gebhart/patrepeval huggingface dataset:
Characterization of type II activin receptors. Binding, processing, and phosphorylation. (1993)

Activins bind to two classes of cell surface proteins, type I receptors of approximately 50-55 kDa and type II receptors of approximately 70-75 kDa. The two cloned type II activin receptors belong to a new subfamily of transmembrane protein serine kinases. Antibodies directed against each of these cloned receptors were generated and used in immunoprecipitation experiments to study the properties of the type II receptors in vivo. Precipitation of affinity-labeled receptors, formed by chemical cross-linking of 125I-activin A, resulted in coprecipitation of type I receptor complexes; denaturation of the lysates prior to interaction with the antibodies resulted in precipitation of only type II receptors. Treatment of both affinity-labeled and metabolically labeled receptors with peptide N-glycosidase F revealed the presence of N-linked carbohydrate chains. Metabolic labeling of cells with [32P]orthophosphate indicated that both type II receptors were phosphoproteins containing predominantly phosphoserine, with small amounts of phosphothreonine, but no detectable phosphotyrosine. Analysis of tryptic phosphopeptide maps of wild-type and kinase-defective mutants suggested that at least some of the phosphorylated sites arose from autophosphorylation.
ECOLOGICAL-NICHE FACTOR ANALYSIS: HOW TO COMPUTE HABITAT-SUITABILITY MAPS WITHOUT ABSENCE DATA? (2002)

We propose a multivariate approach to the study of geographic species distribution which does not require absence data. Building on Hutchinson's concept of the ecological niche, this factor analysis compares, in the multidimensional space of ecological variables, the distribution of the localities where the focal species was observed to a reference set describing the whole study area. The first factor extracted maximizes the marginality of the focal species, defined as the ecological distance between the species optimum and the mean habitat within the reference area. The other factors maximize the specialization of this focal species, defined as the ratio of the ecological variance in mean habitat to that observed for the focal species. Eigenvectors and eigenvalues are readily interpreted and can be used to build habitat-suitability maps. This approach is recommended in situations where absence data are not available (many data banks), unreliable (most cryptic or rare species), or meaningless (invaders). We provide an illustration and validation of the method for the alpine ibex, a species reintroduced in Switzerland which presumably has not yet recolonized its entire range.
Topiramate in Migraine Prevention (2004)

Topiramate, 100 or 200 mg/d, was effective as a preventive therapy for patients with migraine.
Is Relationship Between Serum Cholesterol and Risk of Premature Death From Coronary Heart Disease Continuous and Graded? (1986)

The 356 222 men aged 35 to 57 years, who were free of a history of hospitalization for myocardial infarction, screened by the Multiple Risk Factor Intervention Trial (MRFIT) in its recruitment effort, constitute the largest cohort with standardized serum cholesterol measurements and long-term mortality follow-up. For each five-year age group, the relationship between serum cholesterol and coronary heart disease (CHD) death rate was continuous, gradecf, and strong. For the entire group aged 35 to 57 years at entry, the age-adjusted risks of CHD death in cholesterol quintiles 2 through 5 (182 to 202, 203 to 220, 221 to 244, and ≥245 mg/dL [4.71 to 5.22, 5.25 to 5.69, 5.72 to 6.31, and ≥6.34 mmol/L]) relative to the lowest quintile were 1.29, 1.73, 2.21, and 3.42. Of all CHD deaths, 46% were estimated to be excess deaths attributable to serum cholesterol levels 180 mg/dL or greater (≥4.65 mmol/L), with almost half the excess deaths in serum cholesterol quintiles 2 through 4. The pattern of a continuous, graded, strong relationship between serum cholesterol and six-year age-adjusted CHD death rate prevailed for nonhypertensive nonsmokers, nonhypertensive smokers, hypertensive nonsmokers, and hypertensive smokers. These data of high precision show that the relationship between serum cholesterol and CHD is not a threshold one, with increased risk confined to the two highest quintiles, but rather is a continuously graded one that powerfully affects risk for the great majority of middle-aged American men. (<i>JAMA</i>1986;256:2823-2828)
Estrogen receptor beta--a new dimension in estrogen mechanism of action (1999)

The cloning of estrogen receptor (ER ) has provided the first example of a steroid hormone receptor existing as two isoforms, each of which is encoded by a separate gene (Kuiper et al. 1996). The finding of ER was met with great surprise, as the existence of more than one estrogen receptor had been actively denied for several decades. Attempts to clone a second estrogen receptor on the basis of sequence homology to the classical estrogen receptor (ER ) were not successful, although this approach did lead to the identification of two orphan receptors, namely estrogen receptor-related receptors (ERR) 1 and 2 (Giguere et al. 1988). However, none of these ER-related orphan receptors binds estrogens and it is still unclear whether they require specific ligands in order to be activated. ER seems to be a most important factor in the mechanism of action of estrogen, and it is expressed in many tissues, including the central nervous system, the cardiovascular system, the immune system, the urogenital tract, the gastrointestinal tract, the kidneys and the lungs (Arts et al. 1997, Enmark et al. 1997, Kuiper et al. 1997, 1998a, c, Lindner et al. 1998, O} sterlund et al. 1998). Although ER is also expressed in the mammary gland, it appears that ER is an important estrogen receptor in this particular tissue, and in the uterus also there seems to be much more ER present than ER (Fig. 1). This dominant role of ER in the uterus probably explains why it was the first cloned estrogen receptor, as most purification and cloning attempts were based on uterine tissue. As will be referred to below, it is now obvious that ER plays an important role in the physiology of several tissues, and it cannot be excluded that it is the more generally expressed estrogen receptor, whereas ER dominates in some few specific tissues and is mainly involved in reproductive events. Obviously, these differences in tissue distribution are of extreme importance from the pharmaceutical point of view, as hormone replacement therapy in postmenopausal women is such an increasingly significant health issue. Although the DNA-binding domains of ER and ER show a high degree of homology (only three amino acids differ), the ligand-binding domain shows only 59% homology (Fig. 2). Closer inspection indicates that it should be possible to develop ER and ER -specific ligands. In view of the facts presented above, it is not unreasonable to assume that it might be possible to develop ER -specific estrogen agonists targeting the central nervous system, the urogenital tract, the cardiovascular system and bone, but leaving the mammary gland and uterus relatively unaffected. In this way, much of the current controversy concerning estrogen treatment of postmenopausal women might be resolved (Barkhem et al. 1998, Gustafsson 1998a,b, Kuiper et al. 1998b, Nilsson et al. 1998).
High frequency of autosomal‐recessive DFNB59 hearing loss in an isolated Arab population in Israel (2011)

Autosomal-recessive non-syndromic hearing impairment (DFNB) is usually of prelingual onset with a moderate to profound degree of hearing loss. More than 70 DFNB loci have been mapped and ~40 causative genes have been identified. Non-syndromic hearing impairment caused by mutations of DFNB59 (encoding pejvakin) has been described in a couple of families in which affected individuals presented with either auditory neuropathy or hearing loss of cochlear origin. We have identified and clinically evaluated three consanguineous families of Israeli Arab origin with prelingual non-syndromic hearing impairment and absent otoacoustic emissions in a total of eight affected individuals. All the families originate from the same village and bear the same family name. We have identified a c.406C>T (p.R136X) nonsense mutation in the DFNB59 gene in affected individuals from these families. Among the inhabitants of the village, we found an exceptionally high carrier frequency of ~1 in 12 individuals (7/85; 8.2%). The high prevalence of hearing impairment can be explained by a founder effect and the high consanguinity rate among the inhabitants of this village.
Cutting Edge: IL-26 Signals through a Novel Receptor Complex Composed of IL-20 Receptor 1 and IL-10 Receptor 2 (2004)

The receptor for IL-26 (AK155), a cytokine of the IL-10 family, has not previously been defined. We demonstrate that the active receptor complex for IL-26 is a heterodimer composed of two receptor proteins: IL-20R1 and IL-10R2. Signaling through the IL-26R results in activation of STAT1 and STAT3 which can be blocked by neutralizing Abs against IL-20R1 or IL-10R2. IL-10R2 is broadly expressed on a wide variety of tissues, whereas only a limited number of tissues express IL-20R1. Therefore, the ability to respond to IL-26 is restricted by the expression of IL-20R1. IL-10, IL-19, IL-20, IL-22, and IL-24 fail to signal through the combination of IL-10R2 and IL-20R1 proteins, demonstrating that this receptor combination is unique and specific for IL-26.
In Vitro Cell Models for Ophthalmic Drug Development Applications (2016)

Tissue engineering is a rapidly expanding field that aims to establish feasible techniques to fabricate biologically equivalent replacements for diseased and damaged tissues/organs. Emerging from this prospect is the development of in vitro representations of organs for drug toxicity assessment. Due to the ever-increasing interest in ocular drug delivery as a route for administration as well as the rise of new ophthalmic therapeutics, there is a demand for physiologically accurate in vitro models of the eye to assess drug delivery and safety of new ocular medicines. This review summarizes current existing ocular models and highlights the important factors and limitations that need to be considered during their use.
Gr-1+CD115+ Immature Myeloid Suppressor Cells Mediate the Development of Tumor-Induced T Regulatory Cells and T-Cell Anergy in Tumor-Bearing Host (2006)

The accumulation of myeloid suppressor cells (MSCs) is associated with immune suppression in tumor-bearing mice and in cancer patients. The suppressive activity of MSC correlates with the expression of the myeloid markers Gr-1, CD115 (macrophage colony-stimulating factor receptor), and F4/80. Gr-1(+)CD115(+) MSCs, in addition to being able to suppress T-cell proliferation in vitro, can induce the development of Foxp3(+) T regulatory cells (Treg) in vivo, which are anergic and suppressive. Furthermore, the secretion of interleukin (IL)-10 and transforming growth factor-beta by Gr-1(+)CD115(+) MSCs was induced and enhanced, respectively, on IFN-gamma stimulation. The development of Treg requires antigen-associated activation of tumor-specific T cells, depends on the presence of IFN-gamma and IL-10, and is independent of the nitric oxide-mediated suppressive mechanism by MSC. Our data provide evidence that Gr-1(+)CD115(+) MSC can mediate the development of Treg in tumor-bearing mice and show a novel immune suppressive mechanism by which MSCs can suppress antitumor responses.
Identification of the sequence on NS4A required for enhanced cleavage of the NS5A/5B site by hepatitis C virus NS3 protease (1996)

In addition to NS3 protease, the NS4A protein is required for efficient cleavage of the nonstructural protein region of the hepatitis C virus polyprotein. To investigate the function and the sequence of NS4A required for the enhancement of NS3 protease activity, we developed an in vitro NS3 protease assay system consisting of three purified viral elements: (i) a recombinant NS3 protease which was expressed in Escherichia coli as a maltose-binding protein-NS3 fusion protein (MBP-NS3), (ii) synthetic NS4A fragments, and (iii) a synthetic peptide substrate which mimics the NS5A/5B junction. We showed that the NS3 protease activity of MBP-NS3 was enhanced in a dose-dependent manner by 4A18-40, which is a peptide composed of amino acid residues 18 to 40 of NS4A. The optimal activity was observed at a 10-fold molar excess of 4A18-40 over MBP-NS3. The coefficient for proteolytic efficiency, kcat/Km, of NS3 protease was increased by about 40 times by the addition of a 10-fold molar excess of 4A18-40. Using a series of truncations of 4A18-40, we estimated that amino acid residues 22 to 31 in NS4A (SVVIVGRIIL) constituted the core sequence for the effector activity. Single-substitution experiments with 4A21-34, a peptide composed of amino acid residues 21 to 34 of NS4A, suggested the importance of several residues (Val-23, Ile-25, Gly-27, Arg-28, Ile-29, and Leu-31) for its activity. In addition, we found that some single-amino-acid substitutions in 4A21-34 were able to inhibit the enhancement of NS3 protease activity by 4A18-40. This approach has potential as a novel strategy for inhibiting the NS3 protease activity important for hepatitis C virus proliferation.
Systemic AAV9 gene therapy improves the lifespan of mice with Niemann-Pick disease, type C1 (2016)

Niemann-Pick disease, type C1 (NPC1) is a heritable lysosomal storage disease characterized by a progressive neurological degeneration that causes disability and premature death. A murine model of NPC1 disease (Npc1-/-) displays a rapidly progressing form of NPC1 disease which is characterized by weight loss, ataxia, increased cholesterol storage, loss of cerebellar Purkinje neurons and early lethality. To test the potential efficacy of gene therapy for NPC1, we constructed adeno-associated virus serotype 9 (AAV9) vectors to deliver the NPC1 gene under the transcriptional control of the neuronal-specific (CamKII) or a ubiquitous (EF1a) promoter. The Npc1-/- mice that received a single dose of AAV9-CamKII-NPC1 as neonates (2.6 × 1011GC) or at weaning (1.3 × 1012GC), and the mice that received a single dose of AAV9-EF1a-NPC1 at weaning (1.2 × 1012GC), exhibited an increased life span, characterized by delayed weight loss and diminished motor decline. Cholesterol storage and Purkinje neuron loss were also reduced in the central nervous system of AAV9 treated Npc1-/- mice. Treatment with AAV9-EF1a-NPC1, as compared to AAV9-CamKII-NPC1, resulted in significantly increased survival (mean survival increased from 69 days to 166 and 97 days, respectively) and growth, and reduced hepatic-cholesterol accumulation. Our results provide the first demonstration that gene therapy may represent a therapeutic option for NPC1 patients and suggest that extraneuronal NPC1 expression can further augment the lifespan of the Npc1-/- mice after systemic AAV gene delivery.
Desmin sequence elements regulating skeletal muscle-specific expression in transgenic mice (1993)

During the development of the mouse embryo, desmin is one of the first muscle proteins detected in both the heart and the somites. The expression of the desmin gene differs from most other muscle genes, since it is initiated in replicating myoblasts and accumulates as the muscle differentiates. We have characterized a muscle-specific enhancer which directs the expression of desmin in vitro in the myoblasts and myotubes of C2 cells but not in non-myogenic cells. We report here on the generation and characterization of transgenic mice bearing a transgene in which the 1 kb DNA 5' regulatory sequence of the desmin gene is linked to a reporter gene coding for Escherichia coli beta-galactosidase (Des1-nlacZ). The enhancer activity of the desmin promoter is very strong and the reporter gene expression is easily detected in tissue sections. We have demonstrated that the regulatory elements present in the transgene Des1-nlacZ are sufficient to direct muscle-specific and developmentally regulated expression of nlacZ in skeletal muscles. Endogenous desmin expression and transgene activity were found to be correlated during the development of skeletal muscles. The transgene was expressed in the committed mononucleate myoblasts as well as in the myotubes. In addition, we have shown that the desmin-derived sequences direct a highly selective expression of nlacZ in cells that leave the somites and invade the limb bud, indicating that the cells that migrate from the somites are already predetermined for myogenesis. In contrast, smooth and cardiac muscle cells were beta-galactosidase negative both during embryonic and foetal development. Interestingly, the transgene was found to be expressed in the conduction system of the heart, which exhibits many features characteristic of skeletal muscles.
VARICELLA-ZOSTER VIRUS LATENCY (1991)

Human coronavirus (HCoV) infection causes respiratory diseases with mild to severe outcomes. In the last 15 years, we have witnessed the emergence of two zoonotic, highly pathogenic HCoVs: severe acute respiratory syndrome coronavirus (SARS-CoV) and ...Read More
Ascaris suum-Derived Products Suppress Mucosal Allergic Inflammation in an Interleukin-10-Independent Manner via Interference with Dendritic Cell Function (2006)

We have previously demonstrated that protection from allergic inflammation by Ascaris suum infection was characterized by a global increase in interleukin-10 (IL-10) and the development of protective CD4(+)/CD25(+) T cells (L. Schopf, S. Luccioli, V. Bundoc, P. Justice, C. C. Chan, B. J. Wetzel, H. H. Norris, J. F. Urban, Jr., and A. Keane-Myers, Investig. Ophthalmol. Vis. Sci. 46:2772-2780, 2005). Here, we used A. suum pseudocoelomic fluid (PCF) in lieu of infection to define molecular mechanisms of allergic protection in a mouse model of allergic inflammation. Mice were sensitized with ragweed (RW) and PCF (RW/PCF), PCF alone, or RW alone and then challenged intratracheally, intranasally, and supraocularly with RW. Histological examination of the eyes and lungs, analysis of the bronchoalveolar lavage fluid (BALF), and characterization of ex vivo cytokine responses were performed to determine allergic inflammatory responses. RW/PCF-treated mice had suppressed allergic immune responses compared to mice given RW alone. To investigate whether IL-10 was involved in PCF-mediated allergic protection, similar experiments were performed using mice genetically deficient for IL-10. Persistent protection from allergic disease was observed in the absence of IL-10, indicating the primary mechanism of PCF protection is IL-10 independent. Ex vivo and in vitro analysis of PCF-treated dendritic cells (DC) demonstrated reduced activation receptor expression and cytokine production in response to either RW or lipopolysaccharide stimulation. These findings extend previous studies that showed infection with A. suum alters expression of allergic disease and suggest that PCF can contribute to this effect by interference with DC function.
Pattern classification using neural networks (1989)

The author extends a previous review and focuses on feed-forward neural-net classifiers for static patterns with continuous-valued inputs. He provides a taxonomy of neural-net classifiers, examining probabilistic, hyperplane, kernel, and exemplar classifiers. He then discusses back-propagation and decision-tree classifiers; matching classifier complexity to training data; GMDH (generalized method of data handling) networks and high-order nets; K nearest-neighbor classifiers; the feature-map classifier; the learning vector quantizer; hypersphere classifiers; and radial-basis function classifiers.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Cellular Dynamics of Antisense Oligonucleotides and Short Interfering RNAs (2006)

We aim to compare quantitatively the dynamics of the effectiveness of antisense oligonucleotides (AS ODNs) versus short interfering RNAs (siRNAs) and relate their effectiveness to sequence metrics (e.g., predicted free energy of binding). AS ODNs against a quantitative model target, pd1EGFP (destabilized enhanced GFP [green fluorescent protein]), were selected using our thermodynamic model, and siRNA sequences were designed to be identical to the AS ODN sequences in the antisense strand. We evaluated d1EGFP inhibition in transiently and stably transfected Chinese hamster ovary (CHO) cells over time using flow cytometry. Overall, our results show that the rationally designed AS ODN and siRNA sequences proved effective inhibitors of GFP expression and suggest that certain regions of mRNA may be susceptible to both AS ODNs and siRNAs.
Recombinant anti‐hCG antibodies retained in the endoplasmic reticulum of transformed plants lack core‐xylose and core‐α(1,3)‐fucose residues (2004)

Plant-based expression systems are attractive for the large-scale production of pharmaceutical proteins. However, glycoproteins require particular attention as inherent differences in the N-glycosylation pathways of plants and mammals result in the production of glycoproteins bearing core-xylose and core-alpha(1,3)-fucose glyco-epitopes. For treatments requiring large quantities of repeatedly administered glycoproteins, the immunological properties of these non-mammalian glycans are a concern. Recombinant glycoproteins could be retained within the endoplasmic reticulum (ER) to prevent such glycan modifications occurring in the late Golgi compartment. Therefore, we analysed cPIPP, a mouse/human chimeric IgG1 antibody binding to the beta-subunit of human chorionic gonadotropin (hCG), fused to a C-terminal KDEL sequence, to investigate the efficiency of ER retrieval and the consequences in terms of N-glycosylation. The KDEL-tagged cPIPP antibody was expressed in transgenic tobacco plants or Agrobacterium-infiltrated tobacco and winter cherry leaves. N-Glycan analysis showed that the resulting plantibodies contained only high-mannose (Man)-type Man-6 to Man-9 oligosaccharides. In contrast, the cPIPP antibody lacking the KDEL sequence was found to carry complex N-glycans containing core-xylose and core-alpha(1,3)-fucose, thereby demonstrating the secretion competence of the antibody. Furthermore, fusion of KDEL to the diabody derivative of PIPP, which contains an N-glycosylation site within the heavy chain variable domain, also resulted in a molecule lacking complex glycans. The complete absence of xylose and fucose residues clearly shows that the KDEL-mediated ER retrieval of cPIPP or its diabody derivative is efficient in preventing the formation of non-mammalian complex oligosaccharides.
A smart pill for drug delivery with sensing capabilities (2015)

In this paper a novel system for local drug delivery is described. The actuation principle of the micropump used for drug delivery relies on the electrolysis of a water-based solution, which is separated from a drug reservoir by an elastic membrane. The electrolytically produced gases pressurize the electrolytic solution reservoir, causing the deflection of the elastic membrane. Such deflection, in turn, forces the drug out of its reservoir through a nozzle. The proposed system is integrated in a swallowable capsule, equipped with an impedance sensor useful to acquire information on the physiological conditions of the tissue. Such information can be used to control pump activation.