gebhart/patrepeval huggingface dataset:
GENT-11. SMALL MOLECULE EPIGENETIC SCREEN IDENTIFIES NOVEL EZH2 AND HDAC INHIBITORS THAT TARGET GLIOBLASTOMA BRAIN TUMOR-INITIATING CELLS (2016)

Glioblastoma (GBM) is the most lethal and aggressive adult brain tumor, requiring the development of efficacious therapeutics. Towards this goal, we screened five genetically distinct patient-derived brain-tumor initiating cell lines (BTIC) with a unique collection of small molecule epigenetic modulators from the Structural Genomics Consortium (SGC). We identified multiple hits that inhibited the growth of BTICs in vitro, and further evaluated the therapeutic potential of EZH2 and HDAC inhibitors due to the high relevance of these targets for GBM. We found that the novel SAM-competitive EZH2 inhibitor UNC1999 exhibited low micromolar cytotoxicity in vitro on a diverse collection of BTIC lines, synergized with dexamethasone (DEX) and suppressed tumor growth in vivo in combination with DEX. In addition, a unique brain-penetrant class I HDAC inhibitor exhibited cytotoxicity in vitro on a panel of BTIC lines and extended survival in combination with TMZ in an orthotopic BTIC model in vivo. Finally, we showed that a combination of EZH2 and HDAC inhibitors demonstrated synergy in vitro by augmenting apoptosis and increasing DNA damage. Our findings identify key epigenetic modulators in GBM that regulate BTIC growth and survival and highlight promising combination therapies.
Effect of Spilanthes acmella hydroethanolic extract activity on tumour cell actin cytoskeleton (2013)

Numerous natural products have pharmacological activity such that many biologically active compounds have led to the development of cancer chemotherapy drugs. Spilanthes acmella (Asteraceae) is widely cultivated in the State of Pará, Brazil, being employed in folk medicine for its anti-inflammatory, antimicrobial, antioxidant, analgesic, insecticide, and larvicidal properties. However, its cytotoxicity and influence on actin cytoskeleton organisation in tumour cell lines are practically nonexistent. We have verified the cytotoxicity of a hydroethanolic extract of the inflorescence of S. acmella, and examined its effects on the cytoskeleton of tumour cells. Decreasing concentrations of the extract (250, 500 and 1,000 µg/mL) were given to cultures of neoplastic cells (HEp-2). Cytotoxicity was assessed by the MTT test, and the influence on cytoskeleton organisation was examined by fluorescence microscopy. The IC50 of the hydroethanolic extract was 513 µg/mL, confirming the data obtained from the MTT assay that gave high cytotoxicity. The actin cytoskeleton arrangement of HEp2 cells at 500 and 1,000 µg/mL showed depolymerisation of the filaments, causing loss of morphology and consequently compromising cell adhesion.
Acidic Fibroblast Growth Factor (FGF) Potentiates Glial-mediated Neurotoxicity by Activating FGFR2 IIIb Protein (2011)

Previous studies indicate that astrocytes are the brain cells that express acidic fibroblast growth factor (aFGF) and that the expression is increased upon activation. However, there has been no study investigating the significance of this phenomenon. Here we report that aFGF treatment of IFNγ-stimulated human astrocytes, and LPS/IFNγ-stimulated human microglia, enhances their secretion of inflammatory cytokines and other materials toxic to human neuroblastoma SH-SY5Y cells. The mechanism of aFGF enhancement involves stimulation of the receptor FGFR2 IIIb. We show by RT-PCR that this receptor, but not other FGF receptors, is robustly expressed by astrocytes and microglia. We establish by Western blotting, and immunohistochemistry on postmortem human brain tissue that the FGFR2 IIIb protein is expressed by both of these glial cell types. We blocked the inflammatory stimulant action of aFGF by transfecting microglia and astrocytes with a small inhibitory RNA (siRNA) to FGFR2 IIIb as well as by removal of aFGF using an anti-aFGF antibody. Treatment with bFGF in combination with the stimulants was without effect, but together with aFGF, it partially counteracted the action of aFGF, indicating that it may be a weak antagonist of FGFR2 IIIb. The inflammatory effect was also attenuated by treatment with inhibitors of protein kinase C, Src tyrosine kinase, and MEK-1/2 indicating the involvement of these intracellular pathways. Our data suggest that inhibition of expression or release of aFGF could have therapeutic potential by inhibiting inflammation in neurodegenerative diseases such as Alzheimer disease where many neuroinflammatory molecules are prominently expressed.
Effect of Counterion Condensation on Rigidity of Semiflexible Polyelectrolytes (2006)

I have calculated the effect of counterion condensation on the electrostatic persistence length of semiflexible polyelectrolytes. There are two contributions to the electrostatic persistence length. The first contribution is due to neutralization of the ionized groups by condensed ions that changes the effective linear charge density along the polymer backbone, weakening intrachain electrostatic repulsion. In the case of the monovalent counterions this contribution to the chain persistence length is proportional to the Debye screening length, underlining the fact of the exponential screening of electrostatic interactions on the length scales of the order of Debye screening length. The second contribution is due to correlation/fluctuation-induced attractive interactions between condensed counterions that result in a negative contribution to the chain persistence length. In the case of multivalent ions these interactions are assumed to be due to strong lateral correlations between condensed multivalent ions and were accounted for in the framework of the strongly correlated Wigner liquid approximation.
A dual frequency antenna for RSSI-based DOA estimation — From theory to prototype (2016)

Wildlife monitoring, e.g. tracking bats, is one of many emerging applications applying wireless sensor networks. In this paper, a dual band antenna for field strength-based direction finding is presented. The complete design process including theoretical considerations and simulations towards a working prototype is shown. To meet the networks crucial requirements of robustness and low-cost fabrication, the design of the antenna pursues a passive approach to realize a set of two orthogonal radiation patterns without side-lobes. The antenna is influenced by the small element separation, i.e. additional side-lobes and impedance transformation. The effects are compensated by an optimized element arrangement, as well as a dual-band matching and decoupling of the antenna elements. The proposed directional antenna array provides a gain pattern suitable for precise field strength-based direction of arrival estimation.
In-Situ Contacted Single-Walled Carbon Nanotubes and Contact Improvement by Electroless Deposition (2003)

This work presents a simple and versatile approach for the growth of in-situ contacted single-walled carbon nanotubes (SWCNTs) and subsequent improvement of the contacts using a self-aligned process. We investigated the conditions for the thermal CVD growth of SWCNTs and developed a variety of multilayered metal systems for SWCNT growth at temperatures between 650 °C and 900 °C. The catalytically active layers were either an Fe/Mo bilayer or a Co layer. Further, we report that some of the multilayer systems presented allow lithography free contact improvement by electroless metal deposition.
A Planning Strategy for Diversity‐Oriented Synthesis (2003)

In contrast to target-oriented synthesis (TOS) and medicinal or combinatorial chemistry, which aim to access precise or dense regions of chemistry space, diversity-oriented synthesis (DOS) populates chemical space broadly with small-molecules having diverse structures. The goals of DOS include the development of pathways leading to the efficient (three- to five-step) synthesis of collections of small molecules having skeletal and stereochemical diversity with defined coordinates in chemical space. Ideally, these pathways also yield compounds having the potential to attach appendages site- and stereoselectively to a variety of attachment sites during a post-screening, maturation stage. The diverse skeletons and stereochemistries ensure that the appendages can be positioned in multiple orientations about the surface of the molecules. TOS as well as medicinal and combinatorial chemistries have been advanced by the development of retrosynthetic analysis. Although the distinct goals of DOS do not permit the application of retrosynthetic concepts and thinking, these foundations are being built on, by using parallel logic, to develop a complementary procedure known as forward-synthetic analysis. This analysis facilitates synthetic planning, communication, and teaching in this evolving discipline.
Cell-based interventions for neurologic conditions (2008)

Distinctive challenges confronting US scientists, administrators, institutional review boards, stem cell research oversight committees, and others who will need to make decisions about work involving stem cells and their derivatives and evaluate the ethics of early human trials include evaluating the risks, safety, and benefits of these trials, determining and evaluating cell line provenance, and determining inclusion criteria, informed consent, and the ethics of conducting early human trials in the public spotlight. Further study and deliberation by stakeholders is required to move toward professional and institutional policies and practices governing this research.
Palm NMR and one-chip NMR (2010)

A 0.1 kg palm NMR system using a fully integrated CMOS RF transceiver is reported. It is 20× lighter, 30× smaller, yet 2.5× more spin-mass sensitive than our prior system, and 1200× lighter, 1200× smaller, yet 150× more spin-mass sensitive than a commercial system. A one-chip NMR system for on-chip disease screening is also reported, which detects hCG cancer markers and bladder cancer cells.
Efficient Coupling of High-Intensity Sub-Picosecond Laser Pulses into Solid Grating Targets (1991)

We have experimentally observed very efficient laser-solid coupling of high-intensity (10 16 Wcm –2 ) sub-picosecond (150 fsec) laser pulses into grating targets. 1 This behavior is in contrast to the very high reflectivities observed from flat targets, 2 where we have recently extended our measurements of normal-incidence flat-target reflectivities up to incident intensities exceeding 10 16 W cm –2 . The average flat target reflectivity observed was 86% - the peak reflectivity at the center of the focal spot and peak of the laser is therefore ≥ 90%. This data is shown in Fig. 1.
Applications of multilinear forms to cryptography (2003)

We study the problem of finding efficiently computable non-degenerate multilinear maps from G1 to G2, where G1 and G2 are groups of the same prime order, and where computing discrete logarithms in G1 is hard. We present several applications to cryptography, explore directions for building such maps, and give some reasons to believe that finding examples with n > 2 may be difficult.
Posttranscriptional regulation of an erythromycin resistance protein specified by plasmic pE194. (1980)

Induction of the synthesis of a plasmid-encoded polypeptide (E3) by erythromycin is known to be required for the inducible expression of resistance to the macrolide-lincosamide-streptogramin B group of antibiotics in Bacillus subtilis strains carrying the plasmid pE194. This resistance is mediated by a specific N6-dimethylation of adenine in the 23S rRNA of the large ribosomal subunit. We show in this report that E3 induction is regulated posttranscriptionally in the sense that it can occur when RNA synthesis is blocked and that induction is accompanied by an increase in the functional half-life of E3 mRNA but not of the mRNA species that code for the remaining four known pE194 polypeptides. The induction of E3 is subject to feedback regulation and involves the ribosome. Modification of the erythromycin binding site on the ribosome by methylation or by mutation interferes with induction.
Non-Specific Microbicide Product Development: Then and Now (2012)

Despite the identification of HIV-1 as the etiological agent responsible for AIDS nearly 30 years ago, a sterilizing vaccine capable of preventing transmission of the virus remains elusive. In response to struggles on the vaccine development front, significant effort has been devoted to preventing the transmission of HIV with alternative products, technologies, and strategies. One of the early alternative HIV prevention strategies was microbicides, which are topical products that can be used to prevent sexual transmission of HIV either vaginally or rectally. First generation microbicide products were designed to be simple gel formulations comprised of readily available active agents that were inexpensive and broadly active (i.e., non-specific). Unfortunately, despite the clinical investigation of multiple product concepts satisfying these requirements, none were shown to be efficacious in pivotal trials. More recently, microbicide and oral prevention strategies involving highly specific and potent anti-retroviral (ARV) drugs have shown to be efficacious in trials. Although building on these successes continues, these products have a number of issues including potential toxicity with long term use, selection of HIV resistance, and cost. Further, all of the original justifications for non-specific microbicide products remain valid. This review provides a brief history of non-specific microbicide development, outlines the evolution to, and limitations of, ARV based microbicides, and summarizes the current activity on non-specific microbicide product development.
One-Stop Shop:18F-Flortaucipir PET Differentiates Amyloid-Positive and -Negative Forms of Neurodegenerative Diseases (2020)

Tau protein aggregations are a hallmark of amyloid-associated Alzheimer disease and some forms of non-amyloid-associated frontotemporal lobar degeneration. In recent years, several tracers for in vivo tau imaging have been under evaluation. This study investigated the ability of <sup>18</sup>F-flortaucipir PET not only to assess tau positivity but also to differentiate between amyloid-positive and -negative forms of neurodegeneration on the basis of different <sup>18</sup>F-flortaucipir PET signatures. <b>Methods:</b> The <sup>18</sup>F-flortaucipir PET data of 35 patients with amyloid-positive neurodegeneration, 19 patients with amyloid-negative neurodegeneration, and 17 healthy controls were included in a data-driven scaled subprofile model (SSM)/principal-component analysis (PCA) identifying spatial covariance patterns. SSM/PCA pattern expression strengths were tested for their ability to predict amyloid status in a receiver-operating-characteristic analysis and validated with a leave-one-out approach. <b>Results:</b> Pattern expression strengths predicted amyloid status with a sensitivity of 0.94 and a specificity of 0.83. A support vector machine classification based on pattern expression strengths in 2 different SSM/PCA components yielded a prediction accuracy of 98%. Anatomically, prediction performance was driven by parietooccipital gray matter in amyloid-positive patients versus predominant white matter binding in amyloid-negative patients. <b>Conclusion:</b> SSM/PCA-derived binding patterns of <sup>18</sup>F-flortaucipir differentiate between amyloid-positive and -negative neurodegenerative diseases with high accuracy. <sup>18</sup>F-flortaucipir PET alone may convey additional information equivalent to that from amyloid PET. Together with a perfusion-weighted early-phase acquisition (<sup>18</sup>F-FDG PET-equivalent), a single scan potentially contains comprehensive information on amyloid (A), tau (T), and neurodegeneration (N) status as required by recent biomarker classification algorithms (A/T/N).
Improving the accuracy of protein pKa calculations: Conformational averaging versus the average structure (1998)

Several methods for including the conformational flexibility of proteins in the calculation of titration curves are compared. The methods use the linearized Poisson-Boltzmann equation to calculate the electrostatic free energies of solvation and are applied to bovine pancreatic trypsin inhibitor (BPTI) and hen egg-white lysozyme (HEWL). An ensemble of conformations is generated by a molecular dynamics simulation of the proteins with explicit solvent. The average titration curve of the ensemble is calculated in three different ways: an average structure is used for the pKa calculation; the electrostatic interaction free energies are averaged and used for the pKa calculation; and the titration curve for each structure is calculated and the curves are averaged. The three averaging methods give very similar results and improve the pKa values to approximately the same degree. This suggests, in contrast to implications from other work, that the observed improvement of pKa values in the present studies is due not to averaging over an ensemble of structures, but rather to the generation of a single properly averaged structure for the pKa calculation.
Cu/Zn superoxide dismutase misfolding in amyotrophic lateral sclerosis. (2009)

Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration resulting in progressive paralysis and death. The only known cause of typical ALS is mutations in SOD1; these predominantly missense mutations produce a toxic gain-of-function in the enzyme Cu/Zn superoxide dismutase (SOD1). The prevailing hypotheses regarding the mechanism of toxicity were a) oxidative damage from aberrant SOD1 redox chemistry, and b) misfolding of the mutant protein. The goal of this thesis was to investigate the molecular mechanisms of the mutant SOD1 (mSOD1) misfolding and toxicity. We proposed that oxidative damage to SOD1 itself could cause its misfolding and aggregation. To investigate this hypothesis, we subjected purified SOD1 in vitro to metal catalyzed oxidation. Oxidation of SOD1 produced aggregates reminiscent of those observed in ALS pathology. Aggregation propensity of zinc-deficient SOD1 and several mSOD1s known to have lower zinc-binding affinity was proportional to partial unfolding. Oxidation of SOD1 caused conversion of several His residues to 2-oxo-histidine. Because oxidation of SOD1 primarily affected the metal-binding His residues, we hypothesized that oxidation of wild-type, holo-SOD1 should lead to aggregation. Increasing the concentration of wild-type SOD1 in oxidation reactions produced aggregates similar to those observed earlier. Both wild-type and mSOD1 aggregation kinetics revealed an initial decrease in particle size rather than a monotonic increase using dynamic light scattering. This was consistent with the conversion of SOD1, normally an obligate homodimer, into monomers prior to aggregation. This observation was confirmed using analytical ultracentrifugation. The common aggregation pathway for wild-type and mSOD1 suggested a mechanism for sporadic ALS caused by SOD1 misfolding. To interrogate the in vivo misfolding pathway of SOD1, we used its high-resolution structure to create an antibody that reacts with monomer/misfolded SOD1 but not the native dimer. Upon verifying the reactivity of this antibody, we showed that monomer/misfolded SOD1 is found in a human case of familial ALS and in transgenic animal models of ALS. Misfolded SOD1 is found primarily in affected cells, motor neurons. Misfolded SOD1 is also initially absent, but appears prior to symptom onset. These observations together suggest a causal role for SOD1 misfolding through a monomeric intermediate in ALS pathogenesis.
System-Level Transient Thermal Analysis for Performance Optimization of High Power Microelectronics (2003)

The increasing trend in power levels and densities leads to the need of design thermal optimization, at either module or system level. A numerical study using finite-volume software was conducted to model the transient thermal behavior of a system including a package dissipating large amounts of power over short time durations. The system is evaluated by choosing the appropriate heat sink for the efficient operation of the device under 100W of constant powering, also to enhance the thermal performance of the enclosure/box containing the test stack-up. The intent of the study is to provide a meaningful understanding and prediction of the high transient powering scenarios. The study focuses on several powering and system design scenarios, identifying the main issues encountered during a normal device operation. The power source dissipates 100W for 2 seconds then is cooled for another 2 seconds. This thermal cycle is likely to occur several times during a normal test-up, and it is the main concern of the manufacturers not to exceed a limit temperature during the device testing operation. The transient trend is further extrapolated analytically to extract the steady state peak temperature values, in order to maintain the device peak temperatures below 120°C. The benefit of the study is related to the possibility to extract the maximum/minimum temperatures for a real test involving a large number of heating-cooling cycles, yet maintaining the initial and peak temperatures within a certain range, for the optimal operation of the device. The flow and heat transfer fields are thoroughly investigated. By using a combination of numerical and analytical study, the thermal performance of the device undergoing infinity of periodic thermal cycles is further predicted.
Wireless Fingerprinting via Deep Learning: The Impact of Confounding Factors (2021)

Can we distinguish between two wireless transmitters sending exactly the same message, using the same protocol? The opportunity for doing so arises due to subtle nonlinear variations across transmitters, even those made by the same manufacturer. Since these effects are difficult to model explicitly, we investigate learning device fingerprints using complex-valued deep neural networks (DNNs) that take as input the complex baseband signal at the receiver. We ask whether such fingerprints can be made robust to distribution shifts across time and locations due to clock drift and variations in the wireless channel. In this paper, we point out that, unless proactively discouraged from doing so, DNNs learn these strong confounding features rather than the nonlinear device-specific characteristics that we seek to learn. We propose and evaluate strategies, based on augmentation and estimation, to promote generalization across realizations of these confounding factors, using WiFi data. We conclude that, while DNN training has the advantage of not requiring explicit signal models, significant modeling insights are required to focus the learning on the effects we wish to capture.
ChemInform Abstract: Thiophene Derivatives: A New Series of Potent Norepinephrine and Serotonin Reuptake Inhibitors. (2002)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.