gebhart/patrepeval huggingface dataset:
The transcription factor E2F1 promotes dopamine‐evoked neuronal apoptosis by a mechanism independent of transcriptional activation (2001)

The E2F1 transcription factor plays an important role in promoting neuronal apoptosis; however, it is not clear how E2F1 does this. Here we show that E2F1 is involved in dopamine (DA)-evoked apoptosis in cerebellar granule neurons (CGNs). E2F1 -/- CGNs and CGNs expressing an antisense E2F1 cDNA were significantly protected from DA-toxicity relative to controls. The neuronal protection was accompanied by significantly reduced caspase 3 activity. E2F1-mediated neuronal apoptosis did not require activation of gene transcription because: (1) ectopic expression of E2F1 or its mutants lacking the transactivation domain induced neuronal apoptosis, whereas an E2F1 mutant lacking the DNA-binding domain did not; (2) under all of these conditions, known E2F1 target genes including cyclin A, cdc2 and p19(ARF) were not induced; and (3) DA-evoked neuronal apoptosis was associated with up-regulated E2F1, but not transcription of its target genes. Finally, E2F1-mediated neuronal apoptosis was associated with reduced nuclear factor (NF)-kappaB DNA-binding activity. Taken together, these data suggest that E2F1 promotes DA-evoked caspase 3-dependent neuronal apoptosis by a mechanism independent of gene transactivation, and this may possibly occur through inhibition of anti-apoptotic genes including NF-kappaB.
Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ (2004)

Recent progress in the field of energy homeostasis was triggered by the discovery of adipocyte hormone leptin and revealed a complex regulatory neuroendocrine network. A late addition is the novel stomach hormone ghrelin, which is an endogenous agonist at the growth hormone secretagogne receptor and is the motilin-related family of regulatory peptides. In addition to its ability to stimulate GH secretion and gastric motility, ghrelin stimulates appetite and induces a positive energy balance leading to body weight gain. Leptin and ghrelin are complementary, yet antagonistic, signals reflecting acute and chronic changes in energy balance, the effects of which are mediated by hypothalamic neuropeptides such as neuropeptide Y and agouti-related peptide. Endocrine and vagal afferent pathways are involved in these actions of ghrelin and leptin. Ghrelin is a novel neuroendocrine signal possessing a wide spectrum of biological activities that illustrates the importance of the stomach in providing input into the brain. Defective ghrelin signaling from the stomach could contribute to abnormalities in energy balance, growth, and associated gastrointestinal and neuroendocrine functions.
Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or Leber congenital amaurosis (1998)

RPE65 is a protein of unknown function expressed specifically by the retinal pigment epithelium. We examined all 14 exons of this gene in 147 unrelated patients with autosomal recessive retinitis pigmentosa (RP), in 15 patients with isolate RP, and in 45 patients with Leber congenital amaurosis (LCA). Sequence anomalies that were likely to be pathogenic were found in two patients with recessive RP, in one patient with isolate RP recategorized as recessive, and in seven patients with LCA. Cosegregation analysis in each available family showed that all affected individuals were either homozygotes or compound heterozygotes and that all unaffected individuals were either heterozygote carriers or homozygous wild type. In one family, there was one instance of a new mutation not present in either parent of the affected individual. In another family, affected members with recessive RP in three branches (i.e., three distinct pairs of parents) were compound heterozygotes for the same two mutations or homozygous for one of them. Based on our results, mutations in the RPE65 gene appear to account for approximately 2% of cases of recessive RP and approximately 16% of cases of LCA.
Red Brick Vista/sup TM/: aggregate computation and management (2002)

Aggregate query processing in large data warehouses is computationally intensive. Precomputation is an approach that can be used to speed up aggregate queries. However, in order to make precomputation a truly viable solution to the aggregate query processing problem, it is important to identify the best set of aggregates to precompute and to use these precomputed aggregates effectively. The Red Brick aggregate computation and management system (Red Brick Vista) provides a complete server integrated solution to these problems.
Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior (2012)

Fifty years ago, increased whole-blood serotonin levels, or hyperserotonemia, first linked disrupted 5-HT homeostasis to Autism Spectrum Disorders (ASDs). The 5-HT transporter (SERT) gene (SLC6A4) has been associated with whole blood 5-HT levels and ASD susceptibility. Previously, we identified multiple gain-of-function SERT coding variants in children with ASD. Here we establish that transgenic mice expressing the most common of these variants, SERT Ala56, exhibit elevated, p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia. These effects are accompanied by altered basal firing of raphe 5-HT neurons, as well as 5HT(1A) and 5HT(2A) receptor hypersensitivity. Strikingly, SERT Ala56 mice display alterations in social function, communication, and repetitive behavior. Our efforts provide strong support for the hypothesis that altered 5-HT homeostasis can impact risk for ASD traits and provide a model with construct and face validity that can support further analysis of ASD mechanisms and potentially novel treatments.
Arterial Spin-Labeling MR Imaging Measurements of Timing Parameters in Patients with a Carotid Artery Occlusion (2008)

<b>BACKGROUND AND PURPOSE:</b> Arterial spin-labeling (ASL) with image acquisition at multiple delay times can be exploited in perfusion MR imaging to visualize and quantify the temporal dynamics of arterial blood inflow. In this study, we investigated the consequences of an internal carotid artery (ICA) occlusion and collateral blood flow on regional timing parameters. <b>MATERIALS AND METHODS:</b> Seventeen functionally independent patients with a symptomatic ICA occlusion (15 men, 2 women; mean age, 57 years) and 29 sex- and age-matched control subjects were investigated. ASL at multiple delay times was used to quantify regional cerebral blood flow (CBF) and the transit and trailing edge times (arterial timing parameters) reflecting, respectively, the beginning and end of the labeled bolus. Intra-arterial digital subtraction angiography and MR angiography were used to grade collaterals. <b>RESULTS:</b> In the hemisphere ipsilateral to the ICA occlusion, the CBF was lower in the anterior frontal (31 ± 4 versus 47 ± 3 mL/min/100 g, <i>P</i> &lt; .01), posterior frontal (39 ± 4 versus 55 ± 2 mL/min/100 g, <i>P</i> &lt; .01), and frontal parietal region (49 ± 3 versus 61 ± 3 mL/min/100 g, <i>P</i> = .04) than that in control subjects. The trailing edge of the frontal-parietal region was longer in the hemisphere ipsilateral to the ICA occlusion compared with that in control subjects (2225 ± 167 versus 1593 ± 35 ms, <i>P</i> &lt; .01). In patients with leptomeningeal collateral flow, the trailing edge was longer in the anterior frontal region (2436 ± 275 versus 1648 ± 201 ms, <i>P</i> = .03) and shorter in the occipital region (1815 ± 128 versus 2388 ± 203 ms, <i>P</i> = .04), compared with patients without leptomeningeal collaterals. <b>CONCLUSION:</b> Regional assessment of timing parameters with ASL may provide valuable information on the cerebral hemodynamic status. In patients with leptomeningeal collaterals, the most impaired territory was found in the frontal lobe.
Role of calcium and calmodulin in hemidesmosome formation in vitro. (1984)

Intact epithelial sheets were removed from rabbit corneas using Dispase II, a bacterial neutral protease. The freed sheets were placed on denuded corneal basal laminae and incubated at 35 degrees C for 3, 6, 18, or 24 h. Epithelial-basal lamina preparations were incubated in culture medium that either contained (a) varying concentrations of Ca2+ ions, (b) calmodulin antagonists, (c) exogenous calmodulin following an initial 6-h incubation in the presence of antagonists, or that lacked (d) Mg2+ ions. Tissues were processed for electron microscopy, and micrographs were taken of basal cell membranes. At least four experiments were conducted for each treatment, and for each experiment the total number of hemidesmosomes were counted along the basal membrane-basal lamina surface of eight cells. The number of hemidesmosomes formed was directly proportional to the increasing concentration of Ca2+. The presence of absence of Mg2+ ions did not change the numbers of hemidesmosomes formed. Calmodulin antagonists inhibited hemidesmosome formation, and this inhibition was reversed by the addition of calmodulin. Thus, hemidesmosome formation is Ca2+ dependent and appears to be mediated by a calmodulin-regulated mechanism.
Nerve repair by means of vein filled with muscle grafts I. Clinical results (2000)

Peripheral nerve lesions with a long segment defect need a grafting conduit to heal. Although autogenous nerve grafting is still considered the best method for bridging nerve defects, several alternative types of conduits (biological and synthetic) have been studied. We have demonstrated in previous experimental research in rats that a graft made using a vein (providing a guide for nerve regeneration) filled with fresh skeletal muscle (to prevent vein collapse and support axon regeneration) gave similar results to traditional nerve grafts. On this basis, we decided to use the muscle-vein-combined grafts in clinical cases. From 1993 to 1997, this technique was applied for bridging both sensory and mixed nerve defects (21 cases). We report good results in 85% of our cases with a minimum follow-up of 14 months. These results, obtained on nerve defects ranging from 0.5 to 6 cm in length, seem to be superior to those reported with other kinds of artificial or biological conduits.
FUNCTIONAL PROPERTIES OF VARIOUS FIBERS: PHYSICAL PROPERTIES (1978)

ABSTRACT To investigate differences among fiber sources, physical profiles of 12 fiber types were determined based on particle size, hydrated volume expansion, water‐holding capacity (with respect to ionic strength and pH) and temperature effects. Each fiber was characterized by distinctly different functional or physical properties. In most cases, dry density was found to be directly proportional to hydrated density. The responses to pH effects, varying ionic strength, and mono‐ and divalent cations proved to be highly individualized. Exposure of fiber types to increased temperatures resulted in enlarged, elongated particles and structural damage. Thus, individual fiber responses to possible processing conditions should be taken into consideration when selecting a fiber source. The variability here might also serve to explain the variability often noted when physiological effects of plant fibers are evaluated.
Electronic project work within the national curriculum (1991)

The National Curriculum for Technology is new, it involves a new way of working and to some extent a re-arrangementof familiar knowledge, skills and processes. It seems clear that the major assessment focus will be through project work. In this article I want to show the importance of project work, and in particular electronics project work, by considering an existing scheme, the Leicestershire Modular Framework (LMF), that has many parallels with Design and Technology as laid out in the National Curriculum. I will indicate the kinds of activities that produced successful projects in terms of assessment and show how electronics based projects can be such a useful means of achieving evidence of Design and Technology capability.
Canine viruses and multiple sclerosis (1981)

Serum and cerebrospinal fluid from multiple sclerosis (MS) patients and control subjects were tested and compared for presence and titer of neutralizing antibody against the most common canine viruses. Canine viruses included canine distemper virus (CDV), canine adenovirus 1 (CAV-1), canine parainfluenza virus (CPIV), canine herpesvirus (CHV), canine coronavirus (CCV), and canine parvovirus (CPV). Neutralizing titers against measles virus (MV) and human adenovirus 8 (HA8) were also tested. Significantly elevated (p less than 0.05) antibody levels in sera from MS patients were found only against MV and CDV, but this depended upon the study population and the method of evaluation. The CDV-neutralizing component in serum could be absorbed on MV-infected cells. Results of this study failed to establish a link between canine viruses and MS.
Limb development in mouse embryos. I. Analysis of teratogenic effects of retinoic acid (1973)

Abstract Retinoic (vitamin A) acid produced phocomelia and micromelia in DBA/2J fetuses when administered to pregnant mice on the 12th or 13th day of gestation. The incidence of forelimb defects was higher after 12th‐ (in embryos having 33–41 somite pairs) than 13th–day treatment (40–51 somite pairs); the reverse was true for hindlimb defects. Hindlimb digits continued to be highly susceptible on the 14th day. Limb defects were not accompanied by body growth retardation or other skeletal malformations except cleft palate. The type and severity of limb defects depended on the average developmental stage of the limb bud at the time of treatment. From the beginning of the period of limb susceptibility, the 12th day, the ontogenetic sequence in which the long bones were rendered abnormal was: radius–ulna, humerus, fibula, tibia, femur or tibia‐femur. The sequence in which the long bones lost their susceptibility to retinoic acid was: humerus, femur, ulna, radius, tibia‐fibula. The radius appeared to be susceptible in some embryos at a time when the other long bones had escaped injury. An analysis of the shape of the same bone affected at different periods of prenatal development led to the following proposal. At earlier stages retinoic acid disrupts cellular activities that normally lead to the spatial organization of the mesenchymal cell condensations, resulting in a modified shape of the cartilage models; at later stages it prevents the enlargement of the condensations that have already appeared, resulting in smaller than normal models.
Conformation and Dynamics of Abasic Sites in DNA Investigated by Time-Resolved Fluorescence of 2-Aminopurine (2001)

Abasic sites are highly mutagenic lesions in DNA that arise as intermediates in the excision repair of modified bases. These sites are generated by the action of damage-specific DNA glycosylases and are converted into downstream intermediates by the specific activity of apurinic/apyrimidinic endonucleases. Enzymes in both families have been observed in crystal structures to impose deformations on the abasic-site DNA, including DNA kinking and base flipping. On the basis of these apparent protein-induced deformations, we propose that altered conformation and dynamics of abasic sites may contribute to the specificity of these repair enzymes. Previously, measurements of the steady-state fluorescence of the adenine analogue 2-aminopurine (2AP) opposite an abasic site demonstrated that binding of divalent cations could induce a conformational change that increased the accessibility of 2AP to solute quenching [Stivers, J. T. (1998) Nucleic Acids Res. 26, 3837-44]. We have performed time-resolved fluorescence experiments to characterize the states involved in this conformational change. Interpretation of these studies is based on a recently developed model attributing the static and dynamic fluorescence quenching of 2AP in DNA to aromatic stacking and collisional interactions with neighboring bases, respectively (see the preceding paper in this issue). The time-resolved fluorescence results indicate that divalent cation binding shifts the equilibrium of the abasic site between two conformations: a "closed" state, characterized by short average fluorescence lifetime and complex decay kinetics, and an "open" state, characterized by monoexponential decay with lifetime approximately that of the free nucleoside. Because the lifetime and intensity decay kinetics of 2AP incorporated into DNA are sensitive primarily to collisional interactions with the neighboring bases, the absence of dynamic quenching in the open state strongly suggests that the fluorescent base is extrahelical in this conformation. Consistent with this interpretation, time-resolved quenching studies reveal that the open state is accessible to solute quenching by potassium iodide, but the closed state is not. Greater static quenching is observed in the abasic site when the fluorescent base is flanked by 5'- and 3'-thymines than in the context of 5'- and 3'-adenines, indicating that 2AP is more stacked with the neighboring bases in the former sequence. These results imply that the conformation of the abasic site varies in a sequence-dependent manner. Undamaged sequences in which the abasic site is replaced by thymine do not exhibit an open state and have different levels of both static and dynamic quenching than their damaged homologues. These differences in structure and dynamics may be significant determinants of the high specific affinity of repair enzymes for the abasic site.
Constitutive expression of specific interferon isotypes in peripheral blood leukocytes from normal individuals and in promonocytic U937 cells (1996)

Constitutive expression of IFN-alpha5 and IFN-beta was detected in different lymphoid cells including peripheral blood mononuclear cells from normal individuals following amplification of IFN mRNA by reverse transcriptase-polymerase chain reaction and direct sequencing of the amplified product. The activated form of the interferon-induced transcription factor complex ISGF3 was also detected in nuclear extracts from uninduced cells. Culture supernatants from uninduced U937 cells were also found to activate an ISRE cloned upstream of the luciferase reporter gene, indicating the presence of endogenous IFN activity equivalent to approximately 0.3 to 0.5 IU/mL. This endogenous IFN was also shown to play a role in maintaining the basal level of expression of the major histocompatibility class I genes in lymphoid cells. These results suggest that IFN-alpha5 and IFN-beta are produced at low levels in normal tissues and play an important role in the regulation of cell function and in the maintenance of homeostasis.
Is there a rational method to purify proteins? From expert systems to proteomics (2004)

The purification of recombinant proteins for therapeutic or analytical applications requires the use of several chromatographic steps in order to achieve a high level of purity. A range of techniques is available such as anion and cation exchange chromatography, which can be carried out at different pHs, and hence used at different steps, hydrophobic interaction chromatography, gel filtration and affinity chromatography. Evidently when confronted with a complex mixture of partially unknown proteins or a clarified cell extract there are many different routes one can take in order to choose the minimum and most efficient number of purification steps to achieve a desired level of purity (e.g. 98, 99.5 or 99.9%). In this review we will show how an initial "proteomic" characterization of the complex initial mixture of target protein and protein contaminants can be used to select the most efficient chromatographic separation steps in order to achieve a maximum level of purity with a minimum number of steps. The chosen methodology was implemented in a computer based expert system. The first algorithm developed was used to select the most efficient purification method to separate a protein from its contaminants based on the physicochemical properties of the protein product and the protein contaminants. The second algorithm developed was used to predict the number and concentration of contaminants after each separation as well as protein product purity. The successful application of the expert system approach, based on an initial proteomic characterization, to the practical cases of protein mixtures and clarified fermentation supernatant is presented and discussed. The purification strategy proposed was experimentally tested and validated with a mixture of four proteins and the experimental validation was also carried out with an "unknown" supernatant of Bacillus subtilis producing a recombinant beta-1,3-glucanase. The system was robust to errors <10% which is the range that can be found in the experimental determination of the properties in the database of product and contaminants. On the other hand, the system was sensitive both to larger variations (>20%) in the properties of the contaminant database and the protein product and to variations in one protein property (e.g. hydrophobicity).
Preparation of Highly Alkoxy‐Substituted Naphthaldehyde Derivatives – A Regioselective Approach to Building Blocks for the Synthesis of Rubromycins (2006)

Abstract An efficient synthesis of highly substituted naphthaldehyde derivatives 8 was required for the planned synthesis of compounds of the rubromycin family. Three different routes towards this goal were attempted. Route I started with 1,5‐dihydroxynaphthalene ( 10 ), and the pentaalkoxy‐substituted naphthaldehyde 17 was obtained in a straightforward sequence in moderate overall yield. Route II employed an aryne cycloaddition to generate the functionalized naphthalene skeleton. This sequence smoothly provided the bromonaphthalene derivative 19 , which served as a very suitable precursor of aldehyde 24 , boronic acid 25 , and finally the unsymmetrically substituted hexaalkoxynaphthalene derivative 18 . Unfortunately, though, the regioselective formylation of 18 to provide the desired aldehyde 8a was not possible, this key compound being obtained only in low yield. Whereas an attempted Claisen rearrangement of O ‐allylated derivative 30 furnished the wrong regioisomer 33 , the ortho ‐Fries rearrangement of the easily available carbamate 34 smoothly afforded the expected amide 35 , which turned out to be essentially inert and could not be converted into the corresponding naphthaldeyde 8b . We therefore developed Route III, involving an alternative aryne cycloaddition and a subsequent regioselective ring‐opening of the tricyclic adduct 41 . This sequence enabled us to efficiently prepare acetal 44 , which was transformed into the desired highly substituted and regioselectively protected naphthaldehyde derivative 8b . The synthesis of this key compound could be achieved in a 12‐step sequence in an overall yield of 9 %. Our planned rubromycin synthesis was successfully verified by the conversion of 8b into the protected α‐hydroxy enone 7b by addition of lithiated methoxyallene followed by hydrolysis and subsequent silylation of intermediate 7a . (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2006)
Plasma Insulin-Like Growth Factor-I and Prostate Cancer Risk: A Prospective Study (1998)

Insulin-like growth factor-I (IGF-I) is a mitogen for prostate epithelial cells. To investigate associations between plasma IGF levels and prostate cancer risk, a nested case-control study within the Physicians' Health Study was conducted on prospectively collected plasma from 152 cases and 152 controls. A strong positive association was observed between IGF-I levels and prostate cancer risk. Men in the highest quartile of IGF-I levels had a relative risk of 4.3 (95 percent confidence interval 1.8 to 10.6) compared with men in the lowest quartile. This association was independent of baseline prostate-specific antigen levels. Identification of plasma IGF-I as a predictor of prostate cancer risk may have implications for risk reduction and treatment.