gebhart/patrepeval huggingface dataset:
Danazol Suppresses the Production of Interleukin‐1β and Tumor Necrosis Factor by Human Monocytes (1990)

ABSTRACT: The effects of estradiol (E 2 ), progesterone (P), and danazol on the production of interleukin‐1β (IL‐1β) and tumor necrosis factor (TNF) by OK‐432 (a streptococcal preparation)‐stimulated monocytes were examined. E 2 and P at physiologic concentrations enhanced IL‐1β and TNF production by monocytes from donors with lower control levels (without steroids added) of IL‐1β and TNF. However, E 2 and P at physiologic concentrations did not affect IL‐1β and TNF production by monocytes from donors with higher control levels of IL‐1β and TNF. Danazol inhibited IL‐1β and TNF production by monocytes in a dose‐dependent manner from not only donors with lower control levels of IL‐1β and TNF but also donors with higher control levels of IL‐1β and TNF. Danazol at a concentration of 10 −6 M significantly suppressed IL‐1β and TNF production in the presence of E 2 and/or P at concentrations giving peak responses of IL‐1β production. These findings suggest possible new mechanisms of action for danazol in the treatment of endometriosis and infertility associated with immune abnormalities.
Low-density lipoprotein receptor-related protein 1 is an essential receptor for myelin phagocytosis (2009)

Multiple sclerosis (MS) is an autoimmune disease in which myelin is progressively degraded. Because degraded myelin may both initiate and accelerate disease progression, clearing degraded myelin from extracellular spaces may be critical. In this study, we prepared myelin vesicles (MV) from rat brains as a model of degraded myelin. Murine embryonic fibroblasts (MEFs) rapidly internalized MVs, which accumulated in lysosomes only when these cells expressed low-density lipoprotein receptor-related protein (LRP1). Receptor-associated protein (RAP), which binds LRP1 and inhibits interaction with other ligands, blocked MV uptake by LRP1-expressing MEFs. As a complementary approach, we prepared primary cultures of rat astrocytes, microglia and oligodendrocytes. All three cell types expressed LRP1 and mediated MV uptake, which was inhibited by RAP. LRP1 gene-silencing in oligodendrocytes also blocked MV uptake. Myelin basic protein (MBP), which was expressed as a recombinant protein, bound directly to LRP1. MBP-specific antibody inhibited MV uptake by oligodendrocytes. In experimental autoimmune encephalomyelitis in mice, LRP1 protein expression was substantially increased in the cerebellum and spinal cord. LRP1 colocalized with multiple CNS cell types. These studies establish LRP1 as a major receptor for phagocytosis of degraded myelin, which may function alone or in concert with co-receptors previously implicated in myelin phagocytosis.
Notch Is Expressed in Adult Brain, Is Coexpressed with Presenilin-1, and Is Altered in Alzheimer Disease (1998)

In C. elegans, the Notch family member lin-12 has been shown to have a genetic interaction with sel-12, the homologue of the Alzheimer disease-associated presenilin (PS) genes in humans. Mutations in PS genes cause autosomal dominant Alzheimer disease, with age of onset frequently in the 40s. Notch is known as a developmental protein that plays an important role in lateral inhibition and specifying cell fate decisions in proliferating immature cells, and is not known to be present in adult neurons. We reasoned that, if Notch1/PS-1 interaction is relevant in Alzheimer disease, Notch1 would also need to be expressed in neurons in adult brain and colocalized with PS-1. We found that Notch1, Notch2, and a Notch ligand, Jagged1, are expressed in adult brain in mouse and in human, with strongest expression in the hippocampal formation and Purkinje cells of the cerebellum. Double immunofluorescent staining demonstrates neuronal colocalization of Notch1 with PS-1. Moreover, Notch1 expression in sporadic Alzheimer disease hippocampus is elevated more than 2-fold in comparison to that in control human hippocampus by both immunohistochemistry and Western blot analysis (p < 0.007). These results support the hypothesis that Notch1 continues to play a role in terminally differentiated neurons, and that Notch1/PS-1 interactions may occur in adult mammalian brain. The alteration in Notch1 expression in sporadic Alzheimer disease raises the possibility that disruption of Notch1/PS-1 functional interactions may occur in Alzheimer disease.
SpeechSkimmer (1997)

Listening to a speech recording is much more difficult than visually scanning a document because of the transient and temporal nature of audio. Audio recordings capture the richness of speech, yet it is difficult to directly browse the stored information. This article describes techniques for structuring, filtering, and presenting recorded speech, allowing a user to navigate and interactively find information in the audio domain. This article describes the SpeechSkimmer system for interactively skimming speech recordings. SpeechSkimmer uses speech-processing techniques to allow a user to hear recorded sounds quickly, and at several levels of detail. User interaction, through a manual input device, provides continuous real-time control of the speed and detail level of the audio presentation. SpeechSkimmer reduces the time needed to listen by incorporating time-compressed speech, pause shortening, automatic emphasis detection, and nonspeech audio feedback. This article also presents a multilevel structural approach to auditory skimming and user interface techniques for interacting with recorded speech. An observational usability test of SpeechSkimmer is discussed, as well as a redesign and reimplementation of the user interface based on the results of this usability test.
An array-based algorithm for simultaneous multidimensional aggregates (1997)

Computing multiple related group-bys and aggregates is one of the core operations of On-Line Analytical Processing (OLAP) applications. Recently, Gray et al. [GBLP95] proposed the “Cube” operator, which computes group-by aggregations over all possible subsets of the specified dimensions. The rapid acceptance of the importance of this operator has led to a variant of the Cube being proposed for the SQL standard. Several efficient algorithms for Relational OLAP (ROLAP) have been developed to compute the Cube. However, to our knowledge there is nothing in the literature on how to compute the Cube for Multidimensional OLAP (MOLAP) systems, which store their data in sparse arrays rather than in tables. In this paper, we present a MOLAP algorithm to compute the Cube, and compare it to a leading ROLAP algorithm. The comparison between the two is interesting, since although they are computing the same function, one is value-based (the ROLAP algorithm) whereas the other is position-based (the MOLAP algorithm). Our tests show that, given appropriate compression techniques, the MOLAP algorithm is significantly faster than the ROLAP algorithm. In fact, the difference is so pronounced that this MOLAP algorithm may be useful for ROLAP systems as well as MOLAP systems, since in many cases, instead of cubing a table directly, it is faster to first convert the table to an array, cube the array, then convert the result back to a table.
A Partially Male Sterile Strain of Soybean1 (1970)

A partially male sterile strain of soybeans, Glycine max (L.) Merrill, was found in Arkansas in 1964. Grafts involving partially sterile and fertile plants indicated that this character likely was genetically controlled. Only 5 to 10% of pollen from the partially sterile strain appeared to be viable when stained with aceto‐carmine and glycerine. Plants of the F~ generation from a cross between a partially sterile and a fertile strain were completely fertile. Segregation occurred in the F~o generation and gave further evidence for dominance of fertility over partial sterility. Natural cross‐pollination estimates of 11.21% and 0.26% were obtained for the partially sterile and fertile strains, respectively.
From Pan-Reactive KV7 Channel Opener to Subtype Selective Opener/Inhibitor by Addition of a Methyl Group (2014)

The voltage-gated potassium channels of the KV7 family (KV7.1-5) play important roles in controlling neuronal excitability and are therefore attractive targets for treatment of CNS disorders linked to hyperexcitability. One of the main challenges in developing KV7 channel active drugs has been to identify compounds capable of discriminating between the neuronally expressed subtypes (KV7.2-5), aiding the identification of the subunit composition of KV7 currents in various tissues, and possessing better therapeutic potential for particular indications. By taking advantage of the structure-activity relationship of acrylamide KV7 channel openers and the effects of these compounds on mutant KV7 channels, we have designed and synthesized a novel KV7 channel modulator with a unique profile. The compound, named SMB-1, is an inhibitor of KV7.2 and an activator of KV7.4. SMB-1 inhibits KV7.2 by reducing the current amplitude and increasing the time constant for the slow component of the activation kinetics. The activation of KV7.4 is seen as an increase in the current amplitude and a slowing of the deactivation kinetics. Experiments studying mutant channels with a compromised binding site for the KV7.2-5 opener retigabine indicate that SMB-1 binds within the same pocket as retigabine for both inhibition of KV7.2 and activation of KV7.4. SMB-1 may serve as a valuable tool for KV7 channel research and may be used as a template for further design of better subtype selective KV7 channel modulators. A compound with this profile could hold novel therapeutic potential such as the treatment of both positive and cognitive symptoms in schizophrenia.
Classification of Human Carotid Atherosclerotic Lesions With In Vivo Multicontrast Magnetic Resonance Imaging (2002)

In vivo high-resolution multicontrast MRI is capable of classifying intermediate to advanced atherosclerotic lesions in the human carotid artery and is also capable of distinguishing advanced lesions from early and intermediate atherosclerotic plaque.
Genome‐scale Assessment of Molecular Pathology in Systemic Autoimmune Diseases using Microarray Technology: A Potential Breakthrough Diagnostic and Individualized Therapy‐design Tool (2006)

Systemic autoimmune rheumatic diseases are of complex aetiology, characterized by an intricate interplay of various factors. A myriad of genes lies behind the heterogeneous manifestations of these diseases, and the overexpression and repression of particular genes form a specific gene-expression profile (genetic fingerprints) that is characteristic to the given disease phenotype. Besides the description of various cell types by using gene-expression profiling, the data should be directly applicable to the design of individual therapeutic protocols for patients suffering from various autoimmune diseases. In this review, we summarize the gene-expression profile, various genetic signatures of different autoimmune diseases and give an overview on the possible interpretations of the data. The application of recent breakthroughs in high-throughput molecular profiling technologies, such as microarray technology has been the basis for a revolution in biomedical research, as well as diagnostics and pharmaceutical development. It is easy to envision a day when personalized medicine, which is the diagnosis and treatment of a given patient with agents and procedures tailored to that patient's genetics, physiology and pathology, will become the standard of care.
Safety and Efficacy of Nanosecond Pulsed Electric Field Treatment of Sebaceous Gland Hyperplasia (2019)

ClinicalTrials.gov NCT03612570.
Temperature Dependence of Emission Properties of Self-Assembled InGaN Quantum Dots (2014)

Emission properties of self-assembled green-emitting InGaN quantum dots (QDs) grown on sapphire substrates by using metal organic chemical vapor deposition are studied by temperature-dependent photoluminescence (PL) measurements. As temperature increases (15–300 K), the PL peak energy shows an anomalous V-shaped (redshift—blueshift) variation instead of an S-shaped (redshift—blueshift—redshift) variation, as observed typically in green-emitting InGaN/GaN multi-quantum wells (MQWs). The PL full width at half maximum (FWHM) also shows a V-shaped (decrease—increase) variation. The temperature dependence of the PL peak energy and FWHM of QDs are well explained by a model similar to MQWs, in which carriers transferring in localized states play an important role, while the confinement energy of localized states in the QDs is significantly larger than that in MQWs. By analyzing the integrated PL intensity, the larger confinement energy of localized states in the QDs is estimated to be 105.9 meV, which is well explained by taking into account the band-gap shrinkage and carrier thermalization with temperature. It is also found that the nonradiative combination centers in QD samples are much less than those in QW samples with the same In content.
Filled Microcavity Arrays Produced by Polyelectrolyte Multilayer Membrane Transfer (2005)

Arrays of microcavities sealed by a semipermeable ultrathin polyelectrolyte multilayer membrane (see Figure) are prepared using a novel method. The cavities can be loaded with high-molecular-weight species. If the entrapped molecules have stimuli-responsive properties, such structures can be potentially used as sensor arrays to probe, e.g., solution properties, as demonstrated in model experiments.
Camelid Single-Domain Antibodies: Historical Perspective and Future Outlook (2017)

Tremendous effort has been expended over the past two and a half decades to understand many aspects of camelid heavy chain antibodies, from their biology, evolution, and immunogenetics to their potential applications in various fields of research and medicine. In this article, I present a historical perspective on the development of camelid single-domain antibodies (sdAbs or V<sub>H</sub>Hs, also widely known as nanobodies) since their discovery and discuss the advantages and disadvantages of these unique molecules in various areas of research, industry, and medicine. Commercialization of camelid sdAbs exploded in 2001 with a flurry of patents issued to the Vrije Universiteit Brussel (VUB) and later taken on by the Vlaams Interuniversitair Instituut voor Biotechnologie (VIB) and, after 2002, the VIB-founded spin-off company, Ablynx. While entrepreneurial spirit has certainly catalyzed the exploration of nanobodies as marketable products, IP restrictions may be partially responsible for the relatively long time span between the discovery of these biomolecules and their entry into the pharmaceutical market. It is now anticipated that the first V<sub>H</sub>H-based antibody drug, Caplacizumab, a bivalent anti-vWF antibody for treating rare blood clotting disorders, may be approved and commercialized in 2018 or shortly thereafter. This elusive first approval, along with the expiry of key patents, may substantially alter the scientific and biomedical landscape surrounding camelid sdAbs and pave the way for their emergence as mainstream biotherapeutics.
Mechanism of Action of the Hypoglycemic Agent Diphenyleneiodonium (1973)

Abstract The effects of the hypoglycemic agent diphenyleneiodonium have been studied both in vivo and in vitro. In 2-day-old rats, diphenyleneiodonium lowered whole body and blood glucose concentrations. At higher concentrations of the agent (10 µg per g), this was accompanied by increased glucose utilization and accumulation of lactic acid. At 5 µg per g, diphenyleneiodonium inhibited gluconeogenesis from lactate and aspartate but had no effect on gluconeogenesis from xylitol, d-glyceraldehyde, and dihydroxyacetone. Analysis of hepatic intermediates showed that diphenyleneiodonium (5 µg per g) drastically decreased the ATP concentration, and this was accompanied by a marked decrease of the oxidation-reduction potential of NADH-linked systems in both mitochondria and cytosol. Diphenyleneiodonium did not alter the chloride ion distribution between the blood and hepatocytes of 2-day-old or adult rats but was itself extensively accumulated by the liver (70 µm at 15.5 nmoles per g) and was tightly, though not specifically, bound by mitochondria isolated from injected animals. Mitochondria isolated from rats at various times after injection of 5 µg per g of diphenyleneiodonium showed a time-dependent inhibition of the rate of oxidation of added glutamate-malate or β-hydroxybutyrate, but succinate oxidation was not significantly affected. This effect was independent of the chloride content of the assay medium. Oxidation of NADH-linked substrates in a chloride-free medium was also inhibited when diphenyleneiodonium was added to mitochondria in vitro, and this inhibition was completely overcome by catalytic amounts of menadione. In submitochondrial particles, diphenyleneiodonium inhibited NADH oxidation by the phosphorylating respiratory chain (apparent Ki = 4 µm) but had no effect on cytochrome c-dependent NADH oxidation. The results indicate that diphenyleneiodonium inhibits mitochondrial oxidation in vivo by a direct inhibition of the oxidation of NADH-linked substrates rather than as a result of the chloride-hydroxyl ion exchange across the inner membrane previously reported.
Production of the signalling molecule, autoinducer-2, by Neisseria meningitidis: lack of evidence for a concerted transcriptional response (2003)

Neisseria meningitidis is a Gram-negative bacterium which is an important causative agent of septicaemia and meningitis. LuxS has been shown to be involved in the biosynthesis of a quorum sensing molecule, autoinducer-2 (AI-2), known to play a role in virulence in Escherichia coli, as well as other bacteria. Evidence that serogroup B of N. meningitidis produces AI-2, along with the observation that a luxS mutant of this strain had attenuated virulence in an infant rat model of bacteraemia, led to further investigation of the role of this quorum sensing molecule in N. meningitidis. In this study, it is demonstrated that AI-2 is not involved in regulating growth of meningococci, either in culture or in contact with epithelial cells. Furthermore, transcriptional profiling using DNA microarrays shows an absence of the concerted regulation seen in other bacteria. Taken together, these data suggest that in N. meningitidis, AI-2 may be a metabolic by-product and not a cell-to-cell signalling molecule.
Predictive and prognostic significance of tumor-infiltrating lymphocytes in patients with breast cancer treated with neoadjuvant systemic therapy. (2014)

Despite the progress of tailored therapeutic strategies in patients with breast cancer, there is an unmet medical need for additional biomarkers that would guide therapy, including the administration of targeted agents. It has been demonstrated that the presence of tumor-infiltrating lymphocytes (TILs) is associated with prognosis in patients with early breast cancer. Moreover, TIL counts were shown to predict outcome of neoadjuvant chemotherapy. The neoadjuvant setting is increasingly used to assess the efficacy of new systemic therapies, and TILs are promising as a biomarker reflecting the immune response to tumor. Future studies should investigate on the integration of TILs as predictive biomarkers in patients treated with targeted- agents.
Quinazoline antifolate thymidylate synthase inhibitors: alkyl, substituted alkyl, and aryl substituents in the C-2 position (1990)

Modification of the potent thymidylate synthase (TS) inhibitor N-[4-[N-[(2-amino-3,4-dihydro-4-oxo-6-quinazolinyl)methyl]-N-prop-2- ynylamino]benzoyl]-L-glutamic acid (1a) has led to the synthesis of quinazoline antifolates bearing alkyl, substituted alkyl, and aryl substituents at C2. In general the synthetic route involved the coupling of the appropriate diethyl N-[4-(alkylamino)benzoyl]-L-glutamate with a C2-substituted 6-(bromo-methyl)-3,4-dihydro-4-oxoquinazoline followed by deprotection using mild alkali. Good enzyme inhibition and cytotoxicity were found with compounds containing small nonpolar groups in the C2 position with the 2-desamino-2-methyl analogue 3a being the most potent. Larger C2 substituents were tolerated by the enzyme, but cytotoxicity was reduced. Highly potent series were followed up by the synthesis of a number of analogues in which the N10 substituent was varied. In this manner a number of interesting TS inhibitors have been prepared. Although none of these was more potent than 1a against the isolated enzyme, over half of the compounds prepared were more potent as cytotoxic agents against L1210 cells in culture. The potential of such compounds as useful antitumor agents was further enhanced by the finding that the improved aqueous solubilities of compounds such as 3a over 1a were reflected in vivo in that 3a was at least 5 times less toxic to mice than 1a.
TESTOSTERONE SUPPLEMENTATION FOR ERECTILE DYSFUNCTION: RESULTS OF A META-ANALYSIS (2000)

Our meta-analysis of the usefulness of androgen replacement therapy for erectile dysfunction indicates that the response rate for a primary etiology was improved over that for a secondary etiology, transdermal testosterone therapy was more effective than intramuscular or oral treatment, and intramuscular and oral treatments were equivalent. In addition, there was a statistically significant difference in favor of testosterone over placebo, implying a role for supplementation in select groups.
Humoral and cellular responses of mice to infection with a cold-adapted influenza A virus variant (1982)

The serum antibody response and four different cellular immune responses (cytotoxic T cells, delayed-type hypersensitivity T cells, natural killer cells, and cytotoxic macrophage levels) induced in CBA/H mice were measured at different times after intranasal inoculation of a cold-adapted (ca) variant of influenza A virus, influenza virus A/Ann Arbor/6/60-ca, or the parental virus, influenza virus A/Ann Arbor/6/60. At the highest dose of virus inoculated (5 log10 50% tissue culture infective doses), all four cellular responses reached high levels in the lungs of both groups of mice, and serum antibody titers were detected on day 20 after inoculation of either virus. However, whereas extensive replication of the parental virus occurred in the mouse lungs, very limited replication of the ca variant was observed. Macroscopically, infection with the parental virus caused gross lung damage, whereas such damage was almost absent in mice inoculated with the ca variant. Inoculation of 2 to 5 log10 50% tissue culture infective doses of the parental virus induced high cytotoxic T-cell responses, whereas only the highest dose of the ca variant caused a clearly significant cytotoxic T-cell response. As an inoculum of 5 log10 50% tissue culture infective doses of the ca variant caused a substantial primary immune response without appreciable lung damage, the avirulence of the ca variant may be primarily related to its limited ability to replicate productively in mouse lungs.