based frameless stereotactic device, fMRI data are useful in assisting the neurosurgeon in electrode placement for this indication. Pain control mechanisms and cortical reorganization phenomena can be studied by the use of fMRI.
Chondrogenic differentiation of adipose tissue‐derived mesenchymal stem cells: Greater doses of growth factor are necessary (2008)

There have been controversies regarding the chondrogenic potential of adipose tissue-derived mesenchymal stem cells (ATMSCs) compared with bone marrow-derived mesenchymal stem cells (BMMSCs). The purpose of this study was to confirm the hypothesis that chondrogenesis can be achieved from ATMSCs comparable to that from BMMSCs by using greater dose of currently known chondrogenic growth factors. Chondrogenesis was induced from ATMSCs by culturing them in pellets under the following conditions: #1 without growth factors (negative control); #2 5 ng/mL of TGF-beta2; #3 5 ng/mL of TGF-beta2 and 100 ng/mL of IGF-I; #4 15 ng/mL of TGF-beta2; #5 15 ng/mL of TGF-beta2 and 300 ng/mL of IGF-I; #6 25 ng/mL of TGF-beta2; #7 25 ng/mL of TGF-beta2 and 500 ng/mL of IGF-I. After 4 weeks of in vitro culture, the pellets were harvested for DNA quantification, analysis of the glycosaminoglycan content, reverse transcription, and real-time PCR for collagen type I (COL1A1), collagen type II (COL2A1), and Sox-9. Safranin-O and immunohistochemical staining for type II collagen also were carried out, and histological grading was performed based on the findings. A combination of 25 ng/mL TGF-beta2 and 500 ng/mL IGF-I produced results comparable to the positive control (BMMSCs treated with 5 ng/mL TGF-beta2) as demonstrated by DNA amount, GAG analysis, real-time PCR, and histological findings. Although ATMSCs have lower chondrogenic potentials than BMMSCs, chondrogenesis comparable to BMMSCs can be induced from ATMSCs using a greater dose combination of growth factors. These results lend a further support to the application of ATMSCs for cartilage tissue engineering.
Interpretation of Raman spectra of disordered and amorphous carbon (2000)

The model and theoretical understanding of the Raman spectra in disordered and amorphous carbon are given. The nature of the G and D vibration modes in graphite is analyzed in terms of the resonant excitation of \ensuremath{\pi} states and the long-range polarizability of \ensuremath{\pi} bonding. Visible Raman data on disordered, amorphous, and diamondlike carbon are classified in a three-stage model to show the factors that control the position, intensity, and widths of the G and D peaks. It is shown that the visible Raman spectra depend formally on the configuration of the ${\mathrm{sp}}^{2}$ sites in ${\mathrm{sp}}^{2}$-bonded clusters. In cases where the ${\mathrm{sp}}^{2}$ clustering is controlled by the ${\mathrm{sp}}^{3}$ fraction, such as in as-deposited tetrahedral amorphous carbon (ta-C) or hydrogenated amorphous carbon (a-C:H) films, the visible Raman parameters can be used to derive the ${\mathrm{sp}}^{3}$ fraction.
Supporting FPGA microprocessors through retargetable software tools (1996)

FPGA systems outperform many ASIC and supercomputer systems through effective use of the reconfigurable resource. Reusing design effort across different applications requires a standard, flexible software environment. Driving FPGA systems from ANSI C is possible using 1 cc (an ANSI C compiler) targeted at an FPGA system and dasm (a retargetable, flexible assembler). The compiler supports custom hardware capabilities of FPGA systems, as well as all constructs of C. The assembler reads instruction definitions at assemble time, allowing the user to add new custom hardware functions which dasm can assemble correctly to an instruction stream the hardware executes. A source code debugger has been implemented for this system.
Processive Replication of Single DNA Molecules in a Nanopore Catalyzed by phi29 DNA Polymerase (2010)

Coupling nucleic acid processing enzymes to nanoscale pores allows controlled movement of individual DNA or RNA strands that is reported as an ionic current/time series. Hundreds of individual enzyme complexes can be examined in single-file order at high bandwidth and spatial resolution. The bacteriophage phi29 DNA polymerase (phi29 DNAP) is an attractive candidate for this technology, due to its remarkable processivity and high affinity for DNA substrates. Here we show that phi29 DNAP-DNA complexes are stable when captured in an electric field across the α-hemolysin nanopore. DNA substrates were activated for replication at the nanopore orifice by exploiting the 3'-5' exonuclease activity of wild-type phi29 DNAP to excise a 3'-H terminal residue, yielding a primer strand 3'-OH. In the presence of deoxynucleoside triphosphates, DNA synthesis was initiated, allowing real-time detection of numerous sequential nucleotide additions that was limited only by DNA template length. Translocation of phi29 DNAP along DNA substrates was observed in real time at Ångstrom-scale precision as the template strand was drawn through the nanopore lumen during replication.
An Electrodynamic Levitation System for Studying Individual Cloud Particles under Upper-Tropospheric Conditions (2000)

Abstract A laboratory system composed of an electrodynamic levitation cell within an environmental control chamber has been designed and built. The system is ideal for studies of individual particles, such as pure water droplets, aqueous solution droplets, solid salt particles, and ice crystals, under mid- and upper-tropospheric conditions. The experimental system has several features that make it particularly useful for studies of cloud physics. The levitation cell has a cubic geometry with transparent electrodes, thus allowing for full, three-axis positioning of a levitated particle, as well as a large range of viewing angles for optical access and light-scattering measurements. Particles in the approximate diameter range of 10 to 100 μm can be suspended indefinitely with minimal wall influences. The levitation cell is housed within an environmental control chamber capable of operating at temperatures (T), pressures (p), vertical velocities (w), and saturation ratios (with respect to ice, Si) in the ran...
Relations between excitability and contractility in rat soleus muscle: role of the Na+‐K+ pump and Na+/K+ gradients (1999)

1. The effects of reduced Na+/K+ gradients and Na+-K+ pump stimulation on compound action potentials (M waves) and contractile force were examined in isolated rat soleus muscles stimulated through the nerve. 2. Exposure of muscles to buffer containing 85 mM Na+ and 9 mM K+ (85 Na+/9 K+ buffer) produced a 54% decrease in M wave area and a 50 % decrease in tetanic force compared with control levels in standard buffer containing 147 mM Na+ and 4 mM K+. Subsequent stimulation of active Na+-K+ transport, using the beta2-adrenoceptor agonist salbutamol, induced a marked recovery of M wave area and tetanic force (to 98 and 87% of the control level, respectively). Similarly, stimulation of active Na+-K+ transport with insulin induced a significant recovery of M wave area and tetanic force. 3. During equilibration with 85 Na+/9 K+ buffer and after addition of salbutamol there was a close linear correlation between M wave area and tetanic force (r = 0.92, P < 0.001). Similar correlations were found in muscles where tetrodotoxin was used to reduce excitability and in muscles fatigued by 120 s of continuous stimulation at a frequency of 30 Hz. 4. These results show a close correlation between excitability and tetanic force. Furthermore, in muscles depressed by a reduction in the Na+/K+ gradients, beta-adrenergic stimulation of the Na+-K+ pump induces a recovery of excitability which can fully explain the previously demonstrated recovery of tetanic force following Na+-K+ pump stimulation. Moreover, the data indicate that loss of excitability is an important factor in fatigue induced by high-frequency (30 Hz) stimulation.