gebhart/patrepeval huggingface dataset:
Design, Synthesis, and in Vitro Biological Evaluation of Small Molecule Inhibitors of Estrogen Receptor α Coactivator Binding (2003)

Nuclear receptors (NRs) complexed with agonist ligands activate transcription by recruiting coactivator protein complexes. In principle, one should be able to inhibit the transcriptional activity of the NRs by blocking this transcriptionally critical receptor-coactivator interaction directly, using an appropriately designed coactivator binding inhibitor (CBI). To guide our design of various classes of CBIs, we have used the crystal structure of an agonist-bound estrogen receptor (ER) ligand binding domain (LBD) complexed with a coactivator peptide containing the LXXLL signature motif bound to a hydrophobic groove on the surface of the LBD. One set of CBIs, based on an outside-in design approach, has various heterocyclic cores (triazenes, pyrimidines, trithianes, cyclohexanes) that mimic the tether sites of the three leucines on the peptide helix, onto which are appended leucine residue-like substituents. The other set, based on an inside-out approach, has a naphthalene core that mimics the two most deeply buried leucines, with substituents extending outward to mimic other features of the coactivator helical peptide. A fluorescence anisotropy-based coactivator competition assay was developed to measure the specific binding of these CBIs to the groove site on the ER-agonist complex with which coactivators interact; control ligand-binding assays assured that their interaction was not with the ligand binding pocket. The most effective CBIs were those from the pyrimidine family, the best binding with K(i) values of ca. 30 microM. The trithiane- and cyclohexane-based CBIs appear to be poor structural mimics, because of equatorial vs axial conformational constraints, and the triazene-based CBIs are also conformationally constrained by amine-substituent-to-ring resonance overlap, which is not the case with the higher affinity alkyl-substituted pyrimidines. The pyrimidine-based CBIs appear to be the first small molecule inhibitors of NR coactivator binding.
On-Wire Lithography-Generated Molecule-Based Transport Junctions: A New Testbed for Molecular Electronics (2008)

On-wire lithography (OWL) fabricated nanogaps are used as a new testbed to construct molecular transport junctions (MTJs) through the assembly of thiolated molecular wires across a nanogap formed between two Au electrodes. In addition, we show that one can use OWL to rapidly characterize a MTJ and optimize gap size for two molecular wires of different dimensions. Finally, we have used this new testbed to identify unusual temperature-dependent transport mechanisms for alpha,omega-dithiol terminated oligo(phenylene ethynylene).
Isolation and characterization of a Clostridium botulinum C2 toxin-resistant cell line: evidence for possible involvement of the cellular C2II receptor in growth regulation (1995)

Clostridium botulinum C2 toxin, which consists of the binding component C2II and the enzyme component C2I, acts on eukaryotic cells by selective ADP-ribosylation of G-actin. To obtain C2 toxin-resistant cells, we mutagenized CHO-K1 cells with N-nitroso-N-methylurea and selected for C2 resistance. Cells which survived the selection procedure with 50 ng of C2I and 100 ng of C2II per ml were obtained with a frequency of 30 x 10(-6). The colony-forming ability of CHO wild-type cells was reduced to 50% with 10 ng of C2I and 20 ng of C2II per ml. In contrast, the colony-forming ability of the isolated CHO mutant cells was not influenced by up to 200 ng of C2I and 400 ng of C2II per ml. Toxin-induced ADP-ribosylation of G-actin was not impaired in lysates of mutant cells. The C2 toxin-resistant phenotype remained sensitive to the cell-rounding activities of cytotoxins from C. perfringens (iota-toxin), C. novyi, C. difficile, and C. botulinum (C3) and to cytochalasin D. Binding of component C2II was impaired in resistant CHO cells, suggesting mutation of the toxin cell surface receptor. Serum factors protected wild-type cells against the cytotoxic effect of C2 toxin. Furthermore, the C2-resistant phenotype correlated with an increased serum dependency. The data suggest that the action of C. botulinum C2 toxin is mediated by its binding and uptake via a cell surface receptor which might be involved in growth regulation.
A novel integrated-twin-guide (ITG) optical switch with a built-in TIR region (1992)

The authors propose a novel integrated-twin-guide (ITG) optical switch with a built-in TIR region to enlarge the spatial separation of output lights, which is suitable for a compact optical switching matrix array. A switching operation was observed in a GaInAsP/InP MQW ITG optical switch utilizing electric-field induced refractive index variation.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Characterization of two novel proteins, NgRH1 and NgRH2, structurally and biochemically homologous to the Nogo‐66 receptor (2003)

Nogo-66 receptor (NgR) has recently been identified as the neuronal receptor of the myelin-associated proteins Nogo-A, oligodendrocyte protein (OMgp) and myelin-associated glycoprotein (MAG), and mediates inhibition of axonal regeneration both in vitro and in vivo. Through database searches, we have identified two novel proteins (NgRH1 and NgRH2) that turned out to be homologous in their primary structures, biochemical properties and expression patterns to NgR. Like NgR, the homologues contain eight leucine-rich repeats (LRR) flanked by a leucine-rich repeat C-terminus (LRRCT) and a leucine-rich repeat N-terminus (LRRNT), and also have a C-terminal GPI signal sequence. Northern blot analysis showed predominant expression of NgRH1 and NgRH2 mRNA in the brain. In situ hybridization and immunohistochemistry on rat brain slices revealed neuronal expression of the genes. NgRH1 and NgRH2 were detected on the cell surface of recombinant cell lines as N-glycosylated GPI anchored proteins and, consistent with other GPI anchored proteins, were localized within the lipid rafts of cellular membranes. In addition, an N-terminal proteolytic fragment of NgR comprising the majority of the ectodomain was found to be constitutively secreted from cells. Our data indicate that NgR, NgRH1 and NgRH2 constitute a novel receptor protein family, which may play related roles within the CNS.
The Dopamine D2 Receptor Gene and Alcoholism (1991)

<h3>To the Editor. —</h3> Two JAMA reports differ in describing the association between a D<sub>2</sub>dopamine receptor gene allele and alcoholism. Blum et al<sup>1</sup>found that the Al allele of the D<sub>2</sub>gene was present in a significantly higher percentage of 35 alcoholics (69%) than in 35 nonalcoholic controls (20%). Diagnoses were made post mortem; therefore, limited descriptive information was available. Bolos et al<sup>2</sup>assessed the gene's distribution in a group of 40 white alcoholics (38% Al) and 127 racially matched controls (30% Al) but found no evidence for an association between the D<sub>2</sub>receptor allele and alcoholism. There is a limitation in the second study. Although Bolos et al conducted thorough clinical assessments of alcoholic subjects, they present no characteristics (except race) of their "control" subjects. Their control subjects could be alcoholics (or have other relevant psychiatric diagnoses, such as affective disorder). Further, the
Pathology of inhalational anthrax in 42 cases from the Sverdlovsk outbreak of 1979. (1993)

A large epidemic of anthrax that occurred in Sverdlovsk (now Ekaterinburg), Russia, in 1979 resulted in the deaths of many persons. A series of 42 necropsies, representing a majority of the fatalities from this outbreak, consistently revealed pathologic lesions diagnostic of inhalational anthrax, namely hemorrhagic necrosis of the thoracic lymph nodes in the lymphatic drainage of the lungs and hemorrhagic mediastinitis. Bacillus anthracis was recovered in bacterial cultures of 20 cases, and organisms were detected microscopically in the infected tissues of nearly all of the cases. A novel observation was primary focal hemorrhagic necrotizing pneumonia at the apparent portal of entry in 11 cases. Mesenteric lymphadenitis occurred in only 9 cases. This remarkably large series demonstrated the full range of effects of anthrax bacteremia and toxemia (edema especially adjacent to sites of extensive infection and pleural effusions) and hematogenously disseminated infection [hemorrhagic meningitis (21 cases) and multiple gastrointestinal submucosal hemorrhagic lesions (39 cases)].
Genetic Diversity in the Protective Antigen Gene of Bacillus anthracis (1999)

Bacillus anthracis is a gram-positive spore-forming bacterium that causes the disease anthrax. The anthrax toxin contains three components, including the protective antigen (PA), which binds to eucaryotic cell surface receptors and mediates the transport of toxins into the cell. In this study, the entire 2,294-nucleotide protective antigen gene (pag) was sequenced from 26 of the most diverse B. anthracis strains to identify potential variation in the toxin and to further our understanding of B. anthracis evolution. Five point mutations, three synonymous and two missense, were identified. These differences correspond to six different haploid types, which translate into three different amino acid sequences. The two amino acid changes were shown to be located in an area near a highly antigenic region critical to lethal factor binding. Nested primers were used to amplify and sequence this same region of pag from necropsy samples taken from victims of the 1979 Sverdlovsk incident. This investigation uncovered five different alleles among the strains present in the tissues, including two not seen in the 26-sample survey. One of these two alleles included a novel missense mutation, again located just adjacent to the highly antigenic region. Phylogenetic (cladistic) analysis of the pag corresponded with previous strain grouping based on chromosomal variation, suggesting that plasmid evolution in B. anthracis has occurred with little or no horizontal transfer between the different strains.
A new generation of high voltage MOSFETs breaks the limit line of silicon (2002)

For the first time a new device concept for high voltage power devices has been realized in silicon. Our 600 V-COOLMOS/sup TM/ reaches an area specific on-resistance of typically 3.5 /spl Omega//spl middot/mm/sup 2/. Our technology thus offers a shrink factor of 5 versus the actual state of the art in power MOSFETs. The device concept is based on charge compensation in the drift region of the transistor. We increase the doping of the vertical drift region roughly by one order of magnitude and counterbalance this additional charge by the implementation of fine structured columns of the opposite doping type. The blocking voltage of the transistor remains thus unaltered. The charge compensating columns do not contribute to the current conduction during the turn-on state. Nevertheless the drastically increased doping of the drift region allows the above mentioned reduction of the on-resistance.
An improved predictive recognition model for Cys2-His2 zinc finger proteins (2014)

Cys(2)-His(2) zinc finger proteins (ZFPs) are the largest family of transcription factors in higher metazoans. They also represent the most diverse family with regards to the composition of their recognition sequences. Although there are a number of ZFPs with characterized DNA-binding preferences, the specificity of the vast majority of ZFPs is unknown and cannot be directly inferred by homology due to the diversity of recognition residues present within individual fingers. Given the large number of unique zinc fingers and assemblies present across eukaryotes, a comprehensive predictive recognition model that could accurately estimate the DNA-binding specificity of any ZFP based on its amino acid sequence would have great utility. Toward this goal, we have used the DNA-binding specificities of 678 two-finger modules from both natural and artificial sources to construct a random forest-based predictive model for ZFP recognition. We find that our recognition model outperforms previously described determinant-based recognition models for ZFPs, and can successfully estimate the specificity of naturally occurring ZFPs with previously defined specificities.
Time synchronisation for OFDM-based WLAN systems (2003)

Orthogonal frequency division multiplexing (OFDM) is the key modulation scheme utilised to enable the IEEE 802.11a standard for high-rate WLAN systems. A novel time synchronisation method for the OFDM-based WLAN is presented. The approach utilises coarse and fine estimation. Simulation results exhibit that the algorithm is robust to harsh channel environments.
A network worm vaccine architecture (2004)

The ability of worms to spread at rates that effectively preclude human-directed reaction has elevated them to a first-class security threat to distributed systems. We present the first reaction mechanism that seeks to automatically patch vulnerable software. Our system employs a collection of sensors that detect and capture potential worm infection vectors. We automatically test the effects of these vectors on appropriately-instrumented sandboxed instances of the targeted application, trying to identify the exploited software weakness. Our heuristics allow us to automatically generate patches that can protect against certain classes of attack, and test the resistance of the patched application against the infection vector. We describe our system architecture, discuss the various components, and propose directions for future research.
<title>Activation energies and hole transport in photochemically modified molecularly doped polymers</title> (1996)

The activation energy for charge transport in molecularly doped polymer films containing p-diethylaminobenzaldehyde diphenylhydrazone (DEH) is measured before and after systematic UV irradiation. UV exposure has been shown to induce a photochemical reaction of the DEH molecule which dramatically reduces the molecule's capability to transport charge. Presumably, the reduction in mobility is associated with the substantial increase (above 1 eV) in the ionization potential of the DEH molecule after photocyclization. The increase in ionization potential effectively removes the photochemically modified molecule from the primary transport manifold. In previous work, we have demonstrated that systematic UV irradiation of molecularly doped polymer films containing DEH provides a novel approach for diluting the dopant concentration and effectively increasing the intersite separation between 'active' dopant molecules in situ. Furthermore, ab initio calculations suggest that the dipole moment of the photoproduct is significantly lower than that of the unconverted DEH molecule. We exploit this photochemical process to prove the hopping activation energy, (Delta) , in DEH doped polycarbonate films parametric in UV irradiation time. The principal observation of this work is that despite a systematic and substantial elimination of active hopping sites and despite the systematic increase in the population of lower dipole moment neighbors, the hopping activation energy for the DEH/polycarbonate system remains constant.
Reconstitution of surfactant activity by using the 6 kDa apoprotein associated with pulmonary surfactant (1986)

Lipid extracts of bovine pulmonary surfactant containing the 6 kDa apoprotein, but lacking the 35 kDa apoprotein, can mimic the essential characteristics of pulmonary surfactant on a pulsating-bubble surfactometer. Reconstituted surfactant can be produced by combining silicic acid fractions containing 6 kDa apoprotein and phosphatidylglycerol with phosphatidylcholine. Treatment of the protein-containing fraction with proteolytic enzymes abolishes its efficacy. These results indicate that the presence of the 6 kDa apoprotein can account for some of the essential physical and biological characteristics of pulmonary surfactant. Immunodiffusion studies indicate that, contrary to earlier suggestions, the 6 kDa apoprotein is not structurally related to the major surfactant apoprotein that has a molecular mass of 35 kDa.
Soluble Rank Ligand Produced by Myeloma Cells Causes Generalised Bone Loss in Multiple Myeloma (2012)

Patients with multiple myeloma commonly develop focal osteolytic bone disease, as well as generalised osteoporosis. The mechanisms underlying the development of osteoporosis in patients with myeloma are poorly understood. Although disruption of the RANKL/OPG pathway has been shown to underlie formation of focal osteolytic lesions, its role in the development of osteoporosis in myeloma remains unclear. Increased soluble RANKL in serum from patients with myeloma raises the possibility that this molecule plays a key role. The aim of the present study was to establish whether sRANKL produced by myeloma cells contributes directly to osteoporosis. C57BL/KaLwRij mice were injected with either 5T2MM or 5T33MM murine myeloma cells. 5T2MM-bearing mice developed osteolytic bone lesions (p<0.05) with increased osteoclast surface (p<0.01) and reduced trabecular bone volume (p<0.05). Bone volume was also reduced at sites where 5T2MM cells were not present (p<0.05). In 5T2MM-bearing mice soluble mRANKL was increased (p<0.05), whereas OPG was not altered. In contrast, 5T33MM-bearing mice had no changes in osteoclast surface or trabecular bone volume and did not develop osteolytic lesions. Soluble mRANKL was undetectable in serum from 5T33MM-bearing mice. In separate experiments, RPMI-8226 human myeloma cells were transduced with an human RANKL/eGFP construct, or eGFP alone. RPMI-8226/hRANKL/eGFP cells, but not RPMI-8226/eGFP cells, stimulated osteoclastic bone resorption (p<0.05) in vitro. Sub-cutaneous injection of NOD/SCID mice with RPMI-8226/hRANKL/eGFP or RPMI-8226/eGFP cells resulted in tumour development in all mice. RPMI-8226/hRANKL/eGFP-bearing mice exhibited increased serum soluble hRANKL (p<0.05) and a three-fold increase in osteoclast number (p<0.05) compared to RPMI-8226/eGFP-bearing mice. This was associated with reduced trabecular bone volume (27%, p<0.05), decreased trabecular number (29%, p<0.05) and increased trabecular thickness (8%, p<0.05). Our findings demonstrate that soluble RANKL produced by myeloma cells causes generalised bone loss, suggesting that targeting RANKL may prevent osteoporosis in patients with myeloma.
Early dietary experience influences ontogeny of intestine in response to dietary lipid changes in later life (1998)

This study was undertaken to test the hypothesis that a change in the mother's diet at the time of birth and continued during suckling modifies the intestinal transport of nutrients in the suckling offspring. Pregnant rat dams were fed one of four semisynthetic diets during pregnancy [high or low n-6/n-3 diet or a diet enriched with arachidonic acid (AA) or docosahexaenoic acid (DHA)] and were fed the same diet at the time of birth or switched to another diet. The greatest body weight gain was in the suckling rats (15-16 days of age) fed a low n-6/n-3 diet. Switching from this diet caused weight loss, and the observed weight gain with the low n-6/n-3 diet was prevented by previous exposure of the mother to the high n-6/n-3 diet or the AA- or DHA-containing diet. Although continuous feeding of a high n-6/n-3 diet to the mother during pregnancy and lactation was associated with the lowest in vitro rates of fructose uptake, switching the mother to another diet during lactation did not necessarily correct the low absorption. In contrast, continuous feeding of a high n-6/n-3 diet to the mother during pregnancy and lactation is associated with the highest maximal transport rate of glucose uptake into the jejunum and ileum. Jejunal uptake of fatty acids 12:0, 18:0, 18:3(n-3), and cholesterol was less with the low n-6/n-3 diet compared with the high n-6/n-3 diet, whereas the ileal uptake of 18:0 and 18:3(n-3) was higher with the low n-6/n-3 diet. Thus the ontogeny of the intestine is critically influenced by the mother's diet during gestation as well as during the nursing period. Some of the diet-associated changes in nutrient uptake resulting from the mother's diet during pregnancy could be corrected by dietary interventions introduced after birth.
The Use of Sub-Mental Ultrasonography for Identifying Patients with Severe Obstructive Sleep Apnea (2013)

ClinicalTrials.gov NCT00674076.
Sequence error storms and the landscape of mutations in cancer (2012)

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans the biological, physical, and social sciences.
Ni2+-binding RNA motifs with an asymmetric purine-rich internal loop and a G-A base pair. (1997)

RNA molecules with high affinity for immobilized Ni2+ were isolated from an RNA pool with 50 randomized positions by in vitro selection-amplification. The selected RNAs preferentially bind Ni2+ and Co2+ over other cations from first series transition metals. Conserved structure motifs, comprising about 15 nt, were identified that are likely to represent the Ni2+ binding sites. Two conserved motifs contain an asymmetric purine-rich internal loop and probably a mismatch G-A base pair. The structure of one of these motifs was studied with proton NMR spectroscopy and formation of the G-A pair at the junction of helix and internal loop was demonstrated. Using Ni2+ as a paramagnetic probe, a divalent metal ion binding site near this G-A base pair was identified. Ni2+ ions bound to this motif exert a specific stabilization effect. We propose that small asymmetric purine-rich loops that contain a G-A interaction may represent a divalent metal ion binding site in RNA.
Nucleotide sequence heterogeneity of alpha satellite repetitive DNA: a survey of alphoid sequences from different human chromosomes (1987)

The human alpha satellite DNA family is composed of diverse, tandemly reiterated monomer units of approximately 171 basepairs localized to the centromeric region of each chromosome. These sequences are organized in a highly chromosome-specific manner with many, if not all human chromosomes being characterized by individually distinct alphoid subsets. Here, we compare the nucleotide sequences of 153 monomer units, representing alphoid components of at least 12 different human chromosomes. Based on the analysis of sequence variation at each position within the 171 basepair monomer, we have derived a consensus sequence for the monomer unit of human alpha satellite DNA which we suggest may reflect the monomer sequence from which different chromosomal subsets have evolved. Sequence heterogeneity is evident at each position within the consensus monomer unit and there are no positions of strict nucleotide sequence conservation, although some regions are more variable than others. A substantial proportion of the overall sequence variation may be accounted for by nucleotide changes which are characteristic of monomer components of individual chromosomal subsets or groups of subsets which have a common evolutionary history.
Responses of Vomeronasal Neurons to Natural Stimuli (2000)

The vomeronasal organ (VNO) of mammals plays an essential role in the detection of pheromones. We obtained simultaneous recordings of action potentials from large subsets of VNO neurons. These cells responded to components of urine by increasing their firing rate. This chemosensory activation required phospholipase C function. Unlike most other sensory neurons, VNO neurons did not adapt under prolonged stimulus exposure. The full time course of the VNO spiking response is captured by a simple quantitative model of ligand binding. Many individual VNO neurons were strongly selective for either male or female mouse urine, with the effective concentrations differing as much as a thousandfold. These results establish a framework for understanding sensory coding in the vomeronasal system.