gebhart/patrepeval huggingface dataset:
Highly Efficient “Click” Functionalization of Poly(3-azidopropyl methacrylate) Prepared by ATRP (2005)

To prepare polymers with pendant functionality capable of participating in highly efficient CuI-catalyzed 1,3-dipolar cycloaddition of azide and alkynes, monomers with acetylene or azido groups were polymerized via controlled radical polymerization. Atom transfer radical polymerization (ATRP) of propargyl methacrylate (PgMA) resulted in high polydispersities (Mw/Mn > 3), multimodal molecular weight distributions, and cross-linked networks at moderate to high conversion. The poor results obtained with this monomer were presumably due to addition of the propagating radicals to the acetylene group, transfer reactions, and/or interference with the catalyst. A novel monomer, 3-azidopropyl methacrylate (AzPMA), was polymerized via ATRP with good control of the polymer molecular weight distribution and retention of chain functionality. Poly(3-azidopropyl methacrylate) was coupled with propargyl alcohol, propargyl triphenylphosphonium bromide, propargyl 2-bromoisobutyrate, and 4-pentynoic acid via a highly efficient "click" reaction in the presence of a CuI catalyst. The azido-functionalized polymer demonstrated enhanced reactivity as compared to small molecules with comparable structures. The ability of the coupling reactions to be conducted at room temperature without significant excess of reagents makes this an attractive alternative to preparing (co)polymers with high degrees of functionalization.
Dynamics of the Immune Reaction to Pancreatic Cancer from Inception to Invasion (2007)

The dynamics of cancer immunosurveillance remain incompletely understood, hampering efforts to develop immunotherapy of cancer. We evaluated the evolving in vivo immune response to a spontaneous tumor in a genetically defined mouse model of pancreatic ductal adenocarcinoma from the inception of preinvasive disease to invasive cancer. We observed a prominent leukocytic infiltration even around the lowest grade preinvasive lesions, but immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg), dominated the early response and persisted through invasive cancer. Effector T cells, however, were scarce in preinvasive lesions, found in only a subset of advanced cancers, and showed no evidence of activation. The lack of tumor-infiltrating effector T cells strongly correlated with the presence of intratumoral MDSC with a near mutual exclusion. In vitro, we found that MDSC suppressed T-cell proliferation. Overall, our results show that suppressive cells of the host immune system appear early during pancreatic tumorigenesis, preceding and outweighing antitumor cellular immunity, and likely contribute to disease progression. Thus, in contrast to the hypothesis that an early "elimination phase" of cancer immunosurveillance is eventually overwhelmed by a growing invasive tumor, our findings suggest that productive tumor immunity may be undermined from the start. Efforts to test potent inhibitors of MDSC, tumor-associated macrophages, and Treg, particularly early in the disease represent important next steps for developing novel immunotherapy of cancer.
Tie-2–dependent activation of RhoA and Rac1 participates in endothelial cell motility triggered by angiopoietin-1 (2003)

Angiopoietin-1 is implicated in the maturation and remodeling of the vascular network during embryo development and in adult life. Through its tyrosine kinase receptor Tie-2 it stimulates endothelial cells to migrate and change shape. Here we show that angiopoietin-1 elicits chemokinesis of endothelial cells by a phosphoinositide 3-OH kinase/son of sevenless-dependent modulation of Rac1 and RhoA. The resulting temporal events are associated with cytoskeletal rearrangements and occur in discrete zones of the cell. Endothelial cells carrying dominant-negative mutants of RhoA and Rac1 or treated with LY294002, an inhibitor of phosphoinositide 3-OH kinase, dramatically decrease their chemokinetic velocity. Taken together, these results further expand our understanding of angiopoietin-1-mediated endothelial cell motility during vascular network assembly and angiogenesis.
Combining optical and atomic force microscopy for life sciences research. (1995)

The atomic force microscope (AFM), a three-dimensional imaging tool that can measure structures from the atomic level to micron scale, has been combined with an inverted optical microscope capable of confocal imaging. The robust design of this microscope, termed the BioScope, enables the operator to use fluorescent markers on a wide variety of biological specimens to determine internal structure to 200 nm resolution and determine surface morphology of the same sample to 20 nm resolution while imaging under physiological conditions. In this report we demonstrate the capabilities of the BioScope by examining living Xenopus retinal glial (XR1) cells, Drosophila polytene chromosomes and colloidal gold-labeled plasmid DNA.
Bioreactor Production of Recombinant Herpes Simplex Virus Vectors (2007)

Serotypical application of herpes simplex virus (HSV) vectors to gene therapy (type 1) and prophylactic vaccines (types 1 and 2) has garnered substantial clinical interest recently. HSV vectors and amplicons have also been employed as helper virus constructs for manufacture of the dependovirus adeno-associated virus (AAV). Large quantities of infectious HSV stocks are requisite for these therapeutic applications, requiring a scalable vector manufacturing and processing platform comprised of unit operations which accommodate the fragility of HSV. In this study, production of a replication deficient rHSV-1 vector bearing the rep and cap genes of AAV-2 (denoted rHSV-rep2/cap2) was investigated. Adaptation of rHSV production from T225 flasks to a packed bed, fed-batch bioreactor permitted an 1100-fold increment in total vector production without a decrease in specific vector yield (pfu/cell). The fed-batch bioreactor system afforded a rHSV-rep2/cap2 vector recovery of 2.8 x 10(12) pfu. The recovered vector was concentrated by tangential flow filtration (TFF), permitting vector stocks to be formulated at greater than 1.5 x 10(9) pfu/mL.
Formation of in vivo complexes between the TAL1 and E2A polypeptides of leukemic T cells. (1994)

Tumor-specific activation of the TAL1 gene occurs in approximately 25% of patients with T-cell acute lymphoblastic leukemia (T-ALL). The TAL1 gene products possess a basic helix-loop-helix (bHLH) domain that interacts in vitro with the bHLH proteins (E12 and E47) encoded by the E2A locus. We have now applied two independent methods, the two-hybrid procedure and co-immunoprecipitation analysis, to demonstrate that TAL1 and E2A polypeptides also associate in vivo. These studies show that the bHLH domain of TAL1 selectively interacts with the bHLH domains of E12 and E47, but not with the Id1 helix-loop-helix protein. TAL1 does not self-associate to form homodimeric complexes, implying that the in vivo functions of TAL1 depend on heterologous interaction with other bHLH proteins such as E12 and E47. Co-immunoprecipitation analysis revealed the presence of endogenous TAL1/E2A complexes in Jurkat cells, a leukemic line derived from a T-ALL patient. Thus, the malignant properties of TAL1 may be due to obligate interaction with the E2A polypeptides.
Recent Advances and Prospects of Cathode Materials for Sodium‐Ion Batteries (2015)

Sodium-ion batteries (SIBs) receive significant attention for electrochemical energy storage and conversion owing to their wide availability and the low cost of Na resources. However, SIBs face challenges of low specific energy, short cycling life, and insufficient specific power, owing to the heavy mass and large radius of Na(+) ions. As an important component of SIBs, cathode materials have a significant effect on the SIB electrochemical performance. The most recent advances and prospects of inorganic and organic cathode materials are summarized here. Among current cathode materials, layered transition-metal oxides achieve high specific energies around 600 mW h g(-1) owing to their high specific capacities of 180-220 mA h g(-1) and their moderate operating potentials of 2.7-3.2 V (vs Na(+) /Na). Porous Na3 V2 (PO4 )3 /C nanomaterials exhibit excellent cycling performance with almost 100% retention over 1000 cycles owing to their robust structural framework. Recent emerging cathode materials, such as amorphous NaFePO4 and pteridine derivatives show interesting electrochemical properties and attractive prospects for application in SIBs. Future work should focus on strategies to enhance the overall performance of cathode materials in terms of specific energy, cycling life, and rate capability with cationic doping, anionic substitution, morphology fabrication, and electrolyte matching.
A Hybrid Model for Annotating Named Entity Training Corpora (2010)

In this paper, we present a two-phase, hybrid model for generating training data for Named Entity Recognition systems. In the first phase, a trained annotator labels all named entities in a text irrespective of type. In the second phase, naïve crowdsourcing workers complete binary judgment tasks to indicate the type(s) of each entity. Decomposing the data generation task in this way results in a flexible, reusable corpus that accommodates changes to entity type taxonomies. In addition, it makes efficient use of precious trained annotator resources by leveraging highly available and cost effective crowdsourcing worker pools in a way that does not sacrifice quality.
Respiratory syncytial virus-induced cytokine production by a human bronchial epithelial cell line (1993)

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory infection in infants and young children, but the pathogenesis of RSV-induced inflammation is not well defined. We hypothesized that in vitro infection of a human bronchial epithelial cell line (BEAS) would induce production of proinflammatory cytokines. BEAS cells were infected with RSV, and cells and supernatants were assayed for cytokine mRNA and protein changes at several time points after infection. Cytokine mRNA in BEAS cells was measured by polymerase chain reaction of reverse-transcribed RNA from whole cell lysates; cytokine levels in supernatants were measured by bioassay or immunoassay. Our results indicated that interleukin-5ay or immunoassay. Our results indicated that interleukin-8 (IL-8) was induced at 4 h after infection (during the eclipse phase of RSV infection) with accumulation of IL-8 in supernatants by 24 h after infection. Increased levels of IL-6 and granulocyte macrophage colony-stimulating factor in supernatants were only detected by 96 h after infection, during the RSV replicative phase. Interferon-alpha and -gamma transcripts were not detectable at any time point. We conclude that the effects of RSV on airway inflammation may be at least partly mediated by sequential production of proinflammatory cytokines in infected airway epithelium.
THE MOLECULAR-GENETICS OF NITROGEN ASSIMILATION INTO AMINO ACIDS IN HIGHER PLANTS (1996)

Nitrogen assimilation is a vital process controlling plant growth and development. Inorganic nitrogen is assimilated into the amino acids glutamine, glutamate, asparagine, and aspartate, which serve as important nitrogen carriers in plants. The enzymes glutamine synthetase (GS), glutamate synthase (GOGAT), glutamate dehydrogenase (GDH), aspartate aminotransferase (AspAT), and asparagine synthetase (AS) are responsible for the biosynthesis of these nitrogen-carrying amino acids. Biochemical studies have revealed the existence of multiple isoenzymes for each of these enzymes. Recent molecular analyses demonstrate that each enzyme is encoded by a gene family wherein individual members encode distinct isoenzymes that are differentially regulated by environmental stimuli, metabolic control, developmental control, and tissue/cell-type specificity. We review the recent progress in using molecular-genetic approaches to delineate the regulatory mechanisms controlling nitrogen assimilation into amino acids and to define the physiological role of each isoenzyme involved in this metabolic pathway.
Functional Consequences of Adenovirus-Mediated Murine Pancreatic Gene Transfer (1997)

Pancreatic adenoviral gene transfer can be achieved with high efficiency; however, questions concerning tissue injury from this commonly used vector have not been addressed. In these experiments, the effects of adenoviral gene transfer on pancreatic exocrine function were evaluated. Direct pancreatic injection with an adenoviral vector containing the Escherichia coli beta-galactosidase (beta-Gal; lacZ) transgene (H5.010CBlacZ) resulted in a high level of transgene expression (64 +/- 6% of pancreatic cells expressed beta-Gal) at 3 days following infection. However, amylase levels in four of five different subcellular pancreatic fractions were significantly decreased at this time point. Direct pancreatic injection with either saline or psoralen/UV-inactivated adenovirus did not have this effect, whereas both transduction with an adenoviral vector containing a different transgene and transduction with a homologous transgene resulted in decreased pancreatic amylase. The decrease in subcellular amylase levels persisted at 7 days post-transduction, and then returned to baseline at 21 days post-transduction. There was associated histologic damage (increased edema, inflammation, cell destruction, and vacuolization) at 3 and 7 days post-transduction, which resolved by 21 days. In summary, adenoviral transduction of the pancreas results in increased viral transgene expression and a uniform decrease in host amylase production throughout the pancreas. The normalization of amylase levels and histology suggest that organ recovery occurs. Gene transfer technology as a novel strategy for pancreatic diseases such as diabetes, pancreatitis, and cystic fibrosis is feasible but will benefit from continued approaches to limit toxicity.
Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor (1994)

Inhibitors of the human immunodeficiency virus type 1 protease represent a promising class of antiviral drugs for the treatment of AIDS, and several are now in clinical trials. Here, we report the in vitro selection of viral variants with decreased sensitivity to a C2-symmetric protease inhibitor (A-77003). We show that a single amino acid substitution (Arg to Gln or Lys) at position 8 of the protease results in a substantial decrease in the inhibitory activity of the drug on the enzyme and a comparable increase in viral resistance. These findings, when analyzed by using the three-dimensional structure of the protease-drug complex, provide a strategic guide for the future development of inhibitors of the human immunodeficiency virus type 1 protease.
Improvement of Focused Ion-Beam Optics in Single-Ion Implantation for Higher Aiming Precision of One-by-One Doping of Impurity Atoms into Nano-Scale Semiconductor Devices (2002)

Focused ion-beam (FIB) optics in single-ion implantation (SII), which enables us to implant dopant ions one-by-one into a fine semiconductor region until the necessary number is reached, has been modified in order to improve the controllability of dopant atom position to within 100 nm. The lateral magnification of the objective lens (OL) was remodeled to 1/19 from the original value of 1/6 before modification. Scanning ion microscope (SIM) images at a high magnification of 75,000 were taken using a 60 keV focused Si ion beam with a current of 1 pA to evaluate the resolution of secondary electron images. A diameter of the ion beam less than of 20 nm was obtained. One-by-one, 60 keV Si ions were implanted by means of SII into CR-39 which is a fission track detector for investigating the aiming precision. Deviation of the single ion incident site from the target position was evaluated using atomic force microscopy (AFM) and compared with that before modification of FIB optics. The average aiming precision in SII was improved to be 60 nm which was 1/3 of that before modification.
Collection Protocol for Human Pancreas (2012)

This dissection and sampling procedure was developed for the Network for Pancreatic Organ Donors with Diabetes (nPOD) program to standardize preparation of pancreas recovered from cadaveric organ donors. The pancreas is divided into 3 main regions (head, body, tail) followed by serial transverse sections throughout the medial to lateral axis. Alternating sections are used for fixed paraffin and fresh frozen blocks and remnant samples are minced for snap frozen sample preparations, either with or without RNAse inhibitors, for DNA, RNA, or protein isolation. The overall goal of the pancreas dissection procedure is to sample the entire pancreas while maintaining anatomical orientation. Endocrine cell heterogeneity in terms of islet composition, size, and numbers is reported for human islets compared to rodent islets. The majority of human islets from the pancreas head, body and tail regions are composed of insulin-containing β-cells followed by lower proportions of glucagon-containing α-cells and somatostatin-containing δ-cells. Pancreatic polypeptide-containing PP cells and ghrelin-containing epsilon cells are also present but in small numbers. In contrast, the uncinate region contains islets that are primarily composed of pancreatic polypeptide-containing PP cells. These regional islet variations arise from developmental differences. The pancreas develops from the ventral and dorsal pancreatic buds in the foregut and after rotation of the stomach and duodenum, the ventral lobe moves and fuses with the dorsal. The ventral lobe forms the posterior portion of the head including the uncinate process while the dorsal lobe gives rise to the rest of the organ. Regional pancreatic variation is also reported with the tail region having higher islet density compared to other regions and the dorsal lobe-derived components undergoing selective atrophy in type 1 diabetes. Additional organs and tissues are often recovered from the organ donors and include pancreatic lymph nodes, spleen and non-pancreatic lymph nodes. These samples are recovered with similar formats as for the pancreas with the addition of isolation of cryopreserved cells. When the proximal duodenum is included with the pancreas, duodenal mucosa may be collected for paraffin and frozen blocks and minced snap frozen preparations.
Towards an active network architecture (2007)

Active networks allow their users to inject customized programs into the nodes of the network. An extreme case, in which we are most interested, replaces packets with "capsules" -- program fragments that are executed at each network router/switch they traverse. Active architectures permit a massive increase in the sophistication of the computation that is performed within the network. They will enable new applications, especially those based on application-specific multicast, information fusion, and other services that leverage network-based computation and storage. Furthermore, they will accelerate the pace of innovation by decoupling network services from the underlying hardware and allowing new services to be loaded into the infrastructure on demand. In this paper, we describe our vision of an active network architecture, outline our approach to its design, and survey the technologies that can be brought to bear on its implementation. We propose that the research community mount a joint effort to develop and deploy a wide area ActiveNet.
Mixed-inhibitor-prodrug as a new approach toward systemically active inhibitors of enkephalin-degrading enzymes (1992)

In order to evaluate the possible advantages of potentiating the effects of the endogenous enkephalins, to obtain analgesia without the serious drawbacks of morphine, it was essential to design systemically active compounds which inhibit the two metabolizing enzymes, aminopeptidase N (APN) and neutral endopeptidase 24.11 (NEP). A new concept combining the idea of "prodrug" and "mixed inhibitor" was therefore developed. Given the high efficiency of beta-mercaptoalkylamines as APN inhibitors and of N-(mercaptoacyl) amino acids as NEP inhibitors, compounds associating these molecules through disulfide or thioester bonds, which are known to increase lipophilicity and to favor passage across the blood-brain barrier, have been synthesized. An HPLC study indicated that the disulfide bridge was resistant to serum enzymes but was cleaved by brain membrane homogenates, suggesting that the active inhibitors were released in the central nervous system. The validity of the approach was verified by the efficient antinociceptive responses obtained in the hot plate test in mice after iv administration of disulfide-containing inhibitors (ED50s of from 4 to 26 mg/kg on the jump latency time). The analgesic potencies of the "mixed inhibitor-prodrug" RB 101 [H2NCH(CH2CH2SCH3)CH2SSCH2CH(CH2Ph)CONHCH( CH2Ph)COOCH2Ph] after iv administration were three times greater than those of a similar combined dose of its two constitutive moieties. The separation of the two diastereoisomers constituting RB 101 showed that the analgesia has a stereochemical dependence, the (S,S,S)-isomer being more active than the (S,R,S)-isomer. Furthermore, in the tail flick test in the rat, RB 101 gave 38% analgesia at a dose of 80 mg/kg. Due to its high efficiency and its longer pharmacological effect, RB 101 was selected for a complete study of its analgesic properties.
New basal cell carcinoma susceptibility loci (2015)

In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.
The Mechanism of Locomotion in Gastropod Molluscs (1945)

ABSTRACT As is the case in all terrestrial animals, the progression of a snail or other gastropod depends on the exercise by the animal of an adequate force directed posteriorly against the ground ; in an animal moving horizontally and at constant speed, this force overcomes the frictional resistance encountered by the parts which are gliding forwards. The movements of the pedal surface of some gastropods have been discussed in a previous paper (Lissmann, 1945). The experiments described below were designed to correlate these movements with the forces set up during locomotion. The salient point which appears to be established is that during progression the foot exhibits (i) areas of forward motion, coinciding with phases of longitudinal muscular contraction, followed by extension ; (ii) areas at rest, which remain essentially elongated. However, the state of the muscles is no indication of the tensions they may set up within the body, nor of the propulsive force they may exert; it is by no means obvious how the external forces are produced, or how they lead to progression.