gebhart/patrepeval huggingface dataset:
A Novel M 1 PAM VU0486846 Exerts Efficacy in Cognition Models without Displaying Agonist Activity or Cholinergic Toxicity (2018)

Selective activation of the M<sub>1</sub> subtype of muscarinic acetylcholine receptor, via positive allosteric modulation (PAM), is an exciting strategy to improve cognition in schizophrenia and Alzheimer's disease patients. However, highly potent M<sub>1</sub> ago-PAMs, such as MK-7622, PF-06764427, and PF-06827443, can engender excessive activation of M<sub>1</sub>, leading to agonist actions in the prefrontal cortex (PFC) that impair cognitive function, induce behavioral convulsions, and result in other classic cholinergic adverse events (AEs). Here, we report a fundamentally new and highly selective M<sub>1</sub> PAM, VU0486846. VU0486846 possesses only weak agonist activity in M<sub>1</sub>-expressing cell lines with high receptor reserve and is devoid of agonist actions in the PFC, unlike previously reported ago-PAMs MK-7622, PF-06764427, and PF-06827443. Moreover, VU0486846 shows no interaction with antagonist binding at the orthosteric acetylcholine (ACh) site (e.g., neither bitopic nor displaying negative cooperativity with [<sup>3</sup>H]-NMS binding at the orthosteric site), no seizure liability at high brain exposures, and no cholinergic AEs. However, as opposed to ago-PAMs, VU0486846 produces robust efficacy in the novel object recognition model of cognitive function. Importantly, we show for the first time that an M<sub>1</sub> PAM can reverse the cognitive deficits induced by atypical antipsychotics, such as risperidone. These findings further strengthen the argument that compounds with modest in vitro M<sub>1</sub> PAM activity (EC<sub>50</sub> > 100 nM) and pure-PAM activity in native tissues display robust procognitive efficacy without AEs mediated by excessive activation of M<sub>1</sub>. Overall, the combination of compound assessment with recombinant in vitro assays (mindful of receptor reserve), native tissue systems (PFC), and phenotypic screens (behavioral convulsions) is essential to fully understand and evaluate lead compounds and enhance success in clinical development.
Studies on rotavirus replication (2000)

Rotavirus is the leading cause of dehydrating diarrhea in infants and young children globally. In cells infected with rotavirus SA11 the synthesis of viral RNA and protein predominated already after a few hours. Cellular RNA remained intact, but viral mRNA was preferentially utilised for protein synthesis. As a reaction to the infection, the cellular double-stranded RNA-activated protein kinase (PKR) was induced and activated. Its major substrate, the translation initiation factor 2α became phosphorylated. However, rotavirus protein synthesis was resistant to this antiviral response, even when it was induced before infection by treatment of the cells with interferon alpha. The porcine rotavirus strain CC86, having partial duplication in RNA segment 11, was used for an investigation of genetic stability. In serial cloning of CC86 by plaque to plaque transfer the virus lost fitness, probably due to mutations in all RNA segments. Mutations in segment 11 were identified by nucleotide sequence determination of cDNA. The overall mutation rate of this segment was 1x10-5 per replicted base at two nucleotide positions mutations and reversions occurred at much higher frequencies.The properties of the nonstructural protein NSP5, encoded by gene segment 11, were analysed. NSP5 isolated from infected cells was phosphorylated at multiple serine residues. Similar phosphorylated forms were formed when the polypeptide was expressed in the absence of the other viral proteins. This result and the properties of NSP5 expressed in bacteria show that NSP5 is a protein kinase of unusual type capable of autophosphorylation.
MAML and ANIL Provably Learn Representations (2022)

Recent empirical evidence has driven conventional wisdom to believe that gradient-based meta-learning (GBML) methods perform well at few-shot learning because they learn an expressive data representation that is shared across tasks. However, the mechanics of GBML have remained largely mysterious from a theoretical perspective. In this paper, we prove that two well-known GBML methods, MAML and ANIL, as well as their first-order approximations, are capable of learning common representation among a set of given tasks. Specifically, in the well-known multi-task linear representation learning setting, they are able to recover the ground-truth representation at an exponentially fast rate. Moreover, our analysis illuminates that the driving force causing MAML and ANIL to recover the underlying representation is that they adapt the final layer of their model, which harnesses the underlying task diversity to improve the representation in all directions of interest. To the best of our knowledge, these are the first results to show that MAML and/or ANIL learn expressive representations and to rigorously explain why they do so.
New tunable solid-state lasers Cr^3+:LiCaAIF_6 and Cr^3+:LiSrAIF_6 (1990)

Get PDF Email Share Share with Facebook Tweet This Post on reddit Share with LinkedIn Add to CiteULike Add to Mendeley Add to BibSonomy Get Citation Copy Citation Text Lloyd L. Chase and Stephen A. Payne, "New tunable solid-state lasers Cr3+:LiCaAIF6 and Cr3+:LiSrAIF6," Optics & Photonics News 1(8), 16-19 (1990) Export Citation BibTex Endnote (RIS) HTML Plain Text Citation alert Save article
Mussel-Inspired Polynorepinephrine/MXene-Based Magnetic Nanohybrid for Electromagnetic Interference Shielding in X-Band and Strain-Sensing Performance (2022)

The current work delivers preparation of MXene-based magnetic nanohybrid coating for flexible electronic applications. Herein, we report carbon dot-triggered photopolymerized polynorepinepherene (PNE)-coated MXene and iron oxide hybrid deposited on the cellulose microporous membrane via a vacuum-assisted filtration strategy. The surface morphologies have been monitored by scanning electron microscopy analysis, and the coating thickness was evaluated by the gallium-ion-based focused ion beam method. Coated membranes have been tested against uniaxial tensile stretching and assessed by their fracture edges in order to assure flexibility and mechanical strength. Strain sensors and electromagnetic interference (EMI) shielding have both been tested on the material because of its electrical conductivity. The bending strain sensitivity has been stringent because of their fast 'rupture and reform' percolation network formation on the coated surface. Increased mechanical strength, solvent tolerance, cyclic deformation tolerance, and EMI shielding performance were achieved by decreasing interstitial membrane porosity. Considering a possible application, the membrane also has been tested against simulated static and dynamic water flow conditions that could infer its excellent robustness which also has been confirmed by elemental analysis via ICP-MS. Thus, as of nurturing the works of the literature, it could be believed that the developed material will be an ideal alternative of flexible lightweight cellulose for versatile electronic applications.
Phase separation in mullite-composition glass (2022)

Aluminosilicates (AS) are ubiquitous in ceramics, geology, and planetary science, and their glassy forms underpin vital technologies used in displays, waveguides, and lasers. In spite of this, the nonequilibrium behavior of the prototypical AS compound, mullite (40SiO<sub>2</sub>-60Al<sub>2</sub>O<sub>3</sub>, or AS60), is not well understood. By deeply supercooling mullite-composition liquid via aerodynamic levitation, we observe metastable liquid-liquid unmixing that yields a transparent two-phase glass, comprising a nanoscale mixture of AS7 and AS62. Extrapolations from X-ray scattering measurements show the AS7 phase is similar to vitreous SiO<sub>2</sub> with a few Al species substituted for Si. The AS62 phase is built from a highly polymerized network of 4-, 5-, and 6-coordinated AlO<sub>x</sub> polyhedra. Polymerization of the AS62 network and the composite morphology provide essential mechanisms for toughening the glass.
Supplementary Figure 4 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia (2023)

&lt;p&gt;PDF file - 74K, Knockdown efficiency and BCL2 expression in JURKAT cells.&lt;/p&gt;
Quasicrystalline structures and uses thereof (2023)

This invention relates generally to the field of quasicrystalline strictures. In preferred embodiments, the stopgap structure is more spherically symmetric than periodic structures facilitating the formation of stopgaps in nearly all directions because of higher rotational symmetries. More particularly, the invention relates to the use of quasicrystalline structures for optical, mechanical, electrical and magnetic purposes. In some embodiments, the invention relates to manipulating, controlling, modulating and directing waves including electromagnetic, sound, spin, and surface waves, for pre-selected range of wavelengths propagating in multiple directions.
An iterative approach for symmetrical and asymmetrical Short-circuit calculations with converter-based connected renewable energy sources. Application to wind power (2012)

As more renewable energy sources, especially more wind turbines are installed in the power system, analysis of the power system with the renewable energy sources becomes more important. Short-circuit calculation is a well known fault analysis method which is widely used for early stage analysis and design purposes and tuning of the network protection equipments. However, due to current controlled power converter-based grid connection of the wind turbines, short-circuit calculation cannot be performed with its current form for networks with power converter-based wind turbines. In this paper, an iterative approach for short-circuit calculation of networks with power converter-based wind turbines is developed for both symmetrical and asymmetrical short-circuit grid faults. As a contribution to existing solutions, negative sequence current injection from the wind turbines is also taken into account in calculations in case of asymmetrical faults. The developed iterative short-circuit calculation method is verified with time domain simulations.
Abstract A25: Establishment and characterization of primary human Biomerk Tumorgraft™ Models: Application to oncology drug development (2009)

Abstract One of the key challenges facing oncology drug development is the high attrition rates of compounds that enter the drug development pipeline, where very few achieve successful approval and marketing. Champions Biotechnology, in an effort to enhance the value of preclinical compounds and accelerate oncology drug development, has developed a novel preclinical platform derived from Biomerk Tumorgraft™ models; an innovative approach that utilizes the implantation of primary human tumors in immune-deficient mice in a manner that preserves the biological properties of the original human tumor. Biomerk Tumorgrafts™ differ from traditional xenograft models in that they are not passaged in tissue culture, and are instead exclusively passaged in vivo. Additionally, the Biomerk Tumorgraft™ models: (a) maintain the fundamental genotypic features of the original cancer, (b) represent the genetic heterogeneity of the cancer, and (c) do not change over several passages. Champions has established a bank of over 200 Tumorgraft models encompassing all major solid tumor types, all of which have been extensively characterized. Here we describe a panel of NSCLC lung, colon, and pancreatic tumorgraft models including gene expression profiling, mutational analyses and responses to standard of care agents. Of the NSCLC lung models, 6/8 demonstrated resistance to Erlotinib with 2/8 demonstrating an intermediate response, 2/6 also possessed a mutant K-ras or a mutant EGFR. Similarly, 3/6 K-ras mutant colon Tumorgraft models demonstrated sensitivity to irinotecan. In the case of the pancreatic models, 7/8 showed resistance to Erlotinib with the remaining model showing only a modest response. Through Champions' Personalized Oncology Services, we have also shown a high correlation between the Tumorgraft response and the clinical response. Together, these results demonstrate that each model differs with respect to its genetic composition and response to standard agents, and thus represents the efficacy of a compound on an individual patient. Given the diversity of models, the maintenance of the genomic and phenotypic characteristics of the original patient tumor, and the correlation between Tumorgraft and clinical responses, Champions Biomerk Tumorgraft™ models represent a novel preclinical in vivo platform capable of optimizing drug regimens for cancer patients and predicting the clinical effectiveness of preclinical drug candidates. Overall, the application of Biomerk Tumorgraft™ models has the potential to accelerate and enhance oncology drug development. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A25.
Session 12 Device technology &#8212; Advanced fabrication technology (1986)

Start of the above-titled section of the conference proceedings.
A role for the Cockayne Syndrome B (CSB)-Elongin ubiquitin ligase complex in signal-dependent RNA polymerase II transcription (2021)

The Elongin complex was originally identified as an RNA polymerase II (RNAPII) elongation factor and subsequently as the substrate recognition component of a Cullin-RING E3 ubiquitin ligase. More recent evidence indicates that the Elongin ubiquitin ligase assembles with the Cockayne syndrome B helicase (CSB) in response to DNA damage and can target stalled polymerases for ubiquitylation and removal from the genome. In this report, we present evidence that the CSB-Elongin ubiquitin ligase pathway has roles beyond the DNA damage response in the activation of RNAPII-mediated transcription. We observed that assembly of the CSB-Elongin ubiquitin ligase is induced not just by DNA damage, but also by a variety of signals that activate RNAPII-mediated transcription, including endoplasmic reticulum (ER) stress, amino acid starvation, retinoic acid, glucocorticoids, and doxycycline treatment of cells carrying several copies of a doxycycline-inducible reporter. Using glucocorticoid receptor (GR)-regulated genes as a model, we showed that glucocorticoid-induced transcription is accompanied by rapid recruitment of CSB and the Elongin ubiquitin ligase to target genes in a step that depends upon the presence of transcribing RNAPII on those genes. Consistent with the idea that the CSB-Elongin pathway plays a direct role in GR-regulated transcription, mouse cells lacking the Elongin subunit Elongin A exhibit delays in both RNAPII accumulation on and dismissal from target genes following glucocorticoid addition and withdrawal, respectively. Taken together, our findings bring to light a new role for the CSB-Elongin pathway in RNAPII-mediated transcription.
Raman spectroscopic evidence for conformational deformation in the high pressure phase of polytetrafluoroethylene (1978)

An investigation of polytetrafluoroethylene (PTFE), nC20F42, and a random copolymer of tetrafluoroethylene and hexafluoropropylene (TFE–HFP) under pressure has been carried out using Raman spectroscopy in conjunction with a diamond anvil cell. Both nC20F42 and the TFE–HFP copolymer were found to undergo a phase transition in the 7–9 kbar range similar to PTFE as evidenced by the observation of the 625 cm−1 Raman band characteristic of phase III. With increasing pressure in the 10–52 kbar range, a continual variation in intensity of the bands at 285 and 395 cm−1 was observed and found to differ for the three fluorocarbon materials studied. By correlating a change in the I285/I395 ratio with a change in sample crystallinity (as determined by x- ray), it has been determined that an increase in transplanar content with pressure is responsible for the observed band intensity changes in the high pressure phase of PTFE.
Task decomposition of laparoscopic surgery for objective evaluation of surgical residents' learning curve using hidden Markov Model (2002)

HMMs incorporating haptic and visual information provide an objective tool for evaluating surgical skills. Objective evidence for a "learning curve" suggests that surgical residents acquire a major portion of their laparoscopic skill between year 1 and year 3 of training.
A Smart Mask for Active Defense Against Coronaviruses and Other Airborne Pathogens (2020)

Face masks provide effective, easy-to-use, and low-cost protection against airborne pathogens or infectious agents, including SARS-CoV-2. Existing masks are all passive in nature, i.e., simply act as air filters for the nasal passage and/or mouth. This article presents a new “active mask” paradigm, in which the wearable device is equipped with smart sensors and actuators to both detect the presence of airborne pathogens in real time and take appropriate action to mitigate the threat. The proposed approach is based on a closed-loop control system that senses airborne particles of different sizes near the mask and then makes intelligent decisions to reduce their concentrations. In the current implementation, an on-board controller determines ambient air quality via a commercial particulate matter sensor, and if necessary activates a piezoelectric actuator that generates a mist spray to load these particles, thus causing them to fall to the ground. The system communicates with the user via a smart phone application that provides various alerts, including the need to recharge and/or decontaminate the mask prior to reuse. The application also enables a user to override the on-board control system and manually control the mist generator if necessary. Experimental results from a functional prototype demonstrate significant reduction in airborne PM counts near the mask when the active protection system is enabled.
Narrow-linewidth lasers using on-chip high-Q resonators (2016)

We present heterogeneously integrated widely-tunable semiconductor lasers with narrow-linewidth. 50 kHz integrated linewidth was demonstrated using controlled feedback to the laser, and sub-kHz Lorentzian linewidths are predicted using high-Q ring resonators made in Si. Low-frequency noise was suppressed by more than 30 dB using an ultra-high Q Si 3 N 4 resonator.
CARTILAGE BOUNDARY LUBRICATING ABILITY OF PRG4 (LUBRICIN) MONOMERS AND MULTIMERS WITH HYALURONAN (2014)

INTRODUCTION Proteoglycan 4 (PRG4), or lubricin, is a glycoprotein that exists in synovial fluid (SF) as monomeric and disulfide-bonded multimeric forms [1,2]. PRG4 functions as a critical boundary lubricant on the surface of articular cartilage [1,3]. Hyaluronan (HA) is another lubricant that lubricates at a cartilage-cartilage interface alone, and synergistically with PRG4 to reduce friction levels near that of SF [4]. Previously PRG4-multimers (PRG4-multi) have been shown to lubricate considerably better than PRG4 monomers (PRG4-mono) using an in vitro cartilage-on-cartilage friction testing system [5]. However, it is unknown if the difference in structure of PRG4-multi/-mono affects the synergism with HA. Therefore, the objective of this study was to evaluate the cartilage boundary lubricating ability of PRG4-multi & PRG4-mono with HA. METHODS Samples: PRG4 was purified from media conditioned by mature bovine cartilage explants [4]. PRG4 multi-mono was prepared via size exclusion chromatography [5]. HA (1.5MDa) was obtained from Lifecore Biomedical. Cartilage boundary lubrication: Lubricants of interest were assessed using a previously described in vitro cartilage-cartilage friction test [6]. Briefly, bovine osteochondral samples (n=8) were incubated with test lubricants overnight, compressed by 18%, allowed to stress relax then rotated at an effective velocity of 0.3 mm/s with pre-sliding durations (Tps) of 1200, 120, 12, and 1.2s. Phosphate buffered saline (PBS) and bovine SF served as negative and positive controls, respectively. All samples were prepared at a physiological concentration [4]; PRG4 at 450 μg/mL and HA at 3.33 mg/mL, in PBS. Test sequence: PBS, PRG4-mono+HA, PRG4-multi+HA, PRG4+HA, SF. Static (μ static,Neq ) and kinetic ( ) friction coefficients were calculated [4,6]. ANOVA was used to assess the effect of lubricant and Tps, as a repeated factor, on μ static,Neq and , with Tukey post-hoc on at Tps=1.2s. RESULTS Cartilage boundary lubrication: PRG4-mono/-multi+HA, functioned as effective friction-reducing cartilage boundary lubricants. However, they did not lubricate as well as PRG4+HA or SF. μ static,Neq values increased with Tps; they were highest in PBS and lowest in SF, with PRG4-mono+HA, PRG4-multi+HA, and PRG4+HA being intermediate. For clarity, values at Tps=1.2s are shown since values at Tps=1.2s were within 13.0±2.7% of those at Tps=1200s. values for PRG4-mono+HA and PRG4-multi+HA were similar (p=0.96). PRG4+HA and SF were similar (p=0.53). All other combinations were significantly different from each other (p<0.05). DISCUSSION AND CONCLUSIONS Previous studies have shown that PRG4-multi lubricates better than PRG4-mono [5]. However the results from this study show that PRG4-mono/-multi with HA lubricate in a similar manner. Interestingly, PRG4+HA lubricates better than PRG4-mono/-multi+HA, and close to that of SF. These differences could be due to a potential PRG4+HA “link molecule” [7] being purified from the PRG4-mono/-multi preparations.
Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting (2001)

The transcription factor, forkhead in rhabdomyosarcoma (FKHR), is phosphorylated at three amino acid residues (Thr-24, Ser-256 and Ser-319) by protein kinase B (PKB)alpha. In the present study, mutagenesis has been used to study the roles of these phosphorylation events in regulating FKHR function in transfected HEK-293 cells. We find that the overexpression of FKHR[S256A] (where Ser-256-->Ala) blocks PKB activity in cells, preventing phosphorylation of the endogenous substrates FKHRL1 and glycogen synthase kinase-3. Thus some reported effects of overexpression of this and other mutants may be indirect, and result from suppression of the phosphorylation of other sites on FKHR and/or other PKB substrates. For example, we have shown that Thr-24 phosphorylation alone is critical for interaction with 14-3-3 proteins, and that the substitution of Ser-256 with an alanine residue indirectly blocks 14-3-3 protein binding by preventing the phosphorylation of Thr-24. We also found that insulin-like growth factor (IGF)-1 and serum-induced nuclear exclusion of FKHR[S256A] depends on the degree of overexpression of this mutant. Our results indicated that the interaction of FKHR with 14-3-3 proteins was not required for IGF-1-stimulated exclusion of FKHR from the nucleus. We present evidence in support of another mechanism, which depends on the phosphorylation of Ser-256 and may involve the masking of a nuclear localization signal. Finally, we have demonstrated that the failure of IGF-1 to suppress transactivation by FKHR[S256A] is not explained entirely by its failure to bind 14-3-3 proteins or to undergo nuclear exclusion. This result suggests that Ser-256 phosphorylation may also suppress transactivation by FKHR by yet another mechanism, perhaps by disrupting the interaction of FKHR with target DNA binding sites and/or the function of the transactivation domain.
Determining a Performance Envelope for Capture of Kidney Stones Functionalized with Superparamagnetic Microparticles (2012)

We are able to characterize the potential for kidney stone capture via magnetic attraction. Computer-developed models show good correlation with experimental results using actual magnetized stone samples. Future research efforts can use the proposed techniques to estimate the performance impact of advanced magnetic tools and surface chemistries.