gebhart/patrepeval huggingface dataset:
Design, Synthesis, and Biological Evaluation of Hydroquinone Derivatives of 17-Amino-17-demethoxygeldanamycin as Potent, Water-Soluble Inhibitors of Hsp90 (2006)

17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.
Antifolates: the next generation. (1992)

A number of promising new antifolates have been entered in clinical trials in recent years. These agents have been rationally designed based on the current understanding of folate transport and metabolism and of the mechanisms by which cells become resistant to methotrexate. Methotrexate-resistant cell lines are generally sensitive to one or more of the newer antifolates, which differ from methotrexate by being either more lipid soluble, more extensively polyglutamated, or by inhibiting folate-requiring enzymes other than dihydrofolate reductase. Five of the agents furthest along in clinical testing, trimetrexate, piritrexim, edatrexate, lometrexol, and D1694, are discussed. These drugs offer exciting opportunities to expand the role of antifolates in cancer chemotherapy, as well as in antimicrobial and antirheumatic therapy.
Rapid and efficient analysis of 20,000 RNA-seq samples with Toil (2016)

ABSTRACT Toil is portable, open-source workflow software that supports contemporary workflow definition languages and can be used to securely and reproducibly run scientific workflows efficiently at large-scale. To demonstrate Toil, we processed over 20,000 RNA-seq samples to create a consistent meta-analysis of five datasets free of computational batch effects that we make freely available. Nearly all the samples were analysed in under four days using a commercial cloud cluster of 32,000 preemptable cores.
LY-2140023, a prodrug of the group II metabotropic glutamate receptor agonist LY-404039 for the potential treatment of schizophrenia. (2010)

LY-2140023 is a methionine amide prodrug of the orthosteric metabotropic glutamate receptor (mGluR)2/3 agonist LY-404039, being developed by Eli Lilly & Co, for the potential oral treatment of schizophrenia. LY-404039 is a rigid glutamate analog that selectively binds to mGluR2/3 compared with all other glutamate receptors and transporters, and with other monoaminergic receptors that have been implicated in the therapeutic efficacy of atypical antipsychotic drugs. Activation of mGluR2 has been associated with the antipsychotic-like behavioral effects of LY-404039, as indicated by experiments using mGluR2-/- and mGluR3-/- mice. Furthermore, mGluR2 acts as a glutamatergic autoreceptor in the brain regions that are believed to be important in the pathophysiology of schizophrenia, such as the prefrontal cortex, striatum, hippocampal formation and the thalamus. The antipsychotic efficacy of LY-2140023, predicted by a common battery of preclinical behavioral screens for antipsychotic drugs, was confirmed in a randomized, placebo-controlled, phase II clinical trial in patients with schizophrenia. In addition, LY-2140023 lacked the extrapyramidal and metabolic side effects that are commonly observed with the majority of currently approved antipsychotic drugs. Thus, LY-2140023 represents a rare psychiatric medicine that demonstrates the promise of being rationally developed from bench to bedside.
Correction of Multiple Striated Muscles in Murine Pompe Disease Through Adeno-associated Virus–mediated Gene Therapy (2008)

Glycogen storage disease type II (Pompe disease; MIM 232300) stems from the deficiency of acid alpha-glucosidase (GAA; acid maltase; EC 3.2.1.20), which primarily involves cardiac and skeletal muscles. An adeno-associated virus 2/8 (AAV2/8) vector containing the muscle creatine kinase (MCK) (CK1) reduced glycogen content by approximately 50% in the heart and quadriceps in GAA-knockout (GAA-KO) mice; furthermore, an AAV2/8 vector containing the hybrid alpha-myosin heavy chain enhancer-/MCK enhancer-promoter (MHCK7) cassette reduced glycogen content by >95% in heart and >75% in the diaphragm and quadriceps. Transduction with an AAV2/8 vector was higher in the quadriceps than in the gastrocnemius. An AAV2/9 vector containing the MHCK7 cassette corrected GAA deficiency in the distal hindlimb, and glycogen accumulations were substantially cleared by human GAA (hGAA) expression therein; however, the analogous AAV2/7 vector achieved much lower efficacy. Administration of the MHCK7-containing vectors significantly increased striated muscle function as assessed by increased Rotarod times at 18 weeks after injection, whereas the CK1-containing vector did not increase Rotarod performance. Importantly, type IIb myofibers in the extensor digitalis longus (EDL) were transduced, thereby correcting a myofiber type that is unresponsive to enzyme replacement therapy. In summary, AAV8 and AAV9-pseudotyped vectors containing the MHCK7 regulatory cassette achieved enhanced efficacy in Pompe disease mice.
Effect of Germ and Fiber Removal on Production of Ethanol from Corn (2004)

Ethanol fermentations were conducted using both whole corn, and corn with 100% of the germ, and a portion (~74%) of the fiber removed. Ethanol production increased 11% in the germ and fiber-removed corn vs the whole corn. The protein content of distiller’s dried grains and solubles increased from 30 to 36%, and phosphate levels were 60% lower in corn with germ and fiber removed vs whole corn. Removal of germ and fiber prior to fermentation allows higher starch loading and results in increased ethanol production. The integration of germ and fiber removal in the dry-grind ethanol industry could increase capacity and add valuable coproducts, resulting in increased productivity and profits.
Estimating the Error Rate of a Prediction Rule: Improvement on Cross-Validation (1983)

Abstract We construct a prediction rule on the basis of some data, and then wish to estimate the error rate of this rule in classifying future observations. Cross-validation provides a nearly unbiased estimate, using only the original data. Cross-validation turns out to be related closely to the bootstrap estimate of the error rate. This article has two purposes: to understand better the theoretical basis of the prediction problem, and to investigate some related estimators, which seem to offer considerably improved estimation in small samples.
Why do commercial CT scanners still employ traditional, filtered back-projection for image reconstruction? (2009)

Despite major advances in x-ray sources, detector arrays, gantry mechanical design and especially computer performance, one component of computed tomography (CT) scanners has remained virtually constant for the past 25 years-the reconstruction algorithm. Fundamental advances have been made in the solution of inverse problems, especially tomographic reconstruction, but these works have not been translated into clinical and related practice. The reasons are not obvious and seldom discussed. This review seeks to examine the reasons for this discrepancy and provides recommendations on how it can be resolved. We take the example of field of compressive sensing (CS), summarizing this new area of research from the eyes of practical medical physicists and explaining the disconnection between theoretical and application-oriented research. Using a few issues specific to CT, which engineers have addressed in very specific ways, we try to distill the mathematical problem underlying each of these issues with the hope of demonstrating that there are interesting mathematical problems of general importance that can result from in depth analysis of specific issues. We then sketch some unconventional CT-imaging designs that have the potential to impact on CT applications, if the link between applied mathematicians and engineers/physicists were stronger. Finally, we close with some observations on how the link could be strengthened. There is, we believe, an important opportunity to rapidly improve the performance of CT and related tomographic imaging techniques by addressing these issues.
Efficient detection of large-scale redundancy in enterprise file systems (2009)

In order to catch and reduce waste in the exponentially increasing demand for disk storage, we have developed very efficient technology to detect approximate duplication of large directory hierarchies. Such duplication can be caused, for example, by unnecessary mirroring of repositories by uncoordinated employees or departments. Identifying these duplicate or near-duplicate hierarchies allows appropriate action to be taken at a high level. For example, one could coordinate and consolidate multiple copies in one location.
Analysis of human small cell lung cancer differentiation antigens using a panel of rat monoclonal antibodies. (1984)

The antigen expression of human small cell lung cancer (SCLC) was studied using a panel of 21 independent rat monoclonal antibodies. The panel was selected by isolating hybridomas producing antibodies reactive with two SCLC lines but not with autologous B-lymphoblastoid lines. The antibodies were then tested in radiobinding assays against a panel of 17 SCLC lines, 13 non-small cell lung cancer lines, 6 SCLC necropsy specimens, 13 neuroectodermal lines (melanomas, neuroblastomas, glioblastomas), 15 other human lines, the glycolipid extracts of SCLC, human meconium, and human red blood cells. Using immunohistochemical assays, 14 of the antibodies were tested against normal lung, liver, and kidney, and lung cancer biopsies and xenografts. These analyses revealed the following: (a) SCLC elicited predominantly immunoglobulin M antibodies despite hyperimmunization; (b) the 21 antibodies displayed distinct binding and immunohistochemical phenotypes, indicating that they recognized many different epitopes; (c) 14 of the 21 antibodies reacted with glycolipid determinants; (d) the 21 determinants were expressed on over 80% of SCLC cell lines, necropsy samples, and xenografts; (e) the determinants were also expressed on normal adult bronchial epithelium, proximal tubules of adult kidney, and in a few instances on other normal cell types; (f) the antigens were expressed less frequently on nonsmall cell lung cancer samples but did not clearly distinguish SCLC from non-small cell lung cancer; (g) biochemical and morphological variants of SCLC exhibiting more malignant and undifferentiated behavior and containing greatly amplified c-myconcogenes failed to express several determinants or expressed them at lower levels; (h) and finally, while many human cell lines failed to express the antigens including human melanoma and glioblastoma lines, human neuroblastoma lines frequently did express the SCLC antigens. These detailed studies utilizing a panel of distinct monoclonal antibodies define a series of antigens on the surface of the majority of SCLC undescribed previously.
High‐Level Sustained Transgene Expression in Human Embryonic Stem Cells Using Lentiviral Vectors (2003)

Here we describe the sustained expression of transgenes introduced into human embryonic stem (ES) cells using self-inactivating lentiviral vectors. At low multiplicity of infection, vesicular stomatitis virus-pseudotyped vectors containing a green fluorescent protein (GFP) transgene under the control of a human elongation factor 1alpha promoter transduced human ES cells at high efficiency. The majority of the transduced ES cells, which harbored low numbers of integrated vectors, continued to express GFP after 60 days of culture. Incorporation of a scaffold attachment region (SAR) from the human interferon-beta gene into the lentiviral vector backbone increased the average level of GFP expression, and inclusion of the SAR together with a chromatin insulator from the 5' end of the chicken beta-globin locus reduced the variability in GFP expression. When the transduced ES cells were induced to differentiate into CD34(+) hematopoietic precursors in vitro, GFP expression was maintained with minimal silencing. The ability to efficiently introduce active transgenes into human ES cells will facilitate gain-of-function studies of early developmental processes in the human system. These results also have important implications for the possible future use of gene-modified human ES cells in transplantation and tissue regeneration applications.
Bryostatin 1 induces differentiation and potentiates the antitumor effect of Auristatin PE in a human pancreatic tumor (PANC-1) xenograft model (2001)

Pancreatic cancer has the worst prognosis of all cancers with a dismal 5-year survival rate. Hence, there is a tremendous need for development of new and effective therapy for this tumor. In an earlier study we reported a potent antitumor activity of Auristatin PE (AuriPE) against pancreatic tumor. In addition, we have also reported that bryostatin 1 (bryo1) induces differentiation of leukemia cells, but the effect of bryo1 has not been investigated in pancreatic tumors. This is the first report where we demonstrate that bryo1 induces differentiation and potentiates the antitumor effect of AuriPE in a human pancreatic tumor (PANC-1) xenograft model. A xenograft model was established by injecting the PANC-1 cells s.c. in severe combined immune deficient (SCID) mice. After development of the s.c. tumors, tumors were dissected and small fragments were transplanted in vivo to new SCID mice, with a success rate of 100% and a doubling time of 4.8 days. The SCID mouse xenograft model was used to test the in vivo differentiation effect of bryo1 and its efficacy when given alone or in combination with AuriPE. Sections from paraffin-embedded tumors excised from untreated (control) SCID mice revealed typical poorly differentiated adenocarcinoma of the pancreas. Interestingly, sections of s.c. tumors taken from bryo1-treated mice revealed carcinomas that were much lower grade and less aggressive, and displayed prominent squamous and glandular differentiation. In this study, the tumor growth inhibition (T/C), activity score and cure rate for bryo1, AuriPE and bryo1+AuriPE were 80%, (+) and 0/4; 0.0%, (++++) and 3/5; and 0.0%, (++++) and 3/4, respectively. Mice treated with either AuriPE or bryo1+AuriPE were free of tumors for more than 150 days and were considered cured. The use of bryo1 as a novel differentiating agent and its combination with AuriPE should be further explored for the treatment of adenocarcinoma of the pancreas.
Retinoic acid and development of the central nervous system (1992)

We consider the evidence that RA, the vitamin A metabolite, is involved in three fundamental aspects of the development of the CNS: 1) the stimulation of axon outgrowth in particular neuronal sub-types; 2) the migration of the neural crest; and 3) the specification of rostrocaudal position in the developing CNS (forebrain, midbrain, hindbrain, spinal cord). The evidence we discuss involves RA-induction of neurites in cell cultures and explants of neural tissue; the teratological effects of RA on the embryo's nervous system; the observation that RA can be detected endogenously in the spinal cord; and the fact that the receptors and binding proteins for RA are expressed in precise domains and neuronal cell types within the nervous system.
Forest Species Recognition Using Deep Convolutional Neural Networks (2014)

Forest species recognition has been traditionally addressed as a texture classification problem, and explored using standard texture methods such as Local Binary Patterns (LBP), Local Phase Quantization (LPQ) and Gabor Filters. Deep learning techniques have been a recent focus of research for classification problems, with state-of-the art results for object recognition and other tasks, but are not yet widely used for texture problems. This paper investigates the usage of deep learning techniques, in particular Convolutional Neural Networks (CNN), for texture classification in two forest species datasets - one with macroscopic images and another with microscopic images. Given the higher resolution images of these problems, we present a method that is able to cope with the high-resolution texture images so as to achieve high accuracy and avoid the burden of training and defining an architecture with a large number of free parameters. On the first dataset, the proposed CNN-based method achieves 95.77% of accuracy, compared to state-of-the-art of 97.77%. On the dataset of microscopic images, it achieves 97.32%, beating the best published result of 93.2%.
The IκB/NF-κB system: a key determinant of mucosal inflammation and protection (2000)

The ubiquitous transcription factor NF-kappa B is a central regulator of the transcriptional activation of a number of genes involved in cell adhesion, immune and proinflammatory responses, apoptosis, differentiation, and growth. Induction of these genes in intestinal epithelial cells (IECs) by activated NF-kappa B profoundly influences mucosal inflammation and repair. NF-kappa B activation requires the removal of I kappa B from NF-kappa B by inducible proteolysis, which liberates this transcription factor for migration to the nucleus, where it binds to kappa B-regulatory elements and induces transcription. I kappa B alpha degradation is incomplete and delayed in IECs, resulting in buffered responses to luminal stimuli. The stimulatory environment partially determines whether the effect of NF-kappa B is protective or deleterious for the host. kappa B-dependent proinflammatory gene expression, particularly chemokines, major histocompatibility complex class II antigens, and adhesion molecules may be extremely important in early protective responses to mucosal pathogens but, when dysregulated, could lead to the development of chronic inflammation, as seen in inflammatory bowel diseases. The key role of NF-kappa B in regulating expression of a number of proinflammatory genes makes this protein an attractive target for selective therapeutic intervention.
Van der Waals Density Functional for Layered Structures (2003)

To understand sparse systems, we must account for both strong local atom bonds and weak nonlocal van der Waals forces between atoms separated by empty space. A fully nonlocal functional form [Phys. Rev. B 62, 6997 (2000)]] of density-functional theory (DFT) is applied here to the layered systems graphite, boron nitride, and molybdenum sulfide to compute bond lengths, binding energies, and compressibilities. These key examples show that the DFT with the generalized-gradient approximation does not apply for calculating properties of sparse matter, while use of the fully nonlocal version appears to be one way to proceed.
Polymorphic DNA region adjacent to the 5' end of the human insulin gene. (1981)

The length of a segment of DNA associated with the human insulin gene, which has been localized to the short arm of chromosome 11, is heterozygous in 63% of 52 individuals analyzed. This polymorphic region is approximately 500 base pairs from the nucleotide encoding the 5' end of insulin mRNA. The polymorphism appears to be due to an insertion or deletion of DNA sequences so that DNA fragments of different length are generated when DNA from a heterozygous individual is digested with selected restriction endonucleases.
T cell independent mechanism for copolymer‐1‐induced neuroprotection (2007)

Despite active investigation of copolymer-1 (Cop-1) for nearly 40 years the mechanisms underlying its neuroprotective properties remain contentious. Nonetheless, current dogma for Cop-1 neuroprotective activities in autoimmune and neurodegenerative diseases include bystander suppression of autoimmune T cells and attenuation of microglial responses. In this report, we demonstrate that Cop-1 interacts directly with primary human neurons and decreases neuronal cell death induced by staurosporine or oxidative stress. This neuroprotection is mediated through protein kinase Calpha and brain-derived neurotrophic factor. Dendritic cells (DC) uptake Cop-1, deliver it to the injury site, and release it in an active form. Interactions between Cop-1 and DC enhance DC blood brain barrier migration. In a rat model with optic nerve crush injury, Cop-1-primed DC induce T cell independent neuroprotection. These findings may facilitate the development of neuroprotective approaches using DC-mediated Cop-1 delivery to diseased nervous tissue.
Visualization of the homologous pairing of DNA catalyzed by the bacteriophage T4 UvsX protein. (1987)

The uvsX gene product is essential for DNA repair and general recombination in T4 bacteriophage. The ability of UvsX protein to catalyze the homologous pairing of single-stranded DNA (ssDNA) with double-stranded DNA (dsDNA) in vitro was examined by electron microscopic (EM), nitrocellulose filter binding, and gel electrophoretic methods. Optimal joining was observed at ratios of UvsX protein:ssDNA of 2 nucleotides/protein monomer. At this level, the ssDNA was fully covered by UvsX protein as seen by EM, while the dsDNA appeared protein-free. Using this stoichiometry, the pairing of circular ssDNA with homologous supertwisted dsDNA was found to produce a high frequency of complexes in which a supertwisted dsDNA molecule was joined to a UvsX protein-ssDNA filament over a distance of less than 100 base pairs. These joints were labile to deproteinization and must have been paranemic. Pairing of linear ssDNA containing buried homology to the dsDNA produced identical structures. Pairing of fully homologous linear ssDNA and supertwisted dsDNA yielded D-loop joints (plectonemic) as seen by EM following deproteinization. Both the paranemic and the plectonemic joints were at sites of homology, as demonstrated by restriction cleavage of the complexes. Visualization of the joined complexes prior to deproteinization showed that 50% of the joints had the architecture of the paranemic joints, whereas in the remainder, a topologically relaxed dsDNA circle merged with the UvsX protein-ssDNA filament for a distance of 450 base pairs. The structure of the filament was not visibly altered in this region. These observations are similar, but not identical, to findings in parallel studies utilizing the RecA protein of Escherichia coli.