gebhart/patrepeval huggingface dataset:
Dose translation from animal to human studies revisited (2007)

As new drugs are developed, it is essential to appropriately translate the drug dosage from one animal species to another. A misunderstanding appears to exist regarding the appropriate method for allometric dose translations, especially when starting new animal or clinical studies. The need for education regarding appropriate translation is evident from the media response regarding some recent studies where authors have shown that resveratrol, a compound found in grapes and red wine, improves the health and life span of mice. Immediately after the online publication of these papers, the scientific community and popular press voiced concerns regarding the relevance of the dose of resveratrol used by the authors. The animal dose should not be extrapolated to a human equivalent dose (HED) by a simple conversion based on body weight, as was reported. For the more appropriate conversion of drug doses from animal studies to human studies, we suggest using the body surface area (BSA) normalization method. BSA correlates well across several mammalian species with several parameters of biology, including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins, and renal function. We advocate the use of BSA as a factor when converting a dose for translation from animals to humans, especially for phase I and phase II clinical trials.
TCP westwood with agile probing: dealing with dynamic, large, leaky pipes (2004)

TCP westwood (TCPW) has been shown to provide significant performance improvement over high-speed heterogeneous networks. The key idea of TCPW is to use eligible rate estimation (ERE) methods, to set the congestion window (cwnd) and slow start threshold (ssthresh) after a packet loss. ERE is defined as the transmission rate a sender ought to use to achieve high utilization and remain friendly to other TCP variants. This paper presents TCP westwood with agile probing (TCPW-A), a sender-side only enhancement of TCPW. TCPW-A perform well when faced with highly dynamic bandwidth, large propagation time/bandwidth, and random loss in the current and future heterogeneous Internet. TCPW-A achieves its goal by incorporating the following, two mechanisms: 1) when a connection initially begins or re-starts after a timeout, instead of exponentially expanding cwnd to an arbitrary preset ssthresh and then going into linear increase. TCPW-A uses agile probing, a mechanism that repeatedly resets ssthresh based on ERE and forces cwnd into an exponential climb each time. The result is fast convergence to a more appropriate ssthresh value. 2) In congestion avoidance, TCPW-A invokes agile probing upon indication of unused extra bandwidth via a scheme we call load gauge (LG). Experimental results, both in Ns-2, and in measurements using FreeBSD implementation, show that TCPW-A can significantly improve link utilization over a wide range of bandwidth, propagation delay and dynamic network loading.
Molecular Phylogeny and Evolution of Morphology in the Social Amoebas (2006)

The social amoebas (Dictyostelia) display conditional multicellularity in a wide variety of forms. Despite widespread interest in Dictyostelium discoideum as a model system, almost no molecular data exist from the rest of the group. We constructed the first molecular phylogeny of the Dictyostelia with parallel small subunit ribosomal RNA and a-tubulin data sets, and we found that dictyostelid taxonomy requires complete revision. A mapping of characters onto the phylogeny shows that the dominant trend in dictyostelid evolution is increased size and cell type specialization of fruiting structures, with some complex morphologies evolving several times independently. Thus, the latter may be controlled by only a few genes, making their underlying mechanisms relatively easy to unravel.
Highly Active Palladium Catalysts for Suzuki Coupling Reactions (1999)

Mixtures of palladium acetate and o-(di-tert-butylphosphino)biphenyl (4) catalyze the room-temperature Suzuki coupling of aryl bromides and aryl chlorides with 0.5−1.0 mol % Pd. Use of o-(dicyclohexylphosphino)biphenyl (2) allows Suzuki couplings to be carried out at low catalyst loadings (0.000001−0.02 mol % Pd). The process tolerates a broad range of functional groups and substrate combinations including the use of sterically hindered substrates. This is the most active catalyst system in terms of reaction temperature, turnover number, and steric tolerance which has been reported to date.
Serum B-cell maturation antigen: a novel biomarker to predict outcomes for multiple myeloma patients (2016)

B-cell maturation antigen is expressed on plasma cells. In this study, we have identified serum B-cell maturation antigen as a novel biomarker that can monitor and predict outcomes for multiple myeloma patients. Compared to healthy donors, patients with multiple myeloma showed elevated serum B-cell maturation antigen levels (<i>P</i><0.0001). Serum B-cell maturation antigen levels correlated with the proportion of plasma cells in bone marrow biopsies (Spearman's rho = 0.710; <i>P</i><0.001), clinical status (complete response <i>vs</i> partial response, <i>P</i>=0.0374; complete response <i>vs</i> progressive disease, <i>P</i><0.0001), and tracked with changes in M-protein levels. Among patients with non-secretory disease, serum B-cell maturation antigen levels correlated with bone marrow plasma cell levels and findings from positron emission tomography scans. Kaplan-Meier analysis demonstrated that serum B-cell maturation antigen levels above the median levels were predictive of a shorter progression-free survival (<i>P</i>=0.0006) and overall survival (<i>P</i>=0.0108) among multiple myeloma patients (n=243). Specifically, patients with serum B-cell maturation antigen levels above the median level at the time of starting front-line (<i>P</i>=0.0043) or a new salvage therapy (<i>P</i>=0.0044) were found to have shorter progression-free survival. Importantly, serum B-cell maturation antigen levels did not show any dependence on renal function and maintained independent significance when tested against other known prognostic markers for multiple myeloma such as age, serum β2 microglobulin, hemoglobin, and bone disease. These data identify serum B-cell maturation antigen as a new biomarker to manage multiple myeloma patients.
Autoxidation of oxymyoglobin. An overall stoichiometry including subsequent side reactions. (1987)

Oxymyoglobin (MbO2) is oxidized easily to metmyoglobin (metMb) with generation of the superoxide anion, which can be converted by the spontaneous dismutation into H2O2, this being also a potent oxidant of MbO2. In the presence of sodium azide in stoichiometric amounts, however, the rate of autoxidation of MbO2 increased rapidly with increasing concentration of the anion, but soon reached a saturating level, the extent of which was about twice that of the normal autoxidation in buffer alone. Quantitative analysis has revealed that this enhancement is not due to the nucleophilic displacement of O2- from MbO2 by the anion (Satoh, Y., and Shikama, K. (1981) J. Biol. Chem. 256, 10272-10275), but is due to the additional oxidation of MbO2 by H2O2 freed from the metMb being occupied by the anion at the sixth coordination position. Based on these novel results and stoichiometric considerations, it is possible to propose a new view that H2O2 produced from O2- can be eliminated or decomposed mostly, if not completely, by the metMb resulting from the normal autoxidation reaction of MbO2, presumably via the formation of the ferryl species.
Parkin functions as an E2-dependent ubiquitin– protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1 (2000)

Parkinson's disease is a common neurodegenerative disorder in which familial-linked genes have provided novel insights into the pathogenesis of this disorder. Mutations in Parkin, a ring-finger-containing protein of unknown function, are implicated in the pathogenesis of autosomal recessive familial Parkinson's disease. Here, we show that Parkin binds to the E2 ubiquitin-conjugating human enzyme 8 (UbcH8) through its C-terminal ring-finger. Parkin has ubiquitin-protein ligase activity in the presence of UbcH8. Parkin also ubiquitinates itself and promotes its own degradation. We also identify and show that the synaptic vesicle-associated protein, CDCrel-1, interacts with Parkin through its ring-finger domains. Furthermore, Parkin ubiquitinates and promotes the degradation of CDCrel-1. Familial-linked mutations disrupt the ubiquitin-protein ligase function of Parkin and impair Parkin and CDCrel-1 degradation. These results suggest that Parkin functions as an E3 ubiquitin-protein ligase through its ring domains and that it may control protein levels via ubiquitination. The loss of Parkin's ubiquitin-protein ligase function in familial-linked mutations suggests that this may be the cause of familial autosomal recessive Parkinson's disease.
Desmoglein 2-mediated adhesion is required for intestinal epithelial barrier integrity (2010)

The integrity of intercellular junctions that form the "terminal bar" in intestinal epithelium is crucial for sealing the intestinal barrier. Whereas specific roles of tight and adherens junctions are well known, the contribution of desmosomal adhesion for maintaining the intestinal epithelial barrier has not been specifically addressed. For the present study, we generated a desmoglein 2 antibody directed against the extracellular domain (Dsg2 ED) to test whether impaired Dsg2-mediated adhesion affects intestinal epithelial barrier functions in vitro. This antibody was able to specifically block Dsg2 interaction in cell-free atomic-force microscopy experiments. For in vitro studies of the intestinal barrier we used Caco2 cells following differentiation into tight enterocyte-like epithelial monolayers. Application of Dsg2 ED to Caco2 monolayers resulted in increased cell dissociation compared with controls in a dispase-based enterocyte dissociation assay. Under similar conditions, Dsg2 antibody significantly decreased transepithelial electrical resistance and increased FITC-dextran flux, indicating that Dsg2 interaction is critically involved in the maintenance of epithelial intestinal barrier functions. As revealed by immunostaining, this was due to Dsg2 ED antibody-induced rupture of tight junctions because tight junction proteins claudins 1, 4, and 5, occludin, and tight junction-associated protein zonula occludens-1 were partially removed from cell borders by Dsg2 ED treatment. Similar results were obtained by application of a commercial monoclonal antibody directed against the ED of Dsg2. Antibody-induced effects were blocked by absorption experiments using Dsg2-Fc-coated beads. Our data indicate that Dsg2-mediated adhesion affects tight junction integrity and is required to maintain intestinal epithelial barrier properties.
Association between Serum trans-Monounsaturated Fatty Acids and Breast Cancer Risk in the E3N-EPIC Study (2008)

The authors assessed the association between serum phospholipid fatty acids as biomarkers of fatty acid intake and breast cancer risk among women in the E3N Study (1989-2002), the French component of the European Prospective Investigation into Cancer and Nutrition. During an average of 7 years of follow-up, 363 cases of incident invasive breast cancer were documented among 19,934 women who, at baseline (1995-1998), had completed a diet history questionnaire and provided serum samples. Controls were randomly matched to cases by age, menopausal status at blood collection, fasting status at blood collection, date, and collection center. Serum phospholipid fatty acid composition was assessed by gas chromatography. Adjusted odds ratios for risk of breast cancer with increasing levels of fatty acids were calculated using conditional logistic regression. An increased risk of breast cancer was associated with increasing levels of the trans-monounsaturated fatty acids palmitoleic acid and elaidic acid (highest quintile vs. lowest: odds ratio = 1.75, 95% confidence interval: 1.08, 2.83; p-trend = 0.018). cis-Monounsaturated fatty acids were unrelated to breast cancer risk. A high serum level of trans-monounsaturated fatty acids, presumably reflecting a high intake of industrially processed foods, is probably one factor contributing to increased risk of invasive breast cancer in women.
Monoclonal antibodies in multiple sclerosis treatment: current and future steps (2009)

Multiple sclerosis (MS) is an autoimmune disease in which autoreactive T cells cross the blood—brain barrier and attack the myelin sheath leading to a cascade of inflammation. The result is demyelination, acute axonal transection, gliosis and subsequent axonal degeneration [Trapp et al. 1998]. Unpredictable episodes of neurological disability in young adults are followed by a gradual accumulation of deficits over time as the disease switches from an inflammatory to a degenerative ‘secondary progressive’ phase. Monoclonal antibodies have been used as experimental treatments of MS since the 1980s. Their advantage is high specificity for their target; their disadvantages are that they (usually) require intravenous administration, often are associated with infusion reactions and, as large foreign proteins, they are immunogenic.

Past experience with monoclonal antibodies has taught researchers to interpret results seen in animal models with caution. Anti-TNFα antibodies are successful in the treatment of rheumatoid arthritis and work done using the animal model of MS (experimental autoimmune encephalomyelitis, EAE) suggested a beneficial effect on the disease. Early trials in MS patients, however, showed the opposite effect with worsening of disease activity [Lenercept Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group, 1999]. There have also been reports of de novo MS occurring in rheumatoid arthritis patients treated with anti-TNFα therapy [Sicotte and Voskuhl, 2001].

Data from clinical research trials has however given important insights in to the underlying disease mechanism and suggests that treating MS in the early inflammatory phase gives an opportunity to delay or prevent the onset of disease progression [Coles et al. 2006]. To date only one monoclonal antibody has been licensed as a treatment for MS: natalizumab. Here we review the current and future use of monoclonal antibodies in MS (Table 1).

Table 1.

Current and future monoclonal antibodies in MS.
Design, Synthesis, and Biological Activity of a Potent Smac Mimetic That Sensitizes Cancer Cells to Apoptosis by Antagonizing IAPs (2006)

Designed second mitochondrial activator of caspases (Smac) mimetics based on an accessible [7,5]-bicyclic scaffold bind to and antagonize protein interactions involving the inhibitor of apoptosis (IAP) proteins, X-chromosome-linked IAP (XIAP), melanoma IAP (ML-IAP), and c-IAPs 1 and 2 (cIAP1 and cIAP2). The design rationale is based on a combination of phage-panning data, peptide binding studies, and a survey of potential isosteres. The synthesis of two scaffolds is described. These compounds bind the XIAP-baculoviral IAP repeat 3 (BIR3), cIAP1-BIR3, cIAP2-BIR3, and ML-IAP-BIR domains with submicromolar affinities. The most potent Smac mimetic binds the cIAP1-BIR3 and ML-IAP-BIR domains with a K i of 50 nM. The X-ray crystal structure of this compound bound to an ML-IAP/XIAP chimeric BIR domain protein is compared with that of a complex with a phage-derived tetrapeptide, AVPW. The structures show that these compounds bind to the Smac-binding site on ML-IAP with identical hydrogen-bonding patterns and similar hydrophobic interactions. Consistent with the structural data, coimmunoprecipitation experiments demonstrate that the compounds can effectively block Smac interactions with ML-IAP. The compounds are further demonstrated to activate caspase-3 and -7, to reduce cell viability in assays using MDA-MB-231 breast cancer cells and A2058 melanoma cells, and to enhance doxorubicin-induced apoptosis in MDA-MB-231 cells.
Preclinical pharmacokinetics, tissue distribution, and antitumor activity of a folate-hapten conjugate–targeted immunotherapy in hapten-immunized mice (2006)

Folic acid (pteroylglutamic acid) represents a useful ligand for targeted cancer therapies because it binds to a common epithelial tumor antigen known as the folate receptor. We previously devised an immunotherapy strategy that uses a bispecific ligand, a folate-hapten (FITC) conjugate, to redirect endogenously induced anti-FITC antibodies to folate receptor-positive tumor cells following parenteral administration. Here, we present results from preclinical pharmacokinetic and tissue biodistribution studies using a radioactive folate-FITC conjugate and results from dose optimization studies done in tumor-bearing animals. Folate-FITC was found to be rapidly eliminated in non-immunized mice; however, in immunized hosts, folate-FITC was shown to form immune complexes with FITC-specific antibodies, the consequence of which was a approximately 173-fold increase in drug exposure (i.e., area under the curve). Using a newly developed ELISA assay, the extent of circulating anti-FITC antibodies occupied by parenterally given folate-FITC was determined to be proportional to the given dose. Furthermore, high doses of folate-FITC were found to promote the cosaturation of tumor cell surface folate receptors and circulating FITC-specific antibodies, blocking the immune recognition of tumor cells and thereby reducing antitumor activity. Nonetheless, by extending the duration of treatment and administering subsaturating doses of folate-FITC, enhanced antitumor response was observed in mice bearing established folate receptor-positive M109 tumors. Overall, results from the present study may help to guide clinicians through on-going clinical investigations of folate-targeted immunotherapy.
Activation of Serotonin 2C Receptors in Dopamine Neurons Inhibits Binge-like Eating in Mice (2016)

We identified the 5-HT<sub>2C</sub>R population in DA neurons as one potential target for antibinge therapies, and provided preclinical evidence that 5-HT<sub>2C</sub>R agonists could be used to treat binge eating.
Liposomes as vaccine delivery systems: a review of the recent advances (2014)

Liposomes and liposome-derived nanovesicles such as archaeosomes and virosomes have become important carrier systems in vaccine development and the interest for liposome-based vaccines has markedly increased. A key advantage of liposomes, archaeosomes and virosomes in general, and liposome-based vaccine delivery systems in particular, is their versatility and plasticity. Liposome composition and preparation can be chosen to achieve desired features such as selection of lipid, charge, size, size distribution, entrapment and location of antigens or adjuvants. Depending on the chemical properties, water-soluble antigens (proteins, peptides, nucleic acids, carbohydrates, haptens) are entrapped within the aqueous inner space of liposomes, whereas lipophilic compounds (lipopeptides, antigens, adjuvants, linker molecules) are intercalated into the lipid bilayer and antigens or adjuvants can be attached to the liposome surface either by adsorption or stable chemical linking. Coformulations containing different types of antigens or adjuvants can be combined with the parameters mentioned to tailor liposomal vaccines for individual applications. Special emphasis is given in this review to cationic adjuvant liposome vaccine formulations. Examples of vaccines made with CAF01, an adjuvant composed of the synthetic immune-stimulating mycobacterial cordfactor glycolipid trehalose dibehenate as immunomodulator and the cationic membrane forming molecule dimethyl dioctadecylammonium are presented. Other vaccines such as cationic liposome-DNA complexes (CLDCs) and other adjuvants like muramyl dipeptide, monophosphoryl lipid A and listeriolysin O are mentioned as well. The field of liposomes and liposome-based vaccines is vast. Therefore, this review concentrates on recent and relevant studies emphasizing current reports dealing with the most studied antigens and adjuvants, and pertinent examples of vaccines. Studies on liposome-based veterinary vaccines and experimental therapeutic cancer vaccines are also summarized.
Role for NLRP3 Inflammasome–mediated, IL-1β–Dependent Responses in Severe, Steroid-Resistant Asthma (2017)

NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.
Green Fluorescent Protein Functions as a Reporter for Protein Localization in Escherichia coli (2000)

The use of green fluorescent protein (GFP) as a reporter for protein localization in Escherichia coli was explored by creating gene fusions between malE (encoding maltose-binding protein [MBP]) and a variant of gfp optimized for fluorescence in bacteria (GFPuv). These constructs encode hybrid proteins composed of GFP fused to the carboxy-terminal end of MBP. Fluorescence was not detected when the hybrid protein was synthesized with the MBP signal sequence. In contrast, when the MBP signal sequence was deleted, fluorescence was observed. Cell fractionation studies showed that the fluorescent MBP-GFP hybrid protein was localized in the cytoplasm, whereas the nonfluorescent version was localized to the periplasmic space. Smaller MBP-GFP hybrid proteins, however, exhibited abnormal fractionation. Expression of the gene fusions in different sec mutants, as well as signal sequence processing assays, confirmed that the periplasmically localized hybrid proteins were exported by the sec-dependent pathway. The distinction between fluorescent and nonfluorescent colonies was exploited as a scorable phenotype to isolate malE signal sequence mutations. While expression of hybrid proteins comprised of full-length MBP did not result in overproduction lethality characteristic of some exported beta-galactosidase hybrid proteins, synthesis of shorter, exported hybrid proteins was toxic to the cells. Purification of MBP-GFP hybrid protein from the different cellular compartments indicated that GFP is improperly folded when localized outside of the cytoplasm. These results suggest that GFP could serve as a useful reporter for genetic analysis of bacterial protein export and of protein folding.
Sensitive blood-retinal barrier breakdown quantitation using Evans blue. (2001)

The Evans blue dye technique can be modified to be as sensitive and quantitative as the isotope-dilution method for measuring blood-retinal barrier breakdown. The advantages of the Evans blue technique are its safety, relative simplicity, and economy.
Betaine, A Potent Mediator of Metabolic Programming? (2015)

Metabolic programming is described as the long-lasting impacts that the antenatal environment exerts on the biological functions and health outcomes of an individual organism in later life. The potential role of betaine as a mediator of metabolic programming has garnered much more attention recently. Betaine, or trimethylglycine, is a bioactive product present in a variety of foods such as wheat, spinach, sugar beets and seafood. It can also be derived from the oxidation of choline, a semi-essential nutrient. Betaine serves as a major osmolyte and methyl donor in the body. To serve as a methyl donor, betaine donates one of its labile methyl groups to homocysteine, which remethylates homocysteine to methionine. After methionine is converted to the universal methyl donor S-adenosylmethionine, the betainederived methyl group is used for methylation reactions such as DNA and histone methylation [1]. DNA and histone methylating reactions are major epigenetic events, which produce heritable changes in gene expression without altering DNA sequence. As epigenetics is considered as the cornerstone mechanism by which prenatal nutrition exerts its lasting influence on offspring health, betaine is speculated to affect the process of metabolic programming by serving as an epigenetic modifier.