gebhart/patrepeval huggingface dataset:
Pharmacokinetics of Peginterferons (2003)

Two polyethylene glycol (PEG)-modified interferons are approved for the treatment of chronic hepatitis C. The pharmocokinetic properties of the branched 40 kDa pegylated interferon alfa-2a differ from the linear 12 kDa pegylated interferon alfa-2b. The absorption half-life of standard interferon alfa is 2.3 hours, while absorption half-lives for peginterferon alfa-2a and alfa-2b are 50 hours and 4.6 hours, respectively. The volume of distribution for peginterferon alfa-2a is considerably restricted, while the volume of distribution for peginterferon alfa-2b is only approximately 30% lower than that for conventional interferon. Because of its large size, the 40 kD peginterferon alfa-2a has a more than 100-fold reduction in renal clearance compared with conventional interferon alfa. Clearance of peginterferon alfa-2b is about one-tenth that of unmodified interferon alfa. Although data are limited, both drugs appear to show differences in the initial viral decay pattern in patients with chronic hepatitis C. However, it remains unknown whether these differences in the initial viral decline predict differences in the primary clinical endpoint, sustained virological response.
Human Ovarian Reserve from Conception to the Menopause (2010)

The human ovary contains a fixed number of non-growing follicles (NGFs) established before birth that decline with increasing age culminating in the menopause at 50-51 years. The objective of this study is to model the age-related population of NGFs in the human ovary from conception to menopause. Data were taken from eight separate quantitative histological studies (n = 325) in which NGF populations at known ages from seven weeks post conception to 51 years (median 32 years) were calculated. The data set was fitted to 20 peak function models, with the results ranked by obtained r2 correlation coefficient. The highest ranked model was chosen. Our model matches the log-adjusted NGF population from conception to menopause to a five-parameter asymmetric double Gaussian cumulative (ADC) curve (r2 = 0.81). When restricted to ages up to 25 years, the ADC curve has r2 = 0.95. We estimate that for 95% of women by the age of 30 years only 12% of their maximum pre-birth NGF population is present and by the age of 40 years only 3% remains. Furthermore, we found that the rate of NGF recruitment towards maturation for most women increases from birth until approximately age 14 years then decreases towards the menopause. To our knowledge, this is the first model of ovarian reserve from conception to menopause. This model allows us to estimate the number of NGFs present in the ovary at any given age, suggests that 81% of the variance in NGF populations is due to age alone, and shows for the first time, to our knowledge, that the rate of NGF recruitment increases from birth to age 14 years then declines with age until menopause. An increased understanding of the dynamics of human ovarian reserve will provide a more scientific basis for fertility counselling for both healthy women and those who have survived gonadotoxic cancer treatments.
DNA sensor: A novel electrochemical gene detection method using carbon electrode immobilized DNA probes (1993)

Abstract The authors have developed a novel, rapid, convenient, and specific gene detection method, named the 'DNA sensor,' using a graphite electrode loaded with DNA probes. Synthesized oligonucleotide (5-TGCAGTTCCGGTGGCTGATC-3′) complementary to oncogene v-myc was employed for a model probe. The oligonucleotide was chemically adsorbed on a basal plane pyrolytic graphite (BPPG) electrode. The sensor was able to be applied to a hybridization reaction (40°C) in a linearized pVM623 solution carrying the Pst I fragment of v-myc (1.5 kbp). After the hybridization reaction, the sensor was immersed into an acridine orange solution (1 μM) and washed with a phosphate buffer (pH 7.0). Acridine orange intercalated between base pairs of the formed double stranded DNAs on the electrode. The anodic peak potential of acridine orange that interacted with the DNAs on the electrode was measured. The positive shift of the peak potential increased in proportional to the pVM623 concentration in the hybridization reaction. 10−1 g/ml of pVM623 was able to be detected in the buffer solution using the sensor. This gene detection was completed within an hour.
Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma (2011)

Bevacizumab, an antibody against vascular endothelial growth factor (VEGF), is a promising, yet controversial, drug in human glioblastoma treatment (GBM). Its effects on tumor burden, recurrence, and vascular physiology are unclear. We therefore determined the tumor response to bevacizumab at the phenotypic, physiological, and molecular level in a clinically relevant intracranial GBM xenograft model derived from patient tumor spheroids. Using anatomical and physiological magnetic resonance imaging (MRI), we show that bevacizumab causes a strong decrease in contrast enhancement while having only a marginal effect on tumor growth. Interestingly, dynamic contrast-enhanced MRI revealed a significant reduction of the vascular supply, as evidenced by a decrease in intratumoral blood flow and volume and, at the morphological level, by a strong reduction of large- and medium-sized blood vessels. Electron microscopy revealed fewer mitochondria in the treated tumor cells. Importantly, this was accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma. At the molecular level we observed an increase in lactate and alanine metabolites, together with an induction of hypoxia-inducible factor 1α and an activation of the phosphatidyl-inositol-3-kinase pathway. These data strongly suggest that vascular remodeling induced by anti-VEGF treatment leads to a more hypoxic tumor microenvironment. This favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain. The present work underlines the need to combine anti-angiogenic treatment in GBMs with drugs targeting specific signaling or metabolic pathways linked to the glycolytic phenotype.
In Vivo Antiviral Properties of Biologically Active Compounds (1968)

The in vivo anti-influenza virus and antivaccinia virus activity of 156 biologically active compounds was determined. One of two criteria was used for evaluating activity against the influenza virus. The criteria were increase in survivor number and mean survival time, and reduction in virus-induced lung consolidation in treated, infected Swiss mice. Increase in survivor number and mean survival time were the criteria for evaluation of antivaccinia virus activity. Several drug doses were tested against two virus concentrations to demonstrate antiviral activity more clearly. Two compounds were considered significantly active against the influenza virus: DL-noformicin (NSC 72942) and amantadine hydrochloride (NSC 83653). Eleven compounds had reproducible activity against vaccinia virus: isatin-beta-thiosemicarbazone (NSC 721), 6-azauracil (NSC 3425), 9-alpha-fluoro-2alpha-methylhydrocortisone 21-acetate (NSC 12601), 5-[bis(2-chloroethyl)amino]uracil (NSC 34462), 5-iodo-2'-deoxyuridine (NSC 39661), streptonigrin (NSC 45383), N-methylisatin beta-thiosemicarbazone (NSC 69811), cytovirin (NSC 91770), 9-beta-D-arabinofuranosyladenine (NSC 404241), and 5-(mercaptomethyl)uracil (NSC 529351).
Scale for suicide ideation: Psychometric properties of a self-report version (1988)

A self-report version of the Scale for Suicide Ideation (SSI) was administered to 50 inpatients diagnosed with mixed DSM-III psychiatric disorders and 55 outpatients with affective disorders. The self-report SSI was written for both paper-and-pencil and computer administration. The correlations between the self-reported and clinically rated versions for both inpatients and outpatients were greater than .90, which suggests strong concurrent validity. The Cronbach coefficient alphas for the paper-and-pencil and computer versions were also in the .90s and indicated high internal consistency. Furthermore, the mean SSI scores of the computer version for both the inpatients and outpatients were higher than the mean SSI scores of the clinical ratings; the patients described more severe suicide ideation than clinicians reported.
Potent Kinetic Stabilizers That Prevent Transthyretin-Mediated Cardiomyocyte Proteotoxicity (2011)

A valine-to-isoleucine mutation at position 122 of the serum protein transthyretin (TTR), found in 3 to 4% of African Americans, alters its stability, leading to amyloidogenesis and cardiomyopathy. In addition, 10 to 15% of individuals older than 65 years develop senile systemic amyloidosis and cardiac TTR deposits because of wild-type TTR amyloidogenesis. Although several drugs are in development, no approved therapies for TTR amyloid cardiomyopathy are yet available, so the identification of additional compounds that prevent amyloid-mediated cardiotoxicity is needed. To this aim, we developed a fluorescence polarization-based high-throughput screen and used it to identify several new chemical scaffolds that target TTR. These compounds were potent kinetic stabilizers of TTR and prevented TTR tetramer dissociation, partial unfolding, and aggregation of both wild type and the most common cardiomyopathy-associated TTR mutant, V122I-TTR. High-resolution co-crystal structures and characterization of the binding energetics revealed how these diverse structures bound to tetrameric TTR. These compounds effectively inhibited the proteotoxicity of V122I-TTR toward human cardiomyocytes. Several of these ligands stabilized TTR in human serum more effectively than diflunisal, which is a well-studied inhibitor of TTR aggregation, and may be promising leads for the treatment or prevention of TTR-mediated cardiomyopathy.
HLA‐E/β2 microglobulin overexpression in colorectal cancer is associated with recruitment of inhibitory immune cells and tumor progression (2011)

The host immune response plays a major role in colorectal carcinoma (CRC) progression. A mechanism of tumor immune escape might involve expression of the human leucocyte antigen (HLA)-E/β2m on tumor cells. The inhibitory effect of HLA-E/β2m on CD8+ cytotoxic T lymphocytes and natural killer (NK) cells is mediated by the main HLA-E receptor CD94/NKG2A. As the pathophysiological relevance of this mechanism in CRC remains unknown, this prompted us to examine, in situ, in a series of 80 CRC (i) the HLA-E and β2m coexpression by tumor cells, (ii) the density of CD8+, cytotoxic, CD244+ and NKP46+ intraepithelial tumor-infiltrating lymphocyte (IEL-TIL) and (iii) the expression of CD94/NKG2 receptor on IEL-TIL. These data were then correlated to patient survival. We provided (i) the in situ demonstration of HLA-E/β2m overexpression by tumor cells in 21% of CRC characterized by an overrepresentation of signet ring cell carcinomas, mucinous carcinomas and medullary carcinomas, (ii) the significant association between HLA-E/β2m overexpression by tumor cells and increased density of CD8+ cytotoxic, CD244+ and CD94+ IEL-TIL and (iii) finally, the unfavorable prognosis associated with HLA-E/β2m overexpression by tumor cells. Our findings show that HLA-E/β2m overexpression is a surrogate marker of poor prognosis and point to a novel mechanism of tumor immune escape in CRC in restraining inhibitory IEL-TIL.
An obstacle avoidance algorithm for hyper-redundant manipulators (2002)

Novel kinematic algorithms for implementing planar hyperredundant manipulator obstacle avoidance is presented. Unlike artificial potential field methods, the method outlined is strictly geometric. Tunnels are defined in a workspace in which obstacles are presented. Methods of differential geometry are then used to formulate equations which guarantee that sections of the manipulator are confined to the tunnels and therefore avoid the obstacles. A general formulation is given with examples to illustrate this approach.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Lignans from the Roots ofUrtica dioicaand their Metabolites Bind to Human Sex Hormone Binding Globulin (SHBG) (1997)

Polar extracts of the stinging nettle (Urtica dioica L.) roots contain the ligans (+)-neoolivil, (-)-secoisolariciresinol, dehydrodiconiferyl alcohol, isolariciresinol, pinoresinol, and 3,4-divanillyltetrahydrofuran. These compounds were either isolated from Urtica roots, or obtained semisynthetically. Their affinity to human sex hormone binding globulin (SHBG) was tested in an in vitro assay. In addition, the main intestinal transformation products of plant lignans in humans, enterodiol and enterolactone, together with enterofuran were checked for their activity. All lignans except (-)-pinoresinol developed a binding affinity to SHBG in the in vitro assay. The affinity of (-)-3,4-divanillyltetrahydrofuran was outstandingly high. These findings are discussed with respect to potential beneficial effects of plant lignans on benign prostatic hyperplasia (BPH).
Tyrosylprotein sulfotransferase: Purification and molecular cloning of an enzyme that catalyzes tyrosine O -sulfation, a common posttranslational modification of eukaryotic proteins (1998)

Tyrosine O-sulfation is a common posttranslational modification of proteins in all multicellular organisms. This reaction is mediated by a Golgi enzyme activity called tyrosylprotein sulfotransferase (TPST) that catalyzes the transfer of sulfate from 3'-phosphoadenosine 5'-phosphosulfate to tyrosine residues within acidic motifs of polypeptides. Tyrosine O-sulfation has been shown to be important in protein-protein interactions in several systems. For example, sulfation of tyrosine residues in the leukocyte adhesion molecule P-selectin glycoprotein ligand 1 (PSGL-1) is required for binding to P-selectin on activated endothelium. In this report we describe the purification of TPST from rat liver microsomes based on its affinity for the N-terminal 15 amino acids of PSGL-1. We have isolated human and mouse TPST cDNAs that predict type II transmembrane proteins of 370 amino acid residues with almost identical primary structure. The human cDNA encodes a fully functional N-glycosylated enzyme with an apparent molecular mass of approximately 54 kDa when expressed in mammalian cells. This enzyme defines a new class of Golgi sulfotransferases that may catalyze tyrosine O-sulfation of PSGL-1 and other protein substrates involved in diverse physiologic functions including inflammation and hemostasis.
HpaB from Xanthomonas campestris pv. vesicatoria acts as an exit control protein in type III‐dependent protein secretion (2004)

The hrp (hypersensitive response and pathogenicity) gene cluster of the plant pathogenic bacterium Xanthomonas campestris pv. vesicatoria encodes a type III secretion (TTS) system, which injects bacterial effector proteins into the plant cell. Here, we characterized hpaB (hpa, hrp-associated), which encodes a pathogenicity factor with typical features of a TTS chaperone. We show that HpaB is important for the efficient secretion of at least five effector proteins but is dispensable for the secretion of non-effectors such as XopA and the TTS translocon protein HrpF. GST pull-down assays revealed that HpaB interacts with two unrelated effector proteins, AvrBs1 and AvrBs3, but not with XopA. The HpaB-binding site is located within the first 50 amino acids of AvrBs3. This region also contains the targeting signal for HpaB-dependent secretion, which is missing in HrpF and XopA. Intriguingly, the N-termini of HrpF and XopA target the AvrBs3Delta2 reporter for translocation in a DeltahpaB mutant but not in the wild-type strain. This indicates that HpaB plays an essential role in the exit control of the TTS system. Our data suggest that HpaB promotes the secretion of a large set of effector proteins and prevents the delivery of non-effectors into the plant cell.
Spread and survival of promiscuous IncP-1 plasmids. (2003)

Plasmids classified to the IncP-1 incompatibility group belong to the most stably maintained mobile elements among low copy number plasmids known to date. The remarkable persistence is achieved by various tightly controlled stability mechanisms like active partitioning, efficient conjugative transfer system, killing of plasmid-free segregants and multimer resolution. The unique feature of IncP-1 plasmids is the central control operon coding for global regulators which control the expression of genes involved in vegetative replication, stable maintenance and conjugative transfer. The multivalent regulatory network provides means for coordinated expression of all plasmid functions. The current state of knowledge about two fully sequenced plasmids RK2 and R751, representatives of the IncP-1alpha and IncP-1beta subgroups, is presented.
Fast relocalization for visual odometry using binary features (2013)

State-of-the-art visual odometry algorithms achieve remarkable efficiency and accuracy. Under realistic conditions, however, tracking failures are inevitable and to continue tracking, a recovery strategy is required. In this paper, we propose a relocalization system that enables realtime, 6D pose recovery for wide baselines. Our approach targets specifically resource-constrained hardware such as mobile phones. By exploiting the properties of low-complexity binary feature descriptors, nearest-neighbor search is performed efficiently using Locality Sensitive Hashing. Our method does not require time-consuming offline training of hash tables and it can be applied to any visual odometry system. We provide a thorough evaluation of effectiveness, robustness and runtime on an indoor test sequence with available ground truth poses. We investigate the system parameterization and compare the relocalization performance for the three binary descriptors BRIEF, unscaled BRIEF and ORB. In contrast to previous work on mobile visual odometry, we are able to quickly recover from tracking failures within maps with thousands of 3D feature points.
Cloning of three human multifunctional de novo purine biosynthetic genes by functional complementation of yeast mutations. (1990)

Functional complementation of mutations in the yeast Saccharomyces cerevisiae has been used to clone three multifunctional human genes involved in de novo purine biosynthesis. A HepG2 cDNA library constructed in a yeast expression vector was used to transform yeast strains with mutations in adenine biosynthetic genes. Clones were isolated that complement mutations in the yeast ADE2, ADE3, and ADE8 genes. The cDNA that complemented the ade8 (phosphoribosylglycinamide formyltransferase, GART) mutation, also complemented the ade5 (phosphoribosylglycinamide synthetase) and ade7 [phosphoribosylaminoimidazole synthetase (AIRS; also known as PAIS)] mutations, indicating that it is the human trifunctional GART gene. Supporting data include homology between the AIRS and GART domains of this gene and the published sequence of these domains from other organisms, and localization of the cloned gene to human chromosome 21, where the GART gene has been shown to map. The cDNA that complemented ade2 (phosphoribosylaminoimidazole carboxylase) also complemented ade1 (phosphoribosylaminoimidazole succinocarboxamide synthetase), supporting earlier data suggesting that in some organisms these functions are part of a bifunctional protein. The cDNA that complemented ade3 (formyltetrahydrofolate synthetase) is different from the recently isolated human cDNA encoding this enzyme and instead appears to encode a related mitochondrial enzyme.
Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data (2009)

The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.
Monoclonal antibodies to von Willebrand's factor: reactivity with porcine and human antigens (1981)

Monoclonal antibodies to porcine von Willebrand's factor (vWf) were obtained from hybridomas derived from the fusion of NS-1 plasmacytoma cells and spleen cells from immunized BALB/c mice. Twenty hybrids were positive in a radioimmunoassay based on the ability of immobilized hybridoma antibodies to bind porcine vWf as detected by the subsequent binding of 125I-polyclonal rabbit anti-vWf. Growth of the hybridomas as ascitic tumors yielded fluids having titers in this assay ranging from 8 x 10(7) to 8 x 10(11). All the antibodies were positive when normal, but not von Willebrand's, plasma was used as the source fo antigen in this RIA, and when normal, but not von Willebrand's, acetone-fixed platelets were used in an indirect immunofluorescence assay. Two of these antibodies inhibited both ristocetin-induced platelet aggregation and platelet aggregating factor. In a second radioimmunoassay, only 13 were of the 20 antibodies were reactive with human vWf, and two of these would not react with human antigen in the presence of 2M Nacl. Bases on these assays, six reactivity groups of antibodies could be identified.
Aberrant human tissue kallikrein levels in the stratum corneum and serum of patients with psoriasis: dependence on phenotype, severity and therapy (2007)

We found aberrant KLK levels in the SC and serum of patients with psoriasis and suggest that KLKs might be involved in the pathogenesis of this disease.
T‐cell exhaustion: characteristics, causes and conversion (2010)

T-cell exhaustion is characterized by the stepwise and progressive loss of T-cell functions and can culminate in the physical deletion of the responding cells. Exhaustion is well-defined during chronic lymphocytic choriomeningitis virus infection and commonly develops under conditions of antigen-persistence, which occur following many chronic infections that are of significant public health concern including hepatitis B virus, hepatitis C virus and human immunodeficiency virus infections, as well as during tumour outgrowth. Exhaustion is not a uniformly disabled setting as a gradation of phenotypic and functional defects can manifest, and these cells are distinct from prototypic effector, memory and also anergic T cells. We are gaining insights into the extrinsic and intrinsic factors that determine the severity of exhaustion. These include the duration and magnitude of antigenic activation, availability of CD4 T-cell help, the levels of stimulatory and suppressive cytokines, as well as the expression of activatory and inhibitory receptors. More information is now becoming available regarding the molecular mechanisms that attenuate the responsiveness of exhausted T cells. As the parameters that dictate exhaustion are more thoroughly defined, this is fostering the development of methods that prevent and rejuvenate functionally inferior responses. In this article we discuss our current understanding of the properties of exhausted T cells and the mechanisms that promote and maintain this state.
Discovery and Structure−Activity Relationships of Piperidinone- and Piperidine-Constrained Phenethylamines as Novel, Potent, and Selective Dipeptidyl Peptidase IV Inhibitors (2007)

Dipeptidyl peptidase IV (DPP4) inhibitors are emerging as a new class of therapeutic agents for the treatment of type 2 diabetes. They exert their beneficial effects by increasing the levels of active glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are two important incretins for glucose homeostasis. Starting from a high-throughput screening hit, we were able to identify a series of piperidinone- and piperidine-constrained phenethylamines as novel DPP4 inhibitors. Optimized compounds are potent, selective, and have good pharmacokinetic profiles.