gebhart/patrepeval huggingface dataset:
TETHERED IL-15 TO AUGMENT THE THERAPEUTIC POTENTIAL OF T CELLS EXPRESSING CHIMERIC ANTIGEN RECEPTOR: MAINTAINING MEMORY POTENTIAL, PERSISTENCE, AND ANTITUMOR ACTIVITY (2014)

This paper reports the results from a detailed study on how risk assessments of chemicals are actually made. The study is performed by comparing 29 cancer risk assessments made of one and the same chemical substance, namely, trichloroethylene. In this paper, the conclusions that are drawn in these risk assessment documents are described, and differences between the conclusions are explored. This is made within the framework of a proposed cancer risk assessment index. The selection of scientific data for risk assessment purposes is analyzed and the different risk assessors' interpretations and evaluations of individual primary data are compared. It is concluded that the data sets utilized by the trichloroethylene risk assessors are surprisingly incomplete and that biased data selection may have influenced some of the risk assessors' conclusions. Different risk assessors often interpret and evaluate one and the same study in different ways. There are also indications of both interpretation bias and evaluation bias for some of the risk assessors.
Epidermal Growth Factor Receptor Variant III Status Defines Clinically Distinct Subtypes of Glioblastoma (2007)

Established prognostic factors in GBM were not predictive of outcome in the EGFRvIII-positive subset, although this requires confirmation in independent data sets. GBMs negative for both EGFRvIII and YKL-40 show less aggressive behavior.
Role of homology in site-specific recombination of bacteriophage lambda: evidence against joining of cohesive ends. (1987)

Bacteriophage lambda integration and excision take place at specific loci called attachment sites. Earlier work has shown that efficient recombination requires the identical sequence to be present in both attachment sites throughout the seven-base-pair region between the points of strand exchange. A plausible model for the role of homology postulates that Int, the site-specific recombinase, makes double-strand breaks at attachment sites such that each broken end has a short single-strand protrusion. Recombination would then depend upon the capacity of these protrusions to form Watson-Crick helices--i.e., to anneal--a process that might require perfect complementarity between the cohesive ends. To test this model, we have studied Int-promoted crosses in which one attachment site is a heteroduplex. Specifically, we constructed sites in which the seven-base-pair region between the points of strand exchange contains one or more noncomplementary pairs. The double-strand break and annealing mechanism predicts that crosses with these heteroduplex sites should yield one completed recombinant and one broken site. We find that such nonreciprocal recombination is uncommon and that the typical outcome of crosses involving a heteroduplex site is a reciprocal recombinant in which both products are resealed. Moreover, the occasional appearance of nonreciprocal products can be explained by our finding that Int can cleave heteroduplex attachment sites after recombination is completed. Taken together, our data strongly indicate that bacteriophage lambda recombination does not proceed by the homology-dependent annealing of cohesive ends; acceptable alternatives for the role of homology are discussed.
The drug/metabolite transporter superfamily (2001)

Previous work defined several families of secondary active transporters, including the prokaryotic small multidrug resistance (SMR) and rhamnose transporter (RhaT) families as well as the eukaryotic organellar triose phosphate transporter (TPT) and nucleotide-sugar transporter (NST) families. We show that these families as well as several other previously unrecognized families of established or putative secondary active transporters comprise a large ubiquitous superfamily found in bacteria, archaea and eukaryotes. We have designated it the drug/metabolite transporter (DMT) superfamily (transporter classification number 2.A.7) and have shown that it consists of 14 phylogenetic families, five of which include no functionally well-characterized members. The largest family in the DMT superfamily, the drug/metabolite exporter (DME) family, consists of over 100 sequenced members, several of which have been implicated in metabolite export. Each DMT family consists of proteins with a distinctive topology: four, five, nine or 10 putative transmembrane alpha helical spanners (TMSs) per polypeptide chain. The five TMS proteins include an N-terminal TMS lacking the four TMS proteins. The full-length proteins of 10 putative TMSs apparently arose by intragenic duplication of an element encoding a primordial five-TMS polypeptide. Sequenced members of the 14 families are tabulated and phylogenetic trees for all the families are presented. Sequence and topological analyses allow structural and functional predictions.
Binding of plasminogen to extracellular matrix. (1986)

We have previously demonstrated that plasminogen immobilized on various surfaces forms a substrate for efficient conversion to plasmin by tissue plasminogen activator (t-PA) (Silverstein, R. L., Nachman, R. L., Leung, L. L. K., and Harpel, R. C. (1985) J. Biol. Chem. 260, 10346-10352). We now report the binding of human plasminogen to the extracellular matrix synthesized in vitro by cultured endothelial cell monolayers. The binding was specific, saturable at plasma plasminogen concentrations, reversible, and lysine-binding site-dependent. Functional studies demonstrated that matrix immobilized plasminogen was a much better substrate for t-PA than was fluid phase plasminogen as shown by a 100-fold decrease in Km. Activation of plasminogen by t-PA and urokinase on the matrix was equally efficient. The plasmin generated on the matrix, in marked contrast to fluid phase, was protected from its fast-acting inhibitor, alpha 2-plasmin inhibitor. Matrix-associated plasmin converted bound Glu- into Lys-plasminogen, which in turn is more rapidly activated to plasmin by t-PA. The extracellular matrix not only binds and localizes plasminogen but also improves plasminogen activation kinetics and prolongs plasmin activity in the subendothelial microenvironment.
Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish (2015)

This article reviews the antidepressant actions of ketamine, an N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, and offers a potential neural mechanism for intranasal ketamine's ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5-40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (eg, Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia.
Role of Endoplasmic Reticulum Stress and c-Jun NH2-Terminal Kinase Pathways in Inflammation and Origin of Obesity and Diabetes (2005)

Metabolic and immune systems are the most fundamental requirements for survival, and many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily highly conserved. Consequently, metabolic and immune pathways are also highly integrated and interdependent. In the past decade, it became apparent that this interface plays a critical role in the pathogenesis of chronic metabolic diseases, particularly obesity and type 2 diabetes. Importantly, the inflammatory component in obesity and diabetes is now firmly established with the discovery of causal links between inflammatory mediators, such as tumor necrosis factor (TNF)-alpha and insulin receptor signaling and the elucidation of the underlying molecular mechanisms, such as c-Jun NH2-terminal kinase (JNK)- and inhibitor of nuclear factor-kappaB kinase-mediated transcriptional and posttranslational modifications that inhibit insulin action. More recently, obesity-induced endoplasmic reticulum stress has been demonstrated to underlie the initiation of obesity-induced JNK activation, inflammatory responses, and generation of peripheral insulin resistance. This article will review the link between stress, inflammation, and metabolic disease, particularly type 2 diabetes, and discuss the mechanistic and therapeutic opportunities that emerge from this platform by focusing on JNK and endoplasmic reticulum stress responses.
VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain (1999)

VEGF is mitogenic, angiogenic, and a potent mediator of vascular permeability. VEGF causes extravasation of plasma protein in skin bioassays and increases hydraulic conductivity in isolated perfused microvessels. Reduced tissue oxygen tension triggers VEGF expression, and increased protein and mRNA levels for VEGF and its receptors (Flt-1, Flk-1/KDR) occur in the ischemic rat brain. Brain edema, provoked in part by enhanced cerebrovascular permeability, is a major complication in central nervous system pathologies, including head trauma and stroke. The role of VEGF in this pathology has remained elusive because of the lack of a suitable experimental antagonist. We used a novel fusion protein, mFlt(1-3)-IgG, which sequesters murine VEGF, to treat mice exposed to transient cortical ischemia followed by reperfusion. Using high-resolution magnetic resonance imaging, we found a significant reduction in volume of the edematous tissue 1 day after onset of ischemia in mice that received mFlt(1-3)-IgG. 8-12 weeks after treatment, measurements of the resultant infarct size revealed a significant sparing of cortical tissue. Regional cerebral blood flow was unaffected by the administration of mFlt(1-3)-IgG. These results demonstrate that antagonism of VEGF reduces ischemia/reperfusion-related brain edema and injury, implicating VEGF in the pathogenesis of stroke and related disorders.
The cytoskeleton of the resting human blood platelet: structure of the membrane skeleton and its attachment to actin filaments. (1991)

We used high-resolution EM and immunocytochemistry in combination with different specimen preparation techniques to resolve the ultrastructure of the resting platelet cytoskeleton. The periphery of the cytoskeleton, an electron-dense subplasmalemmal region in thin section electron micrographs, is a tightly woven planar sheet composed of a spectrin-rich network whose interstices contain GPIb/IX-actin-binding protein (ABP) complexes. This membrane skeleton connects to a system of curved actin filaments (F-actin) that emanate from a central oval core of F-actin cross-linked by ABP. The predominant interaction of the radial actin filaments with the membrane skeleton is along their sides, and the strongest connection between the membrane skeleton and F-actin is via ABP-GPIb ligands, although there is evidence for spectrin attaching to the ends of the radial actin filaments as well. Since a mechanical separation of the F-actin cores and radial F-actin-GPIb-ABP complexes from the underlying spectrin-rich skeleton leads to the latter's expansion, it follows that the spectrin-based skeleton of the resting cell may be held in a compressed form by interdigitating GPIb/IX complexes which are immobilized by radial F-actin-ABP anchors.
The Relationship Between the Number of Spermatozoa Inseminated and the Reproductive Efficiency of Individual Dairy Bulls (1998)

The semen of 20 mature, evaluated bulls was split-sample diluted and contained 2.1 x 10(6) to 17.3 x 10(6) total spermatozoa per 0.25-ml French straw. The number of viable inseminated spermatozoa ranged from 1.1 x 10(6) to 11.8 x 10(6). Each bull had 2430 to 5330 first or second inseminations performed. The nonreturn rate at 56 d after AI was estimated for every dilution. The daily nonreturn rates to 180 d were used to estimate conception and calving rates at a given concentration. The relationship was determined between these estimations and the number of spermatozoa that were actually inseminated. The bulls differed significantly in their maximal nonreturn rate at high sperm numbers per AI and in the rate at which they approached this maximum. There was no correlation between the maximum nonreturn at high sperm numbers and the rate of approach, which implies that the ranking of the bulls for nonreturn rate 56 d after AI changes with the number of spermatozoa inseminated. Multiphasic analysis of reproductive efficiency revealed bull differences in estimated conception and calving rates. The estimated calving rate after conception was 82 to 90% and was independent of the number of spermatozoa that were inseminated. The sperm numbers needed to obtain 95% of the maximal conception rate ranged from 1 x 10(6) to 11 x 10(6).
Dicarboxylic Oligopeptide Bolaamphiphiles:  Proton-Triggered Self-Assembly of Microtubes with Loose Solid Surfaces (1998)

A new family of oligopeptide-based bolaamphiphiles, glycylglycine- (1a−h), glycylglycylglycine- (2a−b), sarcosylsarcosine- (3), l-prolyl-l-proline- (4), glycylsarcosylsarcosine- (5), and glycyl-l-prolyl-l-proline (6)-based bolaamphiphiles with a dicarboxylic headgroup at each end, has been synthesized. The oligopeptide fragments were linked via amide bond to a long-chain α,ω-dicarboxylic acid as a hydrocarbon spacer. Self-assembling properties of these bolaamphiphiles in water have been studied by light and cryogenic temperature transmission electron microscopy, infrared spectroscopy, and pH titration. Only sodium or potassium salts (acid soap) of the bolaamphiphiles 1a, 1c, 1e, 2a, and 2b produced well-defined microtubes of 1−3-μm diameter with closed ends. All the tubes encapsulated a number of vesicular assemblies inside the aqueous compartment. The tube formation strongly depends on the connecting alkylene chain length, the alkylene even−odd carbon numbers, and constituent amino acid residues. Vectorial formation of acid−anion dimers and loose interpeptide hydrogen-bond networks are responsible for the microtube self-assembly. The atomic force microscopic observation of the microtube made of 1e revealed a distorted hexagonal arrangement of the headgroups on the surface. A self-assembling model and the tube formation mechanism are also discussed from the viewpoint of proton-triggered self-assembly.
Fisher information matrix for branching processes with application to electron-multiplying charge-coupled devices (2011)

The high quantum efficiency of the charge-coupled device (CCD) has rendered it the imaging technology of choice in diverse applications. However, under extremely low light conditions where few photons are detected from the imaged object, the CCD becomes unsuitable as its readout noise can easily overwhelm the weak signal. An intended solution to this problem is the electron-multiplying charge-coupled device (EMCCD), which stochastically amplifies the acquired signal to drown out the readout noise. Here, we develop the theory for calculating the Fisher information content of the amplified signal, which is modeled as the output of a branching process. Specifically, Fisher information expressions are obtained for a general and a geometric model of amplification, as well as for two approximations of the amplified signal. All expressions pertain to the important scenario of a Poisson-distributed initial signal, which is characteristic of physical processes such as photon detection. To facilitate the investigation of different data models, a "noise coefficient" is introduced which allows the analysis and comparison of Fisher information via a scalar quantity. We apply our results to the problem of estimating the location of a point source from its image, as observed through an optical microscope and detected by an EMCCD.
Gene for Improved Nutritional Value in Barley Seed Protein (1970)

Genetically dependent 20 to 30 percent increase in lysine per 16 grams of nitrogen results in improved nutritional values in feeding trials with mice and rats. The recessive gene was selected from the World Barley Collection. Other amino acids are also influenced by the gene. Protein content segregates independently of the changed amino acid pattern. The gene putatively influences the matrix proteins, which characteristically adhere to the starch grains in meal preparations. The morphological character permits rapid microscopic screening of single seeds without affecting viability. Low yield is considerably improved by crossing and selection.
Pluronic F127 as a Cell Encapsulation Material: Utilization of Membrane-Stabilizing Agents (2005)

Thermoreversible gelation of the copolymer Pluronic F127 (generic name, poloxamer 407) in water makes it a unique candidate for cell encapsulation applications, either alone or to promote cell seeding and attachment in tissue scaffolds. At concentrations of 15-20% (w/w), aqueous Pluronic F127 (F127) solutions gel at physiological temperatures. The effect of F127 on viability and proliferation of human liver carcinoma cells (HepG2) was determined for both liquid and gel formulations. Cell concentration and viability over a 5-day period were measured by the trypan blue assay via hemocytometry and results were confirmed in both the MTT and LDH assays. With 0.1-5% (w/w) F127 (liquid), cells proliferated and maintained high viability over 5 days. However, at 10% (w/w) F127 (liquid), there was a significant decrease in cell viability and no cell proliferation was evident. HepG2 cell encapsulation in F127 concentrations ranging from 15 to 20% (w/w) (gel) resulted in complete cell death by 5 days. This was also true for the HMEC-1 (endothelial) and L6 (muscle) cell lines evaluated. Cell-seeding density did not affect cell survival or proliferation. Membrane-stabilizing agents (hydrocortisone, glucose, and glycerol) were added to the F127 gel formulations to improve cell viability. The steroid hydrocortisone demonstrated the most significant improvement in viability, from <2% (in F127 alone) to >70% (with 60 nM hydrocortisone added). These results suggest that F127 formulations supplemented with membrane-stabilizing agents can serve as viable cell encapsulation materials. In addition, hydrocortisone may be generally useful in the promotion of cell viability for a wide range of encapsulation materials.
Statistical machine translation (2010)

This introductory text to statistical machine translation (SMT) provides all of the theories and methods needed to build a statistical machine translator, such as Google Language Tools and Babelfish. In general, statistical techniques allow automatic translation systems to be built quickly for any language-pair using only translated texts and generic software. With increasing globalization, statistical machine translation will be central to communication and commerce. Based on courses and tutorials, and classroom-tested globally, it is ideal for instruction or self-study, for advanced undergraduates and graduate students in computer science and/or computational linguistics, and researchers in natural language processing. The companion website provides open-source corpora and tool-kits.
Cell-Free DNA—A Marker to Predict Ischemic Brain Damage in a Rat Stroke Experimental Model (2011)

We found that CFD levels correlate well with the extent of ischemic injury, brain edema, and neurologic outcome in rats 24 hours post-MCAO. We have also shown that CFD correlates well with the expected temporal progression of ischemic injury. These findings place CFD in a unique place as a biomarker for stroke, both experimentally and possibly clinically.
Phase II clinical trial of curcumin in patients with advanced pancreatic cancer (2006)

14151 Background: Pancreatic cancer is virtually always lethal, and the only FDA-approved therapies- gemcitabine and erlotinib- produce objective responses in less than 10% of patients. Curcumin (diferuloyl methane) is a plant- derived compound that inhibits the nuclear factor-kappa B (NF-kappa B) transcription factor (central to pancreatic cancer growth) and has substantial antitumor activity in preclinical models. We evaluated the toxicity and anti-tumor activity of curcumin, and its impact on survival and biologic correlates. Methods: Patients received 8 grams of curcumin (Sabinsa Corp.) by mouth daily for two months. Maintenance therapy was continued at the same dose and schedule until disease progression. Results: Seventeen patients were enrolled as of the date of analysis. Six were inevaluable: noncompliance (n = 1), never dosed (n = 1), noted to have gastric obstruction after one dose (n = 1), and too early (n = 3). Eleven patients were evaluable for response and 15 were evaluable for toxicity. To date, four patients have stable disease (2+, 2+, 3+ and 7 months) and one patient had a brief partial remission (73% reduction in tumor size by RECIST) that lasted one month. No toxicities have been observed. Serum was available for evaluation of pre-and post-dose cytokine levels in thirteen patients. Interestingly, the patient with the partial remission had marked increases (4–35 fold) in serum IL-1 receptor antagonist, IL-6, IL-10 and IL-8 levels. One to three other patients also had post-treatment increases in one or more of the above cytokines, albeit to a lesser extent (2–6 fold). Conclusions: We conclude that curcumin is well tolerated and our preliminary results suggest biologic activity in pancreatic cancer. Supported in part by the National Cancer Institute grant R21 CA 104337–01, The Topfer Fund for Pancreatic Cancer and Pancreatic SPORE grant 1 P20 CA10193–03. No significant financial relationships to disclose.
Locality Preserving Projections (2003)

Many problems in information processing involve some form of dimensionality reduction. In this paper, we introduce Locality Preserving Projections (LPP). These are linear projective maps that arise by solving a variational problem that optimally preserves the neighborhood structure of the data set. LPP should be seen as an alternative to Principal Component Analysis (PCA) -- a classical linear technique that projects the data along the directions of maximal variance. When the high dimensional data lies on a low dimensional manifold embedded in the ambient space, the Locality Preserving Projections are obtained by finding the optimal linear approximations to the eigenfunctions of the Laplace Beltrami operator on the manifold. As a result, LPP shares many of the data representation properties of nonlinear techniques such as Laplacian Eigenmaps or Locally Linear Embedding. Yet LPP is linear and more crucially is defined everywhere in ambient space rather than just on the training data points. This is borne out by illustrative examples on some high dimensional data sets.