52 research outputs found
The transcription factors HIF-1 and HNF-4 and the coactivator p300 are involved in insulin-regulated glucokinase gene expression via the phosphatidylinositol 3-kinase/protein kinase B pathway
No full textGlucokinase plays a key role in the regulation of glucose utilization in liver and its expression is strongly enhanced by insulin and modulated by venous pO(2). In primary rat hepatocytes, pO(2) modulated insulin-dependent glucokinase (GK) gene expression was abolished by wortmannin an inhibitor of phosphatidylinositol 3-kinase (PI3K). Transfection of vectors encoding the p110 catalytic subunit of PI3K or constitutively active proteinkinase B (PKB) stimulated GK mRNA and protein expression. The transfection of GK promoter constructs together with expression vectors for p110 or constitutively active PKB revealed that the GK promoter region -87/-80 mediates the response to PI3K/PKB. Transfection experiments and gel shift assays show that this element is able to bind hypoxia-inducible factor-1 (HIF-1) in a hypoxia- and PKB-dependent manner. The ability of HIF-1alpha to activate the GK promoter was enhanced by hepatocyte nuclear factor-4alpha (HNF-4alpha), acting via the sequence -52/-39, and by the coactivator p300. Stimulation of the GK promoter by insulin was dependent on the intact -87/-80 region and maximal stimulation was achieved when HIF-1alpha, HNF-4, and p300 were co-transfected with the -1430 GK promoter Luc construct in primary hepatocytes. Maximal stimulation of GK promoter activity by insulin was inhibited when a p300 vector was used containing a mutation within a PKB phosphorylation site. Thus, a regulatory transcriptional complex consisting of HIF-1, HNF-4, and p300 appears to be involved in insulin-dependent GK gene activation.NIDDK NIH HHS [DKK1430
Single‐stranded‐DNA‐binding proteins from human mitochondria and Escherichia coli have analogous physicochemical properties
No full textThe gene for the mature human mitochondrial single‐stranded‐DNA binding protein (HsmtSSB) has been transferred into a protein‐overproducing vector and expressed in Escherichia coli. The protein was purified to homogeneity and its physicochemical properties were investigated. From sequence comparison, HsmtSSB shows some similarities to the N‐terminal part of the single‐stranded DNA‐binding protein (SSB) from E. coli (EcoSSB). Hydrodynamic measurements show the protein to be tetrameric and give a sedimentation coefficient of 4.1 S corresponding to a C‐terminally shortened EcoSSB. Electron‐microscopic images of the free protein show a globular tetrahedral structure. Binding of poly(desoxythymidylic acid) [poly(dT)] leads to a reduction of the tryptophan fluorescence of the protein up to 96%. Fluorescence titrations with poly(dT) show apparent binding‐site sizes of 50–70 nucleotides/tetramer between 0.05 M and 2 M NaCl. Binding to poly(dT) proceeds in a nearly diffusion‐controlled reaction with an association‐rate constant kass of 4 · 108 M−1S−1. The rate‐limiting step is the formation of a transient complex where less than four binding sites on the protein are involved and the reshuffling of the protein of the protein on the linear matrix is fast. Electron microscopy of the complex with poly(dT) using negative staining shows a nearly random distribution of the protein between the individual poly(dT) strands. This leads to the conclusion that the binding cooperativity is low (ω < 150). The two tryptophans of HsmtSSB were replaced by threonine and tyrosine. The environment of both residues is influenced by nucleic acid binding with mutations of Trp68 strongly reducing the DNA‐binding affinity of the protein. Copyright © 1994, Wiley Blackwell. All rights reserve
Kombination von Planspieltechnik und computer based training zur Schulung von Einkaeufern im Handel: Moeglichkeiten zur Messung und Verbesserung des Entscheidungsverhaltens dargestellt an einem konkreten Schulungsprozess
No full textSIGLEBibliothek Weltwirtschaft Kiel A 168958 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman
Veterinary science : humans, animals and health
No full textThis living book is a collection of open access materials bringing scientific papers to a humanities audienc
A U-turn on Double Descent: Rethinking Parameter Counting in Statistical Learning
Get PDFConventional statistical wisdom established a well-understood relationship
between model complexity and prediction error, typically presented as a
U-shaped curve reflecting a transition between under- and overfitting regimes.
However, motivated by the success of overparametrized neural networks, recent
influential work has suggested this theory to be generally incomplete,
introducing an additional regime that exhibits a second descent in test error
as the parameter count p grows past sample size n - a phenomenon dubbed double
descent. While most attention has naturally been given to the deep-learning
setting, double descent was shown to emerge more generally across non-neural
models: known cases include linear regression, trees, and boosting. In this
work, we take a closer look at evidence surrounding these more classical
statistical machine learning methods and challenge the claim that observed
cases of double descent truly extend the limits of a traditional U-shaped
complexity-generalization curve therein. We show that once careful
consideration is given to what is being plotted on the x-axes of their double
descent plots, it becomes apparent that there are implicitly multiple
complexity axes along which the parameter count grows. We demonstrate that the
second descent appears exactly (and only) when and where the transition between
these underlying axes occurs, and that its location is thus not inherently tied
to the interpolation threshold p=n. We then gain further insight by adopting a
classical nonparametric statistics perspective. We interpret the investigated
methods as smoothers and propose a generalized measure for the effective number
of parameters they use on unseen examples, using which we find that their
apparent double descent curves indeed fold back into more traditional convex
shapes - providing a resolution to tensions between double descent and
statistical intuition.Comment: To appear in the Proceedings of the 37th Conference on Neural
Information Processing Systems (NeurIPS 2023
Ichtyoses kératinopathiques (étude clinique, histologique et moléculaire chez 24 patients)
No full text[Résumé français] Introduction : L ichtyose épidermolytique (IE) et l ichtyose de Curth-Macklin (ICM) sont des ichtyoses kératinopathiques (IK) dues aux mutations des gènes de la kératine 1 (K1) ou 10 (K10). A partir d'une série de 24 cas, nous voudrions souligner leur hétérogénéité. Matériel & Méthodes : Etude clinique, histologique et moléculaire rétrospective sur 24 cas (20IE, 4ICM). Résultats : Histologie typique mais clinique hétérogène: la fragilité cutanée néonatale (90% des IE) perdure chez 18% des plus de 7ans, et laisse place à une hyperkératose (100%) limitée aux plis (35%), intermédiaire (20%), ou diffuse (45%). Kératodermie palmo-plantaire: 40% des IE, 100% des ICM. Atypies : fragilité cutanée chez 3ICM et absence de bulle chez 2IE. De nouvelles mutations K1-K10 ont été identifiées. Discussion : La grande variabilité clinique des IE/ICM semble s inscrire dans un spectre des IK. Les rétinoïdes demeurent le traitement de choix. Conclusion : Les IK sont hétérogènes cliniquement. Les mutations confirment le diagnostic sans préjuger de la sévérité.[Résumé anglais] Introduction : Both epidermolytic ichthyosis (EI) and ichthyosis of Curth-Macklin (ICM) are kératinopathic ichthyosis (KI) caused by mutations in the genes of keratin 1 (K1) or 10 (K10). Through our 24 cases, we would like to highlight their heterogeneity. Material & Methods : Clinical, histological and molecular retrospective study about 24 cases (20EI, 4ICM). Results : Typical histology but clinical heterogeneity: the neonatal skin fragility (90% EI) persists in 18% of the patients after 7 years old. It is followed by hyperkeratosis (100%) that can be limited to the folds (35%), intermediate (20%) or diffuse (45%). Palmoplantar keratoderma: 40% of EI, 100% of ICM. Surprisingly, we noticed skin fragility in 3ICM and no blisters in 2EI. New mutations of K1-K10 have been identified. Discussion : The wide clinical variability of ICM/EI seems to range within a KI spectrum. Retinoids remain the best known treatment. Conclusion : The IK are clinically heterogeneous. Genotype/Phenotype correlations remain complex.PARIS13-BU Serge Lebovici (930082101) / SudocSudocFranceF
SSB and SSB show different influence on the melting behavior of poly(dA–dT)
No full text<p><b>Copyright information:</b></p><p>Taken from "Single-stranded DNA-binding protein of : a biophysical characterization"</p><p>Nucleic Acids Research 2005;33(5):1662-1670.</p><p>Published online 21 Mar 2005</p><p>PMCID:PMC1069009.</p><p>© The Author 2005. Published by Oxford University Press. All rights reserved</p> Samples containing 38 μM nucleotides of poly(dA–dT) in a buffer containing 75 mM NaCl and 20 mM KP were melted in the presence of 3.25 μM SSB (a), 3.25 μM SSB (b) and in the absence of protein (c)
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