gebhart/patrepeval huggingface dataset:
A new mammalian DNA topoisomerase I poison Hoechst 33342: cytotoxicity and drug resistance in human cell cultures. (1993)

Hoechst dye 33342 (Ho33342), like many other DNA minor groove binding ligands and its parent compound Hoechst dye 33258 (Ho33258), nonspecifically inhibits the catalytic activities of many DNA enzymes. However, both Ho33258 and Ho33342 also specifically interrupt the breakage/reunion reaction of mammalian DNA topoisomerase I by trapping reversible topoisomerase I cleavable complexes. The enhanced membrane permeability of Ho33342 over its parent compound Ho33258 has allowed studies of the cellular action of Ho33342. Our results suggest that Ho33342 also traps topoisomerase I but not topoisomerase II into reversible cleavable complexes in human KB cells. Although Ho33342 shares a similar mechanism of action with camptothecin, a prototypic topoisomerase I poison, in trapping topoisomerase I cleavable complexes, Ho33342 differs from camptothecin in its effect on drug-resistant cells. Different from camptothecin, Ho33342 was shown to be about 200-fold less cytotoxic in MDR1-overexpressing human KB V1 cells relative to parental human KB 3-1 cells. Ho33342 is only 5-fold less cytotoxic for camptothecin-resistant CPT-K5 cells, which expresses a highly camptothecin-resistant from of topoisomerase I, than for the wild type human lymphoblast RPMI 8402 cells. Our studies suggest a potential use of Hoechst 33342 as a new topoisomerase I poison in antitumor chemotherapy.
Towards the Extraction of Domain Concepts from the Identifiers (2011)

Program identifiers represent an invaluable source of information for developers who are not familiar with the code to be evolved. Domain concepts and inter-concept relationships can be automatically extracted by means of natural language processing techniques applied to the program identifiers. However, the ontology produced by this approach tends to be very large and to include implementation details that reduce its usefulness for domain concept understanding. In this paper, we analyze the effectiveness of information retrieval based techniques used to filter domain concepts and relations from the implementation details, so as to obtain a smaller, more informative domain ontology. In particular, we show that fully automated techniques based on keywords or topics have quite poor performance, while a semi-automated approach, requiring limited user involvement, can highly improve the filtering of domain concepts.
Advancing CMOS beyond the Si roadmap with Ge and III/V devices (2011)

Over the last years there has been lots of interest in the use of germanium and III-V compounds as potential replacements for silicon channels. Germanium with its high hole mobility has attracted lots of attention for its application in advanced pMOS devices. Indium gallium arsenide compounds, with their intrinsically superior electron mobility and high saturation velocity, are considered as a candidate for nMOS devices beyond 14 nm node technology.
Topographical map of innervation zones within single motor units measured with a grid surface electrode (1988)

A grid electrode with closely spaced contacts was developed to measure the spatial distribution of motor unit action potentials on a skin surface. This electrode was used to estimate the configuration of innervation zones. The derived action potentials showed waveforms originating from the middle length of the muscle belly and propagating bidirectionally along the muscle fibers. The position of the innervation zones was estimated from the source of the propagation. By isolating action potentials from single motor units, the innervation zones for individual motor units were defined. Studies were performed in the biceps brachii of three normal subjects. The innervation zones comprised one to four separate regions and spread over up to 20 mm along the length of muscle fibers. The number and the spreading area of innervation zones varied with the subject and with the motor unit.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
<title>MPEG-4: very low bit rate coding for multimedia applications</title> (1994)

Following the development of digital communications, focus is now on interactive multimedia services on telephone networks. To provide such applications, very low bit rate video coding algorithms have to be designed and optimized. A standardization process is being started within MPEG under the MPEG-4 denomination, to build a generic scheme for bit rates from 10 to 64 kbit/s. The Laboratories d'Electronique Philips are currently involved in European projects which are devoting their efforts to the elaboration of a common European proposal towards MPEG-4. This paper gives an overview of the research status on very low bit rate video coding within Philips and within Europe. Most of the European studies are concerned with region based compression technique; emphasis will therefore be put on the two major algorithms enhancing this technique.
High tolerance for ionizable residues in the hydrophobic interior of proteins (2008)

Internal ionizable groups are quite rare in water-soluble globular proteins. Presumably, this reflects the incompatibility between charges and the hydrophobic environment in the protein interior. Here we show that proteins can have an inherently high tolerance for internal ionizable groups. The 25 internal positions in staphylococcal nuclease were substituted one at a time with Lys, Glu, or Asp without abolishing enzymatic activity and without detectable changes in the conformation of the protein. Similar results with substitutions of 6 randomly chosen internal positions in ribonuclease H with Lys and Glu suggest that the ability of proteins to tolerate internal ionizable groups might be a property common to many proteins. Eighty-six of the 87 substitutions made were destabilizing, but in all but one case the proteins remained in the native state at neutral pH. By comparing the stability of each variant protein at two different pH values it was established that the pK(a) values of most of the internal ionizable groups are shifted; many of the internal ionizable groups are probably neutral at physiological pH values. These studies demonstrate that special structural adaptations are not needed for ionizable groups to exist stably in the hydrophobic interior of proteins. The studies suggest that enzymes and other proteins that use internal ionizable groups for functional purposes could have evolved through the random accumulation of mutations that introduced ionizable groups at internal positions, followed by evolutionary adaptation and optimization to modulate stability, dynamics, and other factors necessary for function.
Fabrication of micro-structures using non-planar lithography (NPL) (2002)

The authors present specific nonplanar lithographic (NPL) techniques for use in fabricating both monolithic micromachines and microcomponents for use in larger systems. The emphasis is on the use of numerically controlled E-beam-based lithography, with the resist exposed over nonplanar surfaces. Previously, nonplanar, optical-mask-based approaches have been used to fabricate devices such as wobble motor rotors, but with less success than the NPL techniques due to depth-of-field problems. The specific focus is on etching cylindrically shaped metal structures which are either (1) homogeneous or (2) layered by successive deposition, masking, and etching. Structures on the order of 80 to 500 microns in diameter have been constructed of either solid metals or sputtered thin metallic layers on quartz shafts. A number of either deep or shallow patterns have been fabricated on and through the structures, with promising results. Examples include helices, longitudinal lines, holes, notches, flexures, barbs, alphanumeric characters, and electrostatic field emitting patterns for use in wobble motors. Efforts are now proceeding toward generating complete systems, including transducers and actuators for industrial and medical applications.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Agonist actions of dihydroergotamine at 5‐HT2B and 5‐HT2C receptors and their possible relevance to antimigraine efficacy (2003)

1. The pharmaceutical compound, dihydroergotamine (DHE) is dispensed to prevent and reduce the occurrence of migraine attacks. Although still controversial, the prophylactic effect of this drug is believed to be caused through blockade and/or activation of numerous receptors including serotonin (5-HT) receptors of the 5-HT2 subtype. 2. To elucidate if 5-HT2 receptors (5-HT2Rs) may be involved in DHE prophylactic effect, we performed investigations aimed to determine the respective pharmacological profile of DHE and of its major metabolite 8'-hydroxy-DHE (8'-OH-DHE) at the 5-HT2B and 5-HT2CRs by binding, inositol triphosphate (IP3) or cyclic GMP (cGMP) coupling studies in transfected fibroblasts. 3. DHE and 8'-OH-DHE are competitive compounds at 5-HT2B and 5-HT2CRs. 8'-OH-DHE interaction at (5-HT2BRs) was best fitted by a biphasic competition curve and displayed the highest affinity with a Ki of 5 nm. These two compounds acted as agonists for both receptors in respect to cGMP production with pEC50 of 8.32+/-0.09 for 8'-OH-DHE at 5-HT2B and 7.83+/-0.06 at 5-HT2CRs. 4. Knowing that the antimigraine prophylactic effect of DHE is only observed after long-term treatment, we chronically exposed the recombinant cells to DHE and 8'-OH-DHE. The number of 5-HT2BR-binding sites was always more affected than 5-HT2CRs. At 5-HT2BRs, 8'-OH-DHE was more effective than DHE, with an uncoupling that persisted for more than 40 h for IP3 or cGMP. By contrast, the 5-HT2CR coupling was reversible after either treatment. 5. Chronic exposure to 8'-OH-DHE caused a persistent agonist-mediated desensitisation of 5-HT2B, but not 5-HT2CRs. This may be of relevance to therapeutic actions of the compound.
Interleukin-17 in systemic lupus erythematosus: A comprehensive review (2015)

Systemic lupus erythematosus (SLE) is a complicated autoimmune disease of multifactorial pathoaetiology. One of the most serious manifestations is lupus nephritis. The pathogenesis of SLE has not been well elucidated, but it has been reported that interleukin-17 (IL-17) and Th17 cells play important roles in the pathogenesis of SLE. IL-17A, a member of IL-17 family, amplifies the immune response by inducing the local production of chemokines and cytokines, recruiting neutrophils and monocytes, augmenting the production of autoantibodies, and aggravating the inflammation and damage of target organs such as the kidney in SLE. In recent years, several IL-17A pathway inhibitors have advanced into clinical trials, including the anti-IL-17A monoclonal antibody and the anti-17RA monoclonal antibody. Several agents have shown great success in Phase II trials in multiple autoimmune diseases such as psoriasis, rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, and non-infectious uveitis, which has sparked the urgent need of anti-IL-17A as innovative therapeutic option in controlling disease activity of moderate-to-severe SLE. Here, we review and summarize current progress in IL-17A and SLE from in vitro studies, human expression studies, and animal models, providing novel insight into its therapeutic potential.
Integrated heterodyne interferometer with on-chip modulators and detectors (2015)

We demonstrate, to our knowledge, the first on-chip heterodyne interferometer fabricated on a 300-mm CMOS compatible process that exhibits root-mean-square (RMS) position noise on the order of 2 nm. Measuring 1 mm by 6 mm, the interferometer is also, to our knowledge, the smallest heterodyne interferometer demonstrated to date and will surely impact numerous interferometric and metrology applications, including displacement measurement, laser Doppler velocimetry and vibrometry, Fourier transform spectroscopy, imaging, and light detection and ranging (LIDAR). Here we present preliminary results that demonstrate the displacement mode.
A genetic variant that disrupts MET transcription is associated with autism (2006)

There is strong evidence for a genetic predisposition to autism and an intense interest in discovering heritable risk factors that disrupt gene function. Based on neurobiological findings and location within a chromosome 7q31 autism candidate gene region, we analyzed the gene encoding the pleiotropic MET receptor tyrosine kinase in a family based study of autism including 1,231 cases. MET signaling participates in neocortical and cerebellar growth and maturation, immune function, and gastrointestinal repair, consistent with reported medical complications in some children with autism. Here, we show genetic association (P = 0.0005) of a common C allele in the promoter region of the MET gene in 204 autism families. The allelic association at this MET variant was confirmed in a replication sample of 539 autism families (P = 0.001) and in the combined sample (P = 0.000005). Multiplex families, in which more than one child has autism, exhibited the strongest allelic association (P = 0.000007). In case-control analyses, the autism diagnosis relative risk was 2.27 (95% confidence interval: 1.41-3.65; P = 0.0006) for the CC genotype and 1.67 (95% confidence interval: 1.11-2.49; P = 0.012) for the CG genotype compared with the GG genotype. Functional assays showed that the C allele results in a 2-fold decrease in MET promoter activity and altered binding of specific transcription factor complexes. These data implicate reduced MET gene expression in autism susceptibility, providing evidence of a previously undescribed pathophysiological basis for this behaviorally and medically complex disorder.
Bovine Polledness – An Autosomal Dominant Trait with Allelic Heterogeneity (2012)

The persistent horns are an important trait of speciation for the family Bovidae with complex morphogenesis taking place briefly after birth. The polledness is highly favourable in modern cattle breeding systems but serious animal welfare issues urge for a solution in the production of hornless cattle other than dehorning. Although the dominant inhibition of horn morphogenesis was discovered more than 70 years ago, and the causative mutation was mapped almost 20 years ago, its molecular nature remained unknown. Here, we report allelic heterogeneity of the POLLED locus. First, we mapped the POLLED locus to a ∼381-kb interval in a multi-breed case-control design. Targeted re-sequencing of an enlarged candidate interval (547 kb) in 16 sires with known POLLED genotype did not detect a common allele associated with polled status. In eight sires of Alpine and Scottish origin (four polled versus four horned), we identified a single candidate mutation, a complex 202 bp insertion-deletion event that showed perfect association to the polled phenotype in various European cattle breeds, except Holstein-Friesian. The analysis of the same candidate interval in eight Holsteins identified five candidate variants which segregate as a 260 kb haplotype also perfectly associated with the POLLED gene without recombination or interference with the 202 bp insertion-deletion. We further identified bulls which are progeny tested as homozygous polled but bearing both, 202 bp insertion-deletion and Friesian haplotype. The distribution of genotypes of the two putative POLLED alleles in large semi-random sample (1,261 animals) supports the hypothesis of two independent mutations.
MDC1 functionally identified as an androgen receptor co-activator participates in suppression of prostate cancer (2015)

Mediator of DNA damage checkpoint protein 1 (MDC1) is essential for DNA damage response. However, the role of MDC1 in modulating gene transcription independently of DNA damage and the underlying mechanisms have not been fully defined. Androgen receptor (AR) is the central signaling pathway in prostate cancer (PCa) and its target genes are involved in both promotion and suppression of PCa. Here, we functionally identified MDC1 as a co-activator of AR. We demonstrate that MDC1 facilitates the association between AR and histone acetyltransferase GCN5, thereby increasing histone H3 acetylation level on cis-regulatory elements of AR target genes. MDC1 knockdown promotes PCa cells growth and migration. Moreover, depletion of MDC1 results in decreased expression of a subset of the endogenous androgen-induced target genes, including cell cycle negative regulator p21 and PCa metastasis inhibitor Vinculin, in AR positive PCa cell lines. Finally, the expression of MDC1 and p21 correlates negatively with aggressive phenotype of clinical PCa. These studies suggest that MDC1 as an epigenetic modifier regulates AR transcriptional activity and MDC1 may function as a tumor suppressor of PCa, and provide new insight into co-factor-AR-signaling pathway mechanism and a better understanding of the function of MDC1 on PCa.
Feedback Inhibition of Macrophage Tumor Necrosis Factor-α Production by Tristetraprolin (1998)

Tumor necrosis factor-alpha (TNF-alpha) is a major mediator of both acute and chronic inflammatory responses in many diseases. Tristetraprolin (TTP), the prototype of a class of Cys-Cys-Cys-His (CCCH) zinc finger proteins, inhibited TNF-alpha production from macrophages by destabilizing its messenger RNA. This effect appeared to result from direct TTP binding to the AU-rich element of the TNF-alpha messenger RNA. TTP is a cytosolic protein in these cells, and its biosynthesis was induced by the same agents that stimulate TNF-alpha production, including TNF-alpha itself. These findings identify TTP as a component of a negative feedback loop that interferes with TNF-alpha production by destabilizing its messenger RNA. This pathway represents a potential target for anti-TNF-alpha therapies.
Growth Hormone and Sex Steroid Administration in Healthy Aged Women and Men (2002)

In this study, GH with or without sex steroids in healthy, aged women and men increased LBM and decreased fat mass. Sex steroid + GH increased muscle strength marginally and VO( 2)max in men, but women had no significant change in strength or cardiovascular endurance. Because adverse effects were frequent (importantly, diabetes and glucose intolerance), GH interventions in the elderly should be confined to controlled studies.
Self-reported cigarette smoking vs. serum cotinine among U.S. adolescents (2004)

No national data have been used to compare self-reported and biochemically assessed cigarette smoking status among adolescents. We investigated discrepancies between self-reported smoking and measurement of serum cotinine concentration among adolescents aged 12-17 years in a representative sample (n=2,107) of the U.S. population. Smoking prevalence was 12.9% among teens who reported in a private interview whether they smoked during the previous 5 days (95% CI=10.9%-14.9%) and 12.5% (95% CI=10.3%-14.7%) according to serum cotinine concentration greater than 11.40 ng/ml (the cutpoint). Among teens who reported being a nonsmoker (i.e., that they did not smoke during the previous 5 days), 2.7% (95% CI=1.6%-3.8%) had a serum cotinine concentration of greater than 11.40 ng/ml. Discrepancies among self-reported nonsmokers were less likely among Mexican Americans than among Whites. Among self-reported smokers, 21.1% (95% CI=13.7%-28.5%) had a serum cotinine concentration of 11.40 ng/ml or less. This discrepancy is explained primarily by the high proportion (37.0%) of teen smokers who reported smoking, on average, less than 1 cigarette per day. We believe that social stigma or fear that their parents would find out about their survey responses may be the main explanation for the 2.7% discrepancy among self-reported nonsmokers, and that smoking patterns (including the extent of nicotine dosing) and a lack of measurement of recency of cigarette smoking are the main explanations for the 21.1% discrepancy among self-reported smokers. Efforts to improve the validity of self-reported cigarette smoking will benefit tobacco-related surveillance, evaluation, and research activities for adolescents.
Loss of white matter integrity in major depressive disorder: Evidence using tract‐based spatial statistical analysis of diffusion tensor imaging (2010)

White matter (WM) has been shown to be affected in elderly patients with major depressive disorders (MDD). There is only limited evidence of WM structural abnormalities in nongeriatric MDD patients. This study investigates WM microstructural integrity in nongeriatric MDD patients recruited as part of the International Study to Predict Optimized Treatment in Depression clinical trial and establishes the validity of diffusion tensor imaging measures for the investigation of depression. Baseline diffusion tensor imaging data from 29 nongeriatric MDD participants (11 with melancholia) and 39 healthy control participants were used in this analysis. We performed tract-based spatial statistics analyses to evaluate WM microstructural integrity (1) between all healthy controls and all MDD participants, (2) between melancholic and nonmelancholic MDD participants, and (3) between each subgroup (melancholic and nonmelancholic) and controls. Significant WM integrity deficits were seen only for the melancholic MDD participants compared with controls. Compared with controls, melancholic participants showed an average reduction of 7.8% in fractional anisotropy over WM regions associated with the limbic system, dorsolateral prefrontal cortex, thalamic projection fibers, corpus callosum, and other association fibers. These fractional anisotropy deficits were also associated with decreased axial and increased radial diffusivity in these WM regions, suggesting a pattern of decreased myelination or other degeneration change. Our findings of WM structural abnormalities associated with the limbic system, the frontal cortex, and the thalamus support the prevailing theory of limbic-dorsolateral prefrontal cortex-thalamic dysfunction in depression. Our results also suggest that these deficits are most prominent in the melancholic subtype of MDD.
Domain structure and conserved epitopes of Sfb protein, the fibronectin‐binding adhesin of Streptococcus pyogenes (1994)

Streptococcus pyogenes expresses a fibronectin-binding surface protein (Sfb protein) which mediates adherence to human epithelial cells. The nucleotide sequence of the sfb gene was determined and the primary sequence of the Sfb protein was analysed. The protein consists of 638 amino acids and comprises five structurally distinct domains. The protein starts with an N-terminal signal peptide followed by an aromatic domain. The central part of the protein is formed by four proline-rich repeats which are flanked by non-repetitive spacer sequences. A second repeat region, consisting of four repeats that are distinct from the proline repeats and have been shown to form the fibronectin-binding domain, is located in the C-terminal part of the protein. The protein ends with a typical cell wall and membrane anchor region. Comparative sequence analysis of the N-terminal aromatic domain revealed similarities with carbohydrate-binding sites of other proteins. The proline repeat region of the Sfb protein shares characteristic features with proline-rich repeats of functionally distinct surface proteins from pathogenic Gram-positive cocci. Immunoelectron microscopy revealed an even distribution of the fibronectin-binding domain of Sfb protein on the surface of streptococcal cells. Analyses of 38 sfb genes originating from different S. pyogenes isolates revealed primary sequence variability in regions coding for the N-termini of mature Sfb proteins, whereas sequences coding for the central and C-terminal repeats were highly conserved. The repeat sequences are postulated to act as target sites for intragenic recombination events that result in variable numbers of repeats within the different sfb genes. A model of the Sfb protein is presented.