gebhart/patrepeval huggingface dataset:
Expanded Utility of the β-Glucuronide Linker: ADCs That Deliver Phenolic Cytotoxic Agents (2010)

The β-glucuronide linker has been used for antibody-drug conjugates (ADCs) to deliver amine-containing cytotoxic agents. The linker is stable in circulation, hydrophilic and provides ADCs that are highly active in vitro and in vivo. To extend the utility of the β-glucuronide linker toward phenol-containing drugs, an N,N'-dimethylethylene diamine self-immolative spacer was incorporated with the linker for release of the potent cytotoxic phenol psymberin A. Exposure of the drug-linker to β-glucuronidase resulted in facile drug release. The corresponding ADCs were active and immunologically selective against CD30-positive L540cy and CD70-positive Caki-1 cell lines.
Extracellular Signal-Regulated Kinase-Regulated Microglia–Neuron Signaling by Prostaglandin E2Contributes to Pain after Spinal Cord Injury (2007)

Many patients with traumatic spinal cord injury (SCI) report pain that persists indefinitely and is resistant to available therapeutic approaches. We recently showed that microglia become activated after experimental SCI and dynamically maintain hyperresponsiveness of spinal cord nociceptive neurons and pain-related behaviors. Mechanisms of signaling between microglia and neurons that help to maintain abnormal pain processing are unknown. In this study, adult male Sprague Dawley rats underwent T9 spinal cord contusion injury. Four weeks after injury when lumbar dorsal horn multireceptive neurons became hyperresponsive and when behavioral nociceptive thresholds to mechanical and thermal stimuli were decreased, we tested the hypothesis that prostaglandin E2 (PGE2) contributes to signaling between microglia and neurons. Immunohistochemical data showed specific localization of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), an upstream regulator of PGE2 release, to microglial cells and a neuronal localization of the PGE2 receptor E-prostanoid 2 (EP2). Enzyme immunoassay analysis showed that PGE2 release was dependent on microglial activation and ERK1/2 phosphorylation. Pharmacological antagonism of PGE2 release was achieved with the mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] and the microglial inhibitor minocycline. Cyclooxygenase-2 expression in microglia was similarly reduced by MEK1/2 inhibition. PD98059 and EP2 receptor blockade with AH6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid) resulted in a decrease in hyperresponsiveness of dorsal horn neurons and partial restoration of behavioral nociceptive thresholds. Selective targeting of dorsal horn microglia with the Mac-1-SAP immunotoxin, a chemical conjugate of mouse monoclonal antibody to CD11b and the ribosome-inactivating protein saporin, resulted in reduced microglia staining, reduction in PGE2 levels, and reversed pain-related behaviors [corrected]. On the basis of these observations, we propose a PGE2-dependent, ERK1/2-regulated microglia-neuron signaling pathway that mediates the microglial component of pain maintenance after injury to the spinal cord.
Hepatoprotective effects of geniposide in a rat model of nonalcoholic steatohepatitis (2011)

Geniposide exerts protective effects against hepatic steatosis in rats fed with a high fat diet; the underlying mechanism may be associated with its antioxidant actions or regulation of adipocytokine release and expression of PPARα.
Comparative Analysis of Antisense Oligonucleotide Sequences for Targeted Skipping of Exon 51 During Dystrophin Pre-mRNA Splicing in Human Muscle (2007)

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene that result in the absence of functional protein. In the majority of cases these are out-of-frame deletions that disrupt the reading frame. Several attempts have been made to restore the dystrophin mRNA reading frame by modulation of pre-mRNA splicing with antisense oligonucleotides (AOs), demonstrating success in cultured cells, muscle explants, and animal models. We are preparing for a phase I/IIa clinical trial aimed at assessing the safety and effect of locally administered AOs designed to inhibit inclusion of exon 51 into the mature mRNA by the splicing machinery, a process known as exon skipping. Here, we describe a series of systematic experiments to validate the sequence and chemistry of the exon 51 AO reagent selected to go forward into the clinical trial planned in the United Kingdom. Eight specific AO sequences targeting exon 51 were tested in two different chemical forms and in three different preclinical models: cultured human muscle cells and explants (wild type and DMD), and local in vivo administration in transgenic mice harboring the entire human DMD locus. Data have been validated independently in the different model systems used, and the studies describe a rational collaborative path for the preclinical selection of AOs for evaluation in future clinical trials.
Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project (2004)

LCIS is a more indolent form of in situ breast carcinoma than DCIS, with which it shares other features of its natural history, particularly very low mortality rates. There is no compelling reason to surgically treat LCIS other than conservatively. The values of other adjuvant modalities in the management of LCIS are discussed. The authors acknowledge that their findings are based on relatively few events and, even at 12 years, may be regarded as "preliminary". Nonetheless, their findings may reflect the true biologic nature of LCIS.
Description and ray-tracing simulations of HYPE: a far-ultraviolet polarimetric spatial-heterodyne spectrometer (2010)

Temperature and velocity-distribution remote-sensing of faint diffuse sources such as the interplanetary medium (IPM), comets and planetary atmospheres, is an instrumental challenge that becomes more pronounced in the ultraviolet. All-reflective Spatial-Heterodyne Spectrometers (SHS), an emerging new class of instruments that combines both high étendue and high resolving power (greater than 10<sup>5</sup>), are ideally suited to these types of observations. Their all-reflective configuration and their self-compensating monolithic design enable them to operate under the tight tolerances of the ultraviolet and to survive the rigors of space launch. An in-development sounding-rocket experiment, the Hydrogen Polarimetric Explorer (HYPE), will merge an all-reflective SHS with a half-wave Brewster reflection polarimeter to obtain the first interferometric polarimetry of an ultraviolet emission line source. Its initial flight will target the IPM at the hydrogen Lyman-alpha transition (121.6nm). HYPE's novel optical configuration also combines several improvements in reflective SHS design, including true zero-path interferometry, no aliasing, and one-dimensional imaging. The optical layout and performance of the HYPE prototype will be described along with simulation results from ray-tracing computations.
Local Field Potentials: Myths and Misunderstandings (2016)

The intracerebral local field potential (LFP) is a measure of brain activity that reflects the highly dynamic flow of information across neural networks. This is a composite signal that receives contributions from multiple neural sources, yet interpreting its nature and significance may be hindered by several confounding factors and technical limitations. By and large, the main factor defining the amplitude of LFPs is the geometry of the current sources, over and above the degree of synchronization or the properties of the media. As such, similar levels of activity may result in potentials that differ in several orders of magnitude in different populations. The geometry of these sources has been experimentally inaccessible until intracerebral high density recordings enabled the co-activating sources to be revealed. Without this information, it has proven difficult to interpret a century's worth of recordings that used temporal cues alone, such as event or spike related potentials and frequency bands. Meanwhile, a collection of biophysically ill-founded concepts have been considered legitimate, which can now be corrected in the light of recent advances. The relationship of LFPs to their sources is often counterintuitive. For instance, most LFP activity is not local but remote, it may be larger further from rather than close to the source, the polarity does not define its excitatory or inhibitory nature, and the amplitude may increase when source's activity is reduced. As technological developments foster the use of LFPs, the time is now ripe to raise awareness of the need to take into account spatial aspects of these signals and of the errors derived from neglecting to do so.
Ectopic Deposition of Lignin in the Pith of Stems of Two Arabidopsis Mutants (2000)

The biosynthesis of lignin in vascular plants is regulated both developmentally and environmentally. In the inflorescence stems of Arabidopsis, lignin is mainly deposited in the walls of xylem cells and interfascicular fiber cells during normal plant growth and development. The mechanisms controlling the spatial deposition of lignin remain unknown. By screening ethyl methanesulfonate-mutagenized populations of Arabidopsis, we have isolated two allelic elp1 (ectopic deposition of lignin in pith) mutants with altered lignin deposition patterns. In elp1 stems, lignin was ectopically deposited in the walls of pith parenchyma cells in addition to its normal deposition in the walls of xylem and fiber cells. Lignin appeared to be deposited in patches of parenchyma cells in the pith of both young and mature elp1 stems. The ectopic deposition of lignin in the pith of elp1 stems was accompanied by an increase in the activities of enzymes in the lignin biosynthetic pathway and with the ectopic expression of caffeoyl coenzyme A O-methyltransferase in pith cells. These results indicate that the ELP1 locus is involved in the repression of the lignin biosynthetic pathway in the pith. Isolation of the elp1 mutants provides a novel means with which to study the molecular mechanisms underlying the spatial control of lignification.
Hepatitis B: The virus and disease # (2009)

Hepatitis B virus (HBV) infects more than 300 million people worldwide and is a common cause of liver disease and liver cancer. HBV, a member of the Hepadnaviridae family, is a small DNA virus with unusual features similar to retroviruses. HBV replicates through an RNA intermediate and can integrate into the host genome. The unique features of the HBV replication cycle confer a distinct ability of the virus to persist in infected cells. Virological and serological assays have been developed for diagnosis of various forms of HBV-associated disease and for treatment of chronic hepatitis B infection. HBV infection leads to a wide spectrum of liver disease ranging from acute (including fulminant hepatic failure) to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Acute HBV infection can be either asymptomatic or present with symptomatic acute hepatitis. Most adults infected with the virus recover, but 5%-10% are unable to clear the virus and become chronically infected. Many chronically infected persons have mild liver disease with little or no long-term morbidity or mortality. Other individuals with chronic HBV infection develop active disease, which can progress to cirrhosis and liver cancer. These patients require careful monitoring and warrant therapeutic intervention. Extrahepatic manifestations of HBV infection are rare but can be difficult to diagnose and manage. The challenges in the area of HBV-associated disease are the lack of knowledge in predicting outcome and progression of HBV infection and an unmet need to understand the molecular, cellular, immunological, and genetic basis of various disease manifestations associated with HBV infection.
3D ShapeNets: A deep representation for volumetric shapes (2015)

3D shape is a crucial but heavily underutilized cue in today's computer vision systems, mostly due to the lack of a good generic shape representation. With the recent availability of inexpensive 2.5D depth sensors (e.g. Microsoft Kinect), it is becoming increasingly important to have a powerful 3D shape representation in the loop. Apart from category recognition, recovering full 3D shapes from view-based 2.5D depth maps is also a critical part of visual understanding. To this end, we propose to represent a geometric 3D shape as a probability distribution of binary variables on a 3D voxel grid, using a Convolutional Deep Belief Network. Our model, 3D ShapeNets, learns the distribution of complex 3D shapes across different object categories and arbitrary poses from raw CAD data, and discovers hierarchical compositional part representation automatically. It naturally supports joint object recognition and shape completion from 2.5D depth maps, and it enables active object recognition through view planning. To train our 3D deep learning model, we construct ModelNet - a large-scale 3D CAD model dataset. Extensive experiments show that our 3D deep representation enables significant performance improvement over the-state-of-the-arts in a variety of tasks.
Neutron dosimetry, moderated energy spectrum, and neutron capture therapy for medical sources (1999)

dosimetry was examined by calculative and experimental means. The Monte Carlo N ‐Particle (MCNP) transport code was used in a distributed computing environment (PVM) to determine neutron dose and neutron energy spectrum from in a variety of clinically relevant materials. A Maxwellian spectrum was used to model neutron emissions in these materials. Mixed‐field dosimetry of applicator tube (AT) sources was measured using tissue‐equivalent ion chambers and a miniature GM counter to formulate a dosimetry protocol. Neutron dose was determined using the AAPM TG‐43 dosimetry protocol. Results demonstrate the overwhelming dependence of dosimetry on the source geometry and no significant neutron attenuation by the source or encapsulation. Gold foils and TLDs were used to measure thermal neutron flux near AT sources and compared with MCNP results. The fast neutron energy spectrum did not change markedly at greater distances from the AT source. Calculations of moderated neutron energy spectrum with various loadings of and were performed, in addition to analysis of neutron capture therapy dosimetry. Radiological concerns such as personnel exposure and shielding of emissions were examined. Feasibility of a high specific‐activity HDR source was investigated through radiochemical and metallurgical studies using stand‐ins such as Tb, Gd, and Issues such as capsule burst strength due to helium production for a variety of proposed HDR sources were addressed. At least 1 mg of was necessary for a HDR source.
New Environmentally Friendly Oxidative Scission of Oleic Acid into Azelaic Acid and Pelargonic Acid (2012)

Abstract Oleic acid (OA) is a renewable monounsaturated fatty acid obtained from high oleic sunflower oil. This work was focused on the oxidative scission of OA, which yields a mono‐acid (pelargonic acid, PA) and a di‐acid (azelaic acid, AA) through an emulsifying system. The conventional method for producing AA and PA consists of the ozonolysis of oleic acid, a process which presents numerous drawbacks. Therefore, we proposed to study a new alternative process using a green oxidant and a solvent‐free system. OA was oxidized in a batch reactor with a biphasic organic‐aqueous system consisting of hydrogen peroxide (H 2 O 2 , 30 %) as an oxidant and a peroxo–tungsten complex Q 3 {PO 4 [WO(O 2 ) 2 ] 4 } as a phase‐transfer catalyst/co‐oxidant. Several phase‐transfer catalysts were prepared in situ from tungstophosphoric acid, H 2 O 2 and different quaternary ammonium salts (Q + , Cl – ). The catalyst [C 5 H 5 N( n ‐C 16 H 33 )] 3 {PO 4 [WO(O 2 ) 2 ] 4 } was found to give the best results and was chosen for the optimization of the other parameters of the process. This optimization led to a complete conversion of OA into AA and PA with high yields (&gt;80 %) using the system OA/H 2 O 2 /[C 5 H 5 N( n ‐C 16 H 33 )] 3 {PO 4 [WO(O 2 ) 2 ] 4 } (1/5/0.02 molar ratio) at 85 °C for 5 h. In addition, a new treatment was developed in order to recover the catalyst.
Modified Nonintrusive Appliance Load Monitoring For Nonlinear Devices (2007)

NIALM is a modern technique to know load profiles of individual appliances by monitoring the whole load at a single point by one recording device[5]. Each appliance has its own characteristics which results in a unique magnitude and sign in active and reactive Power as well as have unique frequency spectrum when it is switched on. Existing technologies use two dimensional signature space of real and reactive Power (DeltaP-DeltaQ Plane) for house hold appliances , while a three dimensional space with axes denoting real power ,reactive power and third harmonic is used in buildings for load monitoring[l]. During last decade , low cost power electronics devices and their efficiency have resulted into their increased use in household appliances, examples of house hold appliance using these devices are CFL , electronic chokes , AC inverter fed motors in washing machine, vacuum cleaner and appliances using variable speed motors etc. These devices are highly nonlinear which results in increased harmonics. These harmonics are used for load identification This research is focused on monitoring and analyzing current harmonics.. Then based upon analysis, frequency domain spectrum is used in combination with real and reactive power to identify nonlinear loads. So this research is focused on the development of appliance signature in frequency domain and time domain both In this way nonlinear devices are also identified. For this purpose current of CFL ,Dimmable fan , dimmable light are observed and their FFT is analyzed. After developing signatures, algorithm is also proposed for identification so that we could use it in real time applications.
Phenyl-Perfluorophenyl Synthon Mediated Cocrystallization of Carboxylic Acids and Amides (2003)

The significance of face-to-face π−π stacking of phenyl and perfluorophenyl rings (Ph-PhF), a robust supramolecular synthon in aromatic and perfluoroaromatic crystal structures, is studied in the cocrystallization of simple aromatic carboxylic acids and amides. X-ray crystal structures of C6H5COOH·C6F5COOH 1, C6H5CONH2·C6F5CONH2 2, and C6H5CONH2·C6F5COOH 3 are analyzed to understand the role of Ph-PhF synthon in directing self-assembly and hydrogen bonding in these cocrystals. The strong hydrogen bond donor acidity of C6F5COOH and C6F5CONH2 together with mixed stacks of phenyl and perfluorophenyl rings steer acid···acid and amide···amide hydrogen bonding in cocrystals 1 and 2. Acid···amide hydrogen bonding is sufficiently strengthened by donor acidity and acceptor basicity in 3 that the role of the Ph-PhF synthon is weaker because the aromatic rings stack with lateral offset. The complex C6H5COOH·C6F5CONH2 4 could not be obtained under similar crystallization conditions. The crystal structure of C6F5CONH2 is determined to compare molecular conformation and hydrogen bonding with motifs in the cocrystals. This study shows the viability of the Ph-PhF synthon in the presence of strong hydrogen bonding COOH and CONH2 groups for crystal engineering.
Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation. (2003)

In addition to inhibiting the mitochondrial respiratory chain, toxins known to cause Parkinson's disease (PD), such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and rotenone, also strongly depolymerize microtubules and increase tubulin degradation. Microtubules are polymers of tubulin alpha/beta heterodimers, whose correct folding requires coordinated actions of cellular chaperonins and cofactors. Misfolded tubulin monomers are highly toxic and quickly degraded through a hitherto unknown mechanism. Here we report that parkin, a protein-ubiquitin E3 ligase linked to PD, was tightly bound to microtubules in taxol-mediated microtubule coassembly assays. In lysates from the rat brain or transfected human embryonic kidney (HEK) 293 cells, alpha-tubulin and beta-tubulin were strongly coimmunoprecipitated with parkin at 4 degrees C in the presence of colchicine, a condition in which tubulin exits as alpha/beta heterodimers. At the subcellular level, parkin exhibited punctate immunostaining along microtubules in rat brain sections, cultured primary neurons, glial cells, and cell lines. This pattern of subcellular localization was abolished in cells treated with the microtubule-depolymerizing drug colchicine. The binding between parkin and tubulin apparently led to increased ubiquitination and accelerated degradation of alpha- and beta-tubulins in HEK293 cells. Similarly ubiquitinated tubulins were also observed in rat brain lysates. Furthermore, parkin mutants found in PD patients did not ubiquitinate or degrade either tubulin. Taken together, our results show that parkin is a novel tubulin-binding protein, as well as a microtubule-associated protein. Its ability to enhance the ubiquitination and degradation of misfolded tubulins may play a significant role in protecting neurons from toxins that cause PD.
Hyaluronic Acid–Antibody Fragment Bioconjugates for Extended Ocular Pharmacokinetics (2019)

Treatment of ocular diseases associated with neovascularization currently requires frequent intravitreal injections of antivascular endothelial growth factor (anti-VEGF) therapies. Reducing the required frequency of anti-VEGF injections and associated clinical visits may improve patient adherence to the prescribed treatment regimen and improve outcomes. Herein, we explore conjugation of rabbit and fragment antibodies (Fab) to the biopolymer hyaluronic acid (HA) as a half-life modifying strategy, and assess the impact on Fab biophysical properties and vitreal pharmacokinetics. HA-Fab conjugates of three distinct molecular weights and hydrodynamic radii (<i>R</i><sub>H</sub>) were assessed for <i>in vivo</i> pharmacokinetic performance relative to unconjugated Fab after intravitreal injection in rabbits. Covalent conjugation to HA did not significantly alter the thermal stability or secondary or tertiary structure, or diminish the potency of the Fab, thereby preserving its pharmacological properties. Conjugation to HA did significantly slow the <i>in vivo</i> clearance of Fab from the rabbit vitreous in an <i>R</i><sub>H</sub>-dependent manner. Compared to free Fab (observed vitreal half-life of 2.8 days), HA-Fab conjugates cleared with observed half-lives of 7.6, 10.2, and 18.3 days for 40 kDa, 200 kDa, and 600 kDa HA conjugates, respectively. This work elucidates a possible strategy for long-acting delivery of proteins intended for the treatment of chronic posterior ocular diseases.
Regulated Delivery of Therapeutic Proteins After in Vivo Somatic Cell Gene Transfer (1999)

Stable delivery of a therapeutic protein under pharmacologic control was achieved through in vivo somatic gene transfer. This system was based on the expression of two chimeric, human-derived proteins that were reconstituted by rapamycin into a transcription factor complex. A mixture of two adeno-associated virus vectors, one expressing the transcription factor chimeras and one containing erythropoietin (Epo) under the control of a promoter responsive to the transcription factor, was injected into skeletal muscle of immune-competent mice. Administration of rapamycin resulted in 200-fold induction of plasma Epo. Stable engraftment of this humanized system in immune-competent mice was achieved for 6 months with similar results for at least 3 months in a rhesus monkey.