gebhart/patrepeval huggingface dataset:
Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview (2021)

The availability of long-acting injectable (LAI) antipsychotics for the treatment of schizophrenia provides clinicians with options that deliver continuous drug exposure and may improve adherence compared with daily oral antipsychotics. However, all LAI antipsychotics have unique formulations and pharmacokinetic characteristics that have implications for medication selection, administration interval, and injection site. This review outlines key differences in drug formulations and pharmacokinetics among LAI antipsychotics. A systematic search of the PubMed database was conducted to identify physical and formulation properties and pharmacokinetic data of commercially available LAI antipsychotics, including flupentixol decanoate, fluphenazine decanoate, haloperidol decanoate, zuclopenthixol decanoate, aripiprazole monohydrate, aripiprazole lauroxil, olanzapine pamoate, paliperidone palmitate, risperidone microspheres, and risperidone polymeric microspheres. Additional information was obtained from package inserts and product monographs. Relevant data on drug properties, administration details, pharmacokinetic parameters, and oral dose equivalencies of LAI antipsychotics are summarized. Based on our analysis, formulation characteristics (e.g., vehicle medium) and administration characteristics (e.g., injection site) can affect rate of absorption and adverse effects and may factor into whether oral supplementation or an additional injection is needed. Dose adjustments may be necessary based on potential drug-drug interactions, and approximate dose equivalence with oral formulations can help inform titration when switching from oral to LAI formulations. Clinicians administering LAI antipsychotics should consider these formulation and pharmacokinetic factors to maximize clinical impact and to adjust to an individual patient's needs and treatment goals.
Fat depot origin affects fatty acid handling in cultured rat and human preadipocytes (2001)

Regional differences in free fatty acid (FFA) handling contribute to diseases associated with particular fat distributions. As cultured rat preadipocytes became differentiated, FFA transfer into preadipocytes increased and was more rapid in single perirenal than in epididymal cells matched for lipid content. Uptake by human omental preadipocytes was greater than uptake by abdominal subcutaneous preadipocytes. Adipose-specific fatty acid binding protein (aP2) and keratinocyte lipid binding protein abundance was higher in differentiated rat perirenal than in epididymal preadipocytes. This interdepot difference in preadipocyte aP2 expression was reflected in fat tissue in older animals. Carnitine palmitoyltransferase 1 activity increased during differentiation and was higher in perirenal than in epididymal preadipocytes, particularly the muscle isoform. Long-chain acyl-CoA levels were higher in perirenal than in epididymal preadipocytes and isolated fat cells. These data are consistent with interdepot differences in fatty acid flux ensuing from differences in fatty acid binding proteins and enzymes of fat metabolism. Heterogeneity among depots results, in part, from distinct intrinsic characteristics of adipose cells. Different depots are effectively separate miniorgans.
Transit Subsidies in New York and Chicago: Local, State, and Federal Assistance in a Historical Context (1997)

Nearly all studies of the impact of government subsidies on the transit industry have excluded systems with rail transit. Thus, previous findings cannot simply be extended to transit systems in major metropolitan areas. As a preliminary step in addressing the issue of subsidies and large transit systems, this paper presents historical information on the financial state of the two largest transit systems in the U.S. – Chicago’s CTA and New York's NYCT. In addition, the subsidies to each system are broken down by level of government-federal, state, and local. The patterns for the two systems are quite differellf. The CTA remained in relative financial health longer than the NYCT. While the CTA’s operating expenses have stabilized recently, its ridership levels (and revenues) have declined sharply. In terms of subsidies, the CTA receives most of these funds at the regional, not state or local, level. In contrast, NYCTs revenues were actually greater in 1995 than they were in 1954 (in constant dollars). Howeve1; its operating costs ballooned throughout the 1980s and only recently have been contained. Subsidies to the NYCT come almost equally from state and local sources.
Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes. (1994)

Several chemotactic agonists including interleukin-8 (IL-8) and related cytokines have been shown to activate and attract leukocytes via seven-transmembrane domain, GTP-binding protein-coupled receptors. A cDNA clone, LESTR, encoding a protein of 352 amino acids, corresponding to a novel receptor of this type, was isolated from a human blood monocyte cDNA library. The sequence of the deduced protein, LESTR (leukocyte-derived seven-transmembrane domain receptor), has 92.6% identity with that of a recently reported bovine neuropeptide Y (NPY) receptor, boLCR1 (Rimland, J., Xin, W., Sweetnam, P., Saijoh, K., Nestler, E. J., and Duman, R. S. (1991) Mol. Pharmacol. 40, 869-875). LESTR, however, is more similar (> 34%) to the IL-8 receptors, IL-8R1 and IL-8R2, than to several NPY receptors of different origin (< 20%). In the monocyte library, LESTR cDNA fragments were about 20 times as frequent as cDNA coding for IL-8R1 and IL-8R2, and much higher levels of LESTR- than IL-8R-specific mRNA were found in human blood neutrophils and lymphocytes. LESTR transcripts, by contrast, were low or undetectable in several neuroblastoma cell lines that are widely used to study NPY functions. Transfected cells expressing high levels of LESTR mRNA did not bind radiolabeled NPY, IL-8, NAP-2, GRO alpha, PF4, IP10, MCP-1, MCP-3, MIP-1 alpha, HC14, I309, RANTES, C3a, or LTB4. NPY also failed to bind to neutrophils, monocytes, and lymphocytes, to elicit responses in vitro such as Ca2+ changes, shape change, chemotaxis, enzyme release, and the respiratory burst, and to induce leukocyte accumulation upon injection in rats and rabbits. Although the ligand for LESTR could not be identified among a large number of chemotactic cytokines, the high expression in white blood cells and the marked sequence relation to IL-8R1 and IL-8R2 suggest that LESTR may function in the activation of inflammatory cells.
Oxidation Resistant Muteins of Antileukoproteinase as Potential Therapeutic Agents (1993)

Native antileukoproteinase (ALP) and two oxidant resistant mutants ALP 242 and ALP 231 were synthesized by means of recombinant DNA technology. In the ALP 242 molecule the methionine residue located in the reactive centre of the binding loop is replaced by a leucine residue. In ALP 231 all four methionine residues of the second domain were substituted by leucine residues. The native inhibitor and the two oxidant resistant molecules show comparable inhibitory capacities towards human neutrophil elastase (HLE) and cathepsin G. All three inhibitors were treated with different reactive oxygen species. After incubation with chloramine T or supernatants of activated polymorphonuclear leukocytes (PMN's) a drastic drop of inhibitory capacity of the native molecule was observed. Compared to the native form of ALP the mutant ALP 242 was less inactivated, whereas ALP 231 was nearly totally resistant towards all reactive oxygen. (Heinzel-Wieland R. et al., Biomed Biochim Acta 50: 677-681 (1991)) The intratracheal administration of HLE into the lung of Syrian Hamsters induced mild to moderate emphysematous lesions. The inhibitory potencies of native ALP and the ALP mutants were determined in this animal model by means of intratracheal instillation of the different molecules one hour prior to the administration of HLE. The inhibitory effects of ALP 242 and ALP 231 towards HLE-induced emphysema were significantly better than that of the native molecule. Surprisingly no significant differences between the two mutants were observed. (Rudolphus A. et al., Clin Sci 81: 777-784 (1991)) In a second animal model the emphysema was induced by repeated intratracheal administration of lipopolysaccharides (LPS) into the hamster lungs. This model is characterized by a chronic process of inflammation probably caused by a continuous release of endogenous elastase from infiltrating PMN's. Repeated applications of 1 mg of ALP 242 reduced the LPS-induced emphysema by 70 to 80%. In contrast, equal amounts of the native molecule resulted in significantly lower inhibition of the LPS-induced emphysema, only 23-30% reduction was observed. Repeated applications of 1 mg of ALP 231 reduced the LPS-induced emphysema only about 50%. So far it is not yet clear, why the totally oxidant resistant ALP 231 was less effective than the ALP 242 molecule. (Stolk J. et al., Pulmonary Pharmacology in press (1992))
A probabilistic classifier ensemble weighting scheme based on cross-validated accuracy estimates (2019)

Our hypothesis is that building ensembles of small sets of strong classifiers constructed with different learning algorithms is, on average, the best approach to classification for real-world problems. We propose a simple mechanism for building small heterogeneous ensembles based on exponentially weighting the probability estimates of the base classifiers with an estimate of the accuracy formed through cross-validation on the train data. We demonstrate through extensive experimentation that, given the same small set of base classifiers, this method has measurable benefits over commonly used alternative weighting, selection or meta-classifier approaches to heterogeneous ensembles. We also show how an ensemble of five well-known, fast classifiers can produce an ensemble that is not significantly worse than large homogeneous ensembles and tuned individual classifiers on datasets from the UCI archive. We provide evidence that the performance of the cross-validation accuracy weighted probabilistic ensemble (CAWPE) generalises to a completely separate set of datasets, the UCR time series classification archive, and we also demonstrate that our ensemble technique can significantly improve the state-of-the-art classifier for this problem domain. We investigate the performance in more detail, and find that the improvement is most marked in problems with smaller train sets. We perform a sensitivity analysis and an ablation study to demonstrate the robustness of the ensemble and the significant contribution of each design element of the classifier. We conclude that it is, on average, better to ensemble strong classifiers with a weighting scheme rather than perform extensive tuning and that CAWPE is a sensible starting point for combining classifiers.
The Clinical and Neuroendocrine Features of Psychotic Depression (1984)

The authors compared 65 patients with major depression and psychotic features to 192 patients with major depression and no psychotic features in terms of clinical features, family history, and hypothalamic-pituitary-adrenocortical axis function. In accord with other studies, patients with psychotic depression were more likely to have bipolar depression, psychomotor disturbance, a family history of schizophrenia, and a more severely disordered hypothalamic-pituitary-adrenocortical axis. Whether psychotic depression is best considered apart from nonpsychotic depression or as simply a more severe form of depression remains unsettled. Nevertheless, research to date does give the diagnosis of psychotic depression a practical significance which is enhanced by its simplicity.
The Largest Synthetic Structure with Molecular Precision: Towards a Molecular Object (2010)

Pushing the limits: A 200×106 Da structurally defined, linear macromolecule (PG5) has a molar mass, cross-section dimension, and cylindrical shape that are comparable to some naturally occurring objects, such as amyloid fibrils or certain plant viruses. The macromolecule is resistant against flattening out on a surface; the picture shows PG5 embracing the tobacco mosaic virus (TMV). Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
AUXIN BIOSYNTHESIS (1997)

Indole-3-acetic acid (IAA) is the most abundant naturally occurring auxin. Plants produce active IAA both by de novo synthesis and by releasing IAA from conjugates. This review emphasizes recent genetic experiments and complementary biochemical analyses that are beginning to unravel the complexities of IAA biosynthesis in plants. Multiple pathways exist for de novo IAA synthesis in plants, and a number of plant enzymes can liberate IAA from conjugates. This multiplicity has contributed to the current situation in which no pathway of IAA biosynthesis in plants has been unequivocally established. Genetic and biochemical experiments have demonstrated both tryptophan-dependent and tryptophan-independent routes of IAA biosynthesis. The recent application of precise and sensitive methods for quantitation of IAA and its metabolites to plant mutants disrupted in various aspects of IAA regulation is beginning to elucidate the multiple pathways that control IAA levels in the plant.
Evaluation of current methods used to analyze the expression profiles of ATP-binding cassette transporters yields an improved drug-discovery database (2009)

The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Resistance exists against every effective anticancer drug and can develop by multiple mechanisms. These mechanisms can act individually or synergistically, leading to MDR, in which the cell becomes resistant to a variety of structurally and mechanistically unrelated drugs in addition to the drug initially administered. Although extensive work has been done to characterize MDR mechanisms in vitro, the translation of this knowledge to the clinic has not been successful. Therefore, identifying genes and mechanisms critical to the development of MDR in vivo and establishing a reliable method for analyzing highly homologous genes from small amounts of tissue is fundamental to achieving any significant enhancement in our understanding of MDR mechanisms and could lead to treatments designed to circumvent it. In this study, we use a previously established database that allows the identification of lead compounds in the early stages of drug discovery that are not ATP-binding cassette (ABC) transporter substrates. We believe this can serve as a model for appraising the accuracy and sensitivity of current methods used to analyze the expression profiles of ABC transporters. We found two platforms to be superior methods for the analysis of expression profiles of highly homologous gene superfamilies. This study also led to an improved database by revealing previously unidentified substrates for ABCB1, ABCC1, and ABCG2, transporters that contribute to MDR.
Epstein-Barr virus latent membrane protein expression in Hodgkin and Reed-Sternberg cells. (1991)

Cryostat sections from lymph nodes of 47 Hodgkin disease patients were examined by immunohistology for the Epstein-Barr virus (EBV)-encoded latent membrane protein (LMP), nuclear antigen 2, and late viral glycoprotein gp350/250. A distinct LMP-specific membrane and cytoplasmic staining was detected exclusively in Hodgkin and Reed-Sternberg cells in 18 patients (38%); EBV nuclear antigen 2 and gp350/250 immunoreactivity was absent in all instances. Thirty-two of 47 (68%) cases contained EBV-specific DNA sequences as detected by PCR, all LMP-positive cases being in this category. Our results confirm previous studies establishing the presence of EBV genomes in Hodgkin and Reed-Sternberg cells by demonstrating expression of an EBV-encoded protein in the tumor-cell population. The finding of LMP expression in the absence of EBV nuclear antigen 2 suggests a pattern of EBV gene expression different from that of B-lymphoblastoid cell lines and Burkitt lymphoma, whereas this finding shows similarities with that seen in undifferentiated nasopharyngeal carcinoma. Because the LMP gene has transforming potential, our findings support the concept of a pathoetiological role of EBV in many cases of Hodgkin disease.
Determinación de la Efectividad de la Remediación de Suelos Accidentalmente Contaminados con Ácido Sulfúrico mediante Métodos Geofísicos (2011)

ResumenEste trabajo muestra que el diagnóstico de suelos contaminados con sustancias peligrosas después de la remediación puede realizarse con técnicas no invasivas, en menos tiempo, con menor costo y evitando los riesgos de contaminación cruzada de muestras del método invasivo.Los métodos no invasivos utilizados para este caso particular de una contaminación accidental con ácido sulfúrico concentrado fueron el de inducción electromagnética y el método geoeléctrico.De acuerdo con los resultados obtenidos, se concluye que la utilización complementaria de ambos métodos permite realizar un diagnóstico correcto de la efectividad de la remediación.
Unprecedentedly fast hydrolysis of the RNA dinucleoside monophosphates ApA and UpU by rare earth metal ions (1992)

M. Komiyama, K. Matsumura and Y. Matsumoto, J. Chem. Soc., Chem. Commun., 1992, 640 DOI: 10.1039/C39920000640
Natural Frequencies of Human Corticothalamic Circuits (2009)

The frequency tuning of a system can be directly determined by perturbing it and by observing the rate of the ensuing oscillations, the so called natural frequency. This approach is used, for example, in physics, in geology, and also when one tunes a musical instrument. In the present study, we employ transcranial magnetic stimulation (TMS) to directly perturb a set of selected corticothalamic modules (Brodmann areas 19, 7, and 6) and high-density electroencephalogram to measure their natural frequency. TMS consistently evoked dominant alpha-band oscillations (8-12 Hz) in the occipital cortex, beta-band oscillations (13-20 Hz) in the parietal cortex, and fast beta/gamma-band oscillations (21-50 Hz) in the frontal cortex. Each cortical area tended to preserve its own natural frequency also when indirectly engaged by TMS through brain connections and when stimulated at different intensities, indicating that the observed oscillations reflect local physiological mechanisms. These findings were reproducible across individuals and represent the first direct characterization of the coarse electrophysiological properties of three associative areas of the human cerebral cortex. Most importantly, they indicate that, in healthy subjects, each corticothalamic module is normally tuned to oscillate at a characteristic rate. The natural frequency can be directly measured in virtually any area of the cerebral cortex and may represent a straightforward and flexible way to probe the state of human thalamocortical circuits at the patient's bedside.
Escherichia coli l-aspartate-α-decarboxylase: preprotein processing and observation of reaction intermediates by electrospray mass spectrometry (1997)

The Escherichia coli panD gene, encoding l-aspartate-alpha-decarboxylase, was cloned by PCR, and shown to complement a panD mutant defective in beta-alanine biosynthesis. Aspartate decarboxylase is a pyruvoyl-dependent enzyme, and is synthesized initially as an inactive proenzyme (the pi-protein), which is proteolytically cleaved at a specific X-Ser bond to produce a beta-subunit with XOH at its C-terminus and an alpha-subunit with a pyruvoyl group at its N-terminus, derived from the serine. The recombinant enzyme, as purified, is a tetramer, and comprises principally the unprocessed pi-subunit (of 13.8 kDa), with a small proportion of the alpha- and beta-subunits (11 kDa and 2.8 kDa respectively). Incubation of the purified enzyme at elevated temperatures for several hours results in further processing. Using fluorescein thiosemicarbazide, the completely processed enzyme was shown to contain three pyruvoyl groups per tetrameric enzyme. The presence of unchanged serine at the N-terminus of some of the alpha-subunits was confirmed by electrospray mass spectrometry (ESMS) and N-terminal amino acid sequencing. A novel HPLC assay for aspartate decarboxylase was established and used to determine the Km and kcat for l-aspartate as 151+/-16 microM and 0.57 s-1 respectively. ESMS was also used to observe substrate and product adducts trapped on the pyruvoyl group by sodium cyanoborohydride treatment.
Comparative study on effects of burn-blast combined injury and burn-firearm combined injury complicated with seawater immersion on vascular endothelial cells. (2005)

In burn-blast injury combined with seawater immersion, the vascular endothelial cells changed most significantly at 4 hours or 7 hours after injury, while burn-firearm injury combined with seawater immersion have the same at 20 hours or 28 hours after injury.
Direct detection and identification of Mycobacterium tuberculosis in smear-positive sputum samples by fluorescence in situ hybridization (FISH) using peptide nucleic acid (PNA) probes. (1999)

PNA probes allow for rapid diagnosis of tuberculosis in smear-positive cases.
l-Thyroxine vs. 3,5,3′-triiodo-l-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase (2009)

3,5,3'-Triiodo-l-thyronine (T(3)), but not l-thyroxine (T(4)), activated Src kinase and, downstream, phosphatidylinositol 3-kinase (PI3-kinase) by means of an alpha(v)beta(3) integrin receptor on human glioblastoma U-87 MG cells. Although both T(3) and T(4) stimulated extracellular signal-regulated kinase (ERK) 1/2, activated ERK1/2 did not contribute to T(3)-induced Src kinase or PI3-kinase activation, and an inhibitor of PI3-kinase, LY-294002, did not block activation of ERK1/2 by physiological concentrations of T(3) and T(4). Thus the PI3-kinase, Src kinase, and ERK1/2 signaling cascades are parallel pathways in T(3)-treated U-87 MG cells. T(3) and T(4) both caused proliferation of U-87 MG cells; these effects were blocked by the ERK1/2 inhibitor PD-98059 but not by LY-294002. Small-interfering RNA knockdown of PI3-kinase confirmed that PI3-kinase was not involved in the proliferative action of T(3) on U-87 MG cells. PI3-kinase-dependent actions of T(3) in these cells included shuttling of nuclear thyroid hormone receptor-alpha (TRalpha) from cytoplasm to nucleus and accumulation of hypoxia-inducible factor (HIF)-1alpha mRNA; LY-294002 inhibited these actions. Results of studies involving alpha(v)beta(3) receptor antagonists tetraiodothyroacetic acid (tetrac) and Arg-Gly-Asp (RGD) peptide, together with mathematical modeling of the kinetics of displacement of radiolabeled T(3) from the integrin by unlabeled T(3) and by unlabeled T(4), are consistent with the presence of two iodothyronine receptor domains on the integrin. A model proposes that one site binds T(3) exclusively, activates PI3-kinase via Src kinase, and stimulates TRalpha trafficking and HIF-1alpha gene expression. Tetrac and RGD peptide both inhibit T(3) action at this site. The second site binds T(4) and T(3), and, via this receptor, the iodothyronines stimulate ERK1/2-dependent tumor cell proliferation. T(3) action here is inhibited by tetrac alone, but the effect of T(4) is blocked by both tetrac and the RGD peptide.