gebhart/patrepeval huggingface dataset:
α-Synuclein Suppression by Targeted Small Interfering RNA in the Primate Substantia Nigra (2010)

The protein alpha-synuclein is involved in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. Its toxic potential appears to be enhanced by increased protein expression, providing a compelling rationale for therapeutic strategies aimed at reducing neuronal alpha-synuclein burden. Here, feasibility and safety of alpha-synuclein suppression were evaluated by treating monkeys with small interfering RNA (siRNA) directed against alpha-synuclein. The siRNA molecule was chemically modified to prevent degradation by exo- and endonucleases and directly infused into the left substantia nigra. Results compared levels of alpha-synuclein mRNA and protein in the infused (left) vs. untreated (right) hemisphere and revealed a significant 40-50% suppression of alpha-synuclein expression. These findings could not be attributable to non-specific effects of siRNA infusion since treatment of a separate set of animals with luciferase-targeting siRNA produced no changes in alpha-synuclein. Infusion with alpha-synuclein siRNA, while lowering alpha-synuclein expression, had no overt adverse consequences. In particular, it did not cause tissue inflammation and did not change (i) the number and phenotype of nigral dopaminergic neurons, and (ii) the concentrations of striatal dopamine and its metabolites. The data represent the first evidence of successful anti-alpha-synuclein intervention in the primate substantia nigra and support further development of RNA interference-based therapeutics.
Understanding and revamping of industrial scale SMB units for p‐xylene separation (2006)

Abstract One of the first applications of Simulated Moving Bed (SMB) technology was in p‐xylene recovery from mixed xylenes. The three main industrial processes for p‐xylene separation from mixed xylenes based on SMB technology are: UOP's Parex, IFP's Eluxyl, and Toray's Aromax. These units operate in liquid phase (T = 180°C and P = 9 bar), achieving high recovery of almost pure p‐xylene with high on‐stream efficiency and extended adsorbent life. In this work, the industrial scale SMB process is investigated from modeling, simulation, and optimization points of view, using experimentally measured xylene adsorption equilibrium and kinetics data on ion exchanged faujasite zeolite. The aim is to develop tools for training of SMB unit operators and choice of the best operating conditions. Useful studies for better understanding of the influence of the operating parameters, adsorbent packing, and separation requirements on unit productivity are presented. SMB unit revamping strategies and operative actions are proposed. The practical application of “separation volume” methodology in the selection of optimum operating conditions that lead to maximum p‐xylene productivity with minimal desorbent consumption is described. © 2006 American Institute of Chemical Engineers AIChE J, 2007
Type 2 diabetes mellitus as a conformational disease. (2005)

Conformational diseases are conditions that arise from the dysfunctional aggregation of proteins in non-native conformations. Type 2 diabetes mellitus can be defined as a conformational disease because a constituent beta cell protein, islet amyloid polypeptide, undergoes a change in tertiary structure followed by self-association and tissue deposition. Type 2 diabetes mellitus is associated with multiple metabolic derangements that result in the excessive production of reactive oxygen species and oxidative stress. These reactive oxygen species set in motion a host of redox reactions which can result in unstable nitrogen and thiol species that contribute to additional redox stress. The ability of a cell to deal with reactive oxygen species and oxidative stress requires functional chaperones, antioxidant production, protein degradation and a cascade of intracellular events collectively known as the unfolded protein response. It is known that beta cells are particularly susceptible to perturbations in this quality control system and that reactive oxygen species play an important role in the development and/or progression of diabetes mellitus. Oxidative stress and increased insulin production contribute to endoplasmic reticulum stress, protein misfolding, and induction of the unfolded protein response. As the cell's quality control system becomes overwhelmed, conformational changes occur to islet amyloid polypeptide intermediates, generating stable oligomers with an anti-parallel crossed beta-pleated sheet structure that eventually accumulate as space-occupying lesions within the islets. By approaching type 2 diabetes mellitus as a conformational disease in which there is a structural transition from physiological protein to pathological protein, it is possible that the relentless nature of disease progression can be understood in relation to other conformational diseases.
Obesity and Cancer: A Gut Microbial Connection (2014)

Multiple epidemiological studies have revealed that excess bodyweight, such as in people who are overweight or obese (defined by a body mass index higher than 25 kg/m(2)), is a major risk factor for not only diabetes and cardiovascular diseases but also cancer. Effective strategies for obesity prevention are therefore needed for cancer prevention. However, because the prevalence of excess bodyweight in most developed countries has been increasing markedly over the past several decades, with no signs of abating, alternative approaches are also required to conquer obesity-associated cancer. Therefore, we sought to understand the molecular mechanisms underlying obesity-associated cancer. Although several phenomena have been proposed to explain how obesity increases cancer risk, the exact molecular mechanisms that integrate these phenomena have remained largely obscure. Recently, we have traced the association between obesity and increased cancer risk to gut microbiota communities that produce a DNA-damaging bile acid. The analyses also revealed the role of cellular senescence in cancer, which we have been studying for the past few decades. In this review, we provide an overview of our work and discuss the next steps, focusing on the potential clinical implications of these findings.
Once-Daily Dosing in Dogs Optimizes Daptomycin Safety (2000)

Daptomycin is a novel lipopeptide antibiotic with potent bactericidal activity against most clinically important gram-positive bacteria, including resistant strains. Daptomycin has been shown to have an effect on skeletal muscle. To guide the clinical dosing regimen with the potential for the least effect on skeletal muscle, two studies were conducted with dogs to compare the effects of repeated intravenous administration every 24 h versus every 8 h for 20 days. The data suggest that skeletal-muscle effects were more closely related to the dosing interval than to either the maximum concentration of the drug in plasma or the area under the concentration-time curve. Both increases in serum creatine phosphokinase activity and the incidence of myopathy observed at 25 mg/kg of body weight every 8 h were greater than those observed at 75 mg/kg every 24 h despite the lower maximum concentration of drug in plasma. Similarly, the effects observed at 25 mg/kg every 8 h were greater than those observed at 75 mg/kg every 24 h at approximately the same area under the concentration-time curve from 0 to 24 h. Once-daily administration appeared to minimize the potential for daptomycin-related skeletal-muscle effects, possibly by allowing for more time between doses for repair of subclinical effects. Thus, these studies with dogs suggest that once-daily dosing of daptomycin in humans should have the potential to minimize skeletal-muscle effects. In fact, interim results of ongoing clinical trials, which have focused on once-daily dosing, appear to be consistent with this conclusion.
Effect of modified alpha 2macroglobulin on leucocyte locomotion and chemotaxis. (1983)

The effects of human alpha 2macroglobulin (alpha 2M) on locomotion of human neutrophils and monocytes in micropore filter assays in vitro were studied. Native alpha 2M had no effect on cell locomotion. In contrast, alpha 2M which had been modified by interaction with proteases (trypsin, collagenase), or with ammonium sulphate, stimulated locomotion of both cell types. The degree of locomotory response induced in the cells by alpha 2M correlated closely with changes in molecular conformation of alpha 2M as estimated by measurements of binding of the fluorescent probe, 1-anilinonaphthalene-8-sulphonic acid (ANS). However neutrophil locomotion stimulated by modified alpha 2M appeared to be solely chemokinetic, whereas monocytes showed both chemokinetic and chemotactic responses to modified alpha 2M. The reason for this difference in response between the two cell types is unclear, but it is reflected in the lack of specific binding of alpha 2M-protease complexes by neutrophils. Earlier workers had shown specific binding of such complexes by mononuclear phagocytes.
Assessing Fixed-Income Fund Manager Style and Performance from Historical Returns (2001)

A fixed income money manager9s style and the extent to which the manager9s style effects the fund performance is typically determined by examining the positions taken by the manager. However, in many cases detailed data on the portfolio holdings over a long time period are not available. This article develops a methodology for estimating an active fund manager9s style and the sources of over or underperformance using only historical returns.
Low temperature deposition of patterned TiO2 thin films using photopatterned self-assembled monolayers (1996)

Patterned thin films of TiO2 were deposited from aqueous solution onto photopatterned self-assembled monolayer (SAM) films on Si substrates. Regions of the SAM containing sulfonate surface functionality were created by the photo-oxidation of initially deposited thioacetate groups through a mask. The nanocrystalline TiO2-on-SAM films were deposited selectively on the photolyzed regions of the SAM. The electrical properties of such films were assessed for potential microelectronic device applications. Current–voltage and capacitance–voltage measurements made on nonpatterned TiO2 films yielded values of relative permittivity ranging from 24 to 57, film resistivities of 1.0–1.5×109 Ω cm and breakdown voltages in excess of 1 MV/cm.
Dengue type 4 virus mutants containing deletions in the 3' noncoding region of the RNA genome: analysis of growth restriction in cell culture and altered viremia pattern and immunogenicity in rhesus monkeys (1996)

The dengue type 4 virus (DEN4) genome contains a 384-nucleotide (nt) 3' noncoding sequence in which the last 81 nt, predicted to form a secondary structure, are thought to be essential for virus replication. Immediately upstream of the secondary structure, short RNA sequences that are conserved among mosquito-borne flaviviruses have been identified. A series of deletions that range from 30 to 262 nt were introduced into this upstream region of full-length DEN4 cDNA to create viable deletion mutants, some of which might prove to be useful for inclusion in a live attenuated virus vaccine. When studied by an infectious-center assay, most full-length RNA transcripts of the deletion constructs exhibited reduced infectivity when transfected into simian LLC-MK2 cells compared with the full-length RNA transcripts of wild-type parental virus. Deletion mutations that extended as far as the 5' boundary of the 3' noncoding region and whose 3' boundary did not extend beyond the last 113 nt of the 3' end were viable. With the exception of mutant 3'd 303-183, which contained a deletion of nt 303 to 183 from the 3' terminus, deletion mutants produced plaques that appeared late on simian LLC-MK2 cells or exhibited a small-plaque morphology on mosquito C6/36 cells compared with the wild-type virus. These mutants also replicated less efficiently and attained a lower titer in LLC-MK2 cells than parental wild-type virus. Significantly, mutant 3'd 303-183 grew to a high titer and was least restricted in growth. Mutant 3'd 303-183 and four other moderately to severely restricted mutants were selected for evaluation of infectivity and immunogenicity in rhesus monkeys. There was a suggestion that occurrence and duration of viremia were reduced for some of the deletion mutants compared with the wild-type virus. However, more convincing evidence for attenuation of some of the mutants was provided by an analysis of antibody response to infection. Mutant 3'd 303-183 induced an antibody response equivalent to that stimulated by wild-type virus, whereas other mutants induced low to moderate levels of antibodies, as measured by radioimmunoprecipitation and virus neutralization. The immunogenicity of these 3' DEN4 deletion mutants in monkeys appeared to correlate with their efficiency of growth in simian LLC-MK2 cells. One or more mutants described in this paper may prove to be useful for immunization of humans against disease caused by dengue virus.
CpG oligodeoxynucleotides potentiate the antitumor effects of chemotherapy or tumor resection in an orthotopic murine model of rhabdomyosarcoma. (2003)

These data are the first to show that immune stimulatory agents such as CpGs may enhance the antitumor effects of chemotherapeutic agents and improve survival after surgical resection of a solid tumor.
Experimental Induction of Hepatomas, Mammary Tumors, and Other Tumors With Metronidazole in Noninbred Sas:MRC(WI)BR Rats2 (1979)

Metronidazole, a chemotherapeutic agent against trichomonas infection, was tested for carcinogenicity in noninbred Sas:MRC(WI)BR rats. Three groups were given the drug for life at dose levels of 0.6%, 0.3%, and 0.06% in a powdered diet. The incidence of mammary tumors (P less than 0.020) and hepatomas (P less than 0.050) increased significantly among females given the highest dose (0.6%). Also, the rates of Leydig cell tumors of the testes (P less than 0.040) and pituitary adenomas (P less than 0.040) were statistically significant among males given the highest dose (0.6%). Results are discussed in light of a possible hazard of this drug to humans.
Formation and Antitumor Activity of PNU-159682, A Major Metabolite of Nemorubicin in Human Liver Microsomes (2005)

CYP3A4, the major CYP in human liver, converts MMDX to a more cytotoxic metabolite, PNU-159682, which retains antitumor activity in vivo.
Modulation of pro-epidermal growth factor, pro-transforming growth factor alpha and epidermal growth factor receptor gene expression in human renal carcinomas. (1990)

We have analyzed the expression of the genes for the precursors of epidermal growth factor (pro-EGF) and transforming growth factor alpha (proTGF-alpha) as well as for the EGF receptor in tissue specimens of a large number of adult patients with renal cell carcinoma. Since normal kidney tissue was available from the same patients we could directly compare the expression of these genes in tumors with that in adjacent normal renal tissue. Our experiments reveal underexpression of the proEGF gene in all tumors analyzed (21 of 21) and overexpression of the genes for proTGF-alpha (33 of 33 analyzed) and EGF receptor (22 of 23 analyzed) in tumor samples, when compared with normal kidney tissue. The expression of the proTGF-alpha gene appeared to depend on grade and differentiation of the tumor, since well differentiated tumors (grade 1) expressed more proTGF-alpha mRNA than the adjacent normal tissue but significantly less than poorly differentiated tumors (grade 2 or 3), which are the most aggressive ones. In none of these tissue specimens did we find, by Southern analysis, amplification of the proTGF-alpha or EGF receptor gene. Therefore, overexpression of these genes must be due to another effect, perhaps an alteration of their mRNA turnover. Although the EGF receptor gene (c-erbB1) is overexpressed in nearly all carcinomas analyzed, there was no linear coexpression with the proTGF-alpha gene. In contrast, transcription of the proEGF gene was completely turned off in tumor tissue. Although we have found by restriction fragment length polymorphism analysis, in one of three tumor samples, evidence for a somatic mutation within the proEGF gene, we do not know yet, due to the limited number of Southern analyses, whether this somatic mutation is causally involved in the decrease of proEGF mRNA expression and, hence, is representative of renal cell carcinoma. To our knowledge, this is the first observation on primary tumor tissue in humans that upon malignant transformation the gene for a polypeptide growth factor gene is underexpressed.
REARRANGEMENTS OF SOME NEW HYDROXAMIC ACIDS RELATED TO HETEROCYCLIC ACIDS AND TO DIPHENYL- AND TRIPHENYL-ACETIC ACIDS.1 (1921)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTREARRANGEMENTS OF SOME NEW HYDROXAMIC ACIDS RELATED TO HETEROCYCLIC ACIDS AND TO DIPHENYL- AND TRIPHENYL-ACETIC ACIDS.1Lauder W. Jones and Charles D. HurdCite this: J. Am. Chem. Soc. 1921, 43, 11, 2422–2448Publication Date (Print):November 1, 1921Publication History Published online1 May 2002Published inissue 1 November 1921https://pubs.acs.org/doi/10.1021/ja01444a016https://doi.org/10.1021/ja01444a016research-articleACS PublicationsRequest reuse permissionsArticle Views559Altmetric-Citations32LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Combined Targeting of the Epidermal Growth Factor Receptor and Cyclooxygenase-2 Pathways (2005)

Extensive evidence implicates both the epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) in carcinogenesis. Stimulation of EGFR signaling or enhanced synthesis of COX-2–derived prostanoids can influence several processes that are linked to carcinogenesis, including cell
Coupled translation and replication of poliovirus RNA in vitro: synthesis of functional 3D polymerase and infectious virus (1993)

Poliovirus RNA polymerase and infectious virus particles were synthesized by translation of virion RNA in vitro in HeLa S10 extracts. The in vitro translation reactions were optimized for the synthesis of the viral proteins found in infected cells and in particular the synthesis of the viral polymerase 3Dpol. There was a linear increase in the amount of labeled protein synthesized during the first 6 h of the reaction. The appearance of 3Dpol in the translation products was delayed because of the additional time required for the proteolytic processing of precursor proteins. 3Dpol was first observed at 1 h in polyacrylamide gels, with significant amounts being detected at 6 h and later. Initial attempts to assay for polymerase activity directly in the translation reaction were not successful. Polymerase activity, however, was easily detected by adding a small amount (3 microliters) of translation products to a standard polymerase assay containing poliovirion RNA. Full-length minus-strand RNA was synthesized in the presence of an oligo(U) primer. In the absence of oligo(U), product RNA about twice the size of virion RNA was synthesized in these reactions. RNA stability studies and plaque assays indicated that a significant fraction of the input virion RNA in the translation reactions was very stable and remained intact for 20 h or more. Plaque assays indicated that infectious virus was synthesized in the in vitro translation reactions. Under optimal conditions, the titer of infectious virus produced in the in vitro translation reactions was greater than 100,000 PFU/ml. Virus was first detected at 6 h and increased to maximum levels by 12 h. Overall, the kinetics of poliovirus replication (protein synthesis, polymerase activity, and virus production) observed in the HeLa S10-initiation factor in vitro translation reactions were similar to those observed in infected cells.
Pathophysiology of nonalcoholic steatohepatitis. (2006)

Nonalcoholic fatty liver disease (NAFLD) affects approximately 30% of adults and 20% of children in the United States. Nonalcoholic steatohepatitis (NASH) is its most severe histologic form and progresses to cirrhosis in 20% of these patients. Once developed, 30% to 40% of patients with NASH cirrhosis will experience a liver-related death. Consequently, it has become extremely important to understand the pathophysiology of NASH to develop sound therapeutic interventions. It is now recognized that nonhepatic mechanisms are largely responsible for the development of insulin resistance, which causes hepatic steatosis. Once developed, oxidative stress and diminished antioxidants within the liver initiate the progression from steatosis alone to NASH and ultimately to cirrhosis. However, not all patients progress to cirrhosis. As is the case for other common complex metabolic diseases, it is the interaction between the environment and genetics that will determine the phenotypic expression of NAFLD and NASH in each individual patient. Which of the pathophysiologic factors (which are discussed in this review), either alone or in combination, will eventually provide the basis for the most effective therapy has yet to be determined.
Computational Methods for Inverse Problems (2002)

In verse problems arise in a number of important practical applications, ranging from biomedical imaging to seismic prospecting. This book provides the reader with a basic understanding of both the underlying mathematics and the computational methods used to solve inverse problems. It also addresses specialized topics like image reconstruction, parameter identification, total variation methods, nonnegativity constraints, and regularization parameter selection methods. Because inverse problems typically involve the estimation of certain quantities based on indirect measurements, the estimation process is often ill-posed. Regularization methods, which have been developed to deal with this ill-posedness, are carefully explained in the early chapters of Computational Methods for Inverse Problems. The book also integrates mathematical and statistical theory with applications and practical computational methods, including topics like maximum likelihood estimation and Bayesian estimation. Several web-based resources are available to make this monograph interactive, including a collection of MATLAB m-files used to generate many of the examples and figures.
Physicochemical Stability of Papaverine Hydrochloride-Phentolamine Mesylate Mixtures Used for Intracavernous Injection: A Preliminary Evaluation (1988)

Physicochemical stability of intracavernous injections of 30 mg. per ml. papaverine hydrochloride with 0.5 or 1.0 mg. per ml. phentolamine mesylate used to induce erection in patients with impotence was examined. The samples were stored at room temperature, in the refrigerator at 4C and in the freezer at -20C for 6 months. The examination consisted of visual observation for change in color or evidence of precipitation, measurement of pH and thin layer chromatography at different intervals. During the 6 months of storage no change had occurred in pH, color development, precipitation or formation of new moieties. Therefore, the aforementioned injection solutions of papaverine hydrochloride with phentolamine mesylate can be dispensed safely with instruction to patients for adequate storage and manipulation.