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41.
Sebastian Kummer Susanne Rinn Gunnar Seemann Nadine Bachmann Katherine Timothy Paul S. Thornton Frank Pillekamp Ertan Mayatepek Carsten Bergmann Thomas Meissner Niels Decher 《International journal of molecular sciences》2022,23(15)
The voltage-dependent L-type calcium channel isoform CaV1.2 is critically involved in many physiological processes, e.g., in cardiac action potential formation, electromechanical coupling and regulation of insulin secretion by beta cells. Gain-of-function mutations in the calcium voltage-gated channel subunit alpha 1 C (CACNA1C) gene, encoding the CaV1.2 α1-subunit, cause Timothy syndrome (TS), a multisystemic disorder that includes autism spectrum disorders and long QT (LQT) syndrome. Strikingly, TS patients frequently suffer from hypoglycemia of yet unproven origin. Using next-generation sequencing, we identified a novel heterozygous CACNA1C mutation in a patient with congenital hyperinsulinism (CHI) and associated hypoglycemic episodes. We characterized the electrophysiological phenotype of the mutated channel using voltage-clamp recordings and in silico action potential modeling experiments. The identified CaV1.2L566P mutation causes a mixed electrophysiological phenotype of gain- and loss-of-function effects. In silico action potential modeling supports that this mixed electrophysiological phenotype leads to a tissue-specific impact on beta cells compared to cardiomyocytes. Thus, CACNA1C variants may be associated with non-syndromic hyperinsulinemic hypoglycemia without long-QT syndrome, explained by very specific electrophysiological properties of the mutated channel. We discuss different biochemical characteristics and clinical impacts of hypoglycemia in the context of CACNA1C variants and show that these may be associated with significant morbidity for Timothy Syndrome patients. Our findings underline that the potential of hypoglycemia warrants careful attention in patients with CACNA1C variants, and such variants should be included in the differential diagnosis of non-syndromic congenital hyperinsulinism. 相似文献
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P. A. Thornton 《Journal of Materials Science》1971,6(4):347-356
The literature regarding the influence of nonmetallic inclusions on the mechanical properties of steel is reviewed, with critical
comments on various studies. A brief discussion of inclusion rating methods and a synopsis of the effects of applied stress
on inclusions in an isotropic, elastic matrix are presented. The parameters considered are tensile strength, impact strength,
reduction of area, fatigue properties and fracture toughness. It is concluded that in many applications, the type of inclusions
are more important than the total content and as matrix strength increases, the notch effect of inclusions becomes more significant.
Also, mechanical properties can be influenced by any one or a combination of the following inclusion parameters; shape, size,
quantity, interspacing, distribution, orientation, interfacial strength, and physical properties relative to the matrix. 相似文献
44.
Lila?KariEmail author Stavros?Konstantinidis Elena?Losseva Geoff?Wozniak 《Acta Informatica》2003,40(2):119-157
An essential step of any DNA computation is encoding the input data on single or double DNA strands. Due to the biochemical properties of DNA, complementary single strands can bind to one another forming double-stranded DNA. Consequently, data-encoding DNA strands can sometimes interact in undesirable ways when used in computations. It is crucial thus to analyze properties that guard against such phenomena and study sets of sequences that ensure that no unwanted bindings occur during any computation. This paper formalizes and investigates properties of DNA languages that guarantee their robusteness during computations. After defining and investigating several types of DNA languages possessing good encoding properties, such as sticky-free and overhang-free languages, we give algorithms for deciding whether regular DNA languages are invariant under bio-operations. We also give a method for constructing DNA languages that, in addition to being invariant and sticky-free, possess error-detecting properties. Finally, we present the results of running tests that check whether several known gene languages (the set of genes of a given organism) as well as the input DNA languages used in Adlemans DNA computing experiment, have the defined properties.Received: 6 February 2003, Published online: 2 September 2003Research partially supported by Grants R2824A01 and R220259 of the Natural Sciences and Engineering Research Council of Canada. 相似文献
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Assessment of conformational parameters as predictors of limited proteolytic sites in native protein structures 总被引:4,自引:0,他引:4
Hubbard SJ; Beynon RJ; Thornton JM 《Protein engineering, design & selection : PEDS》1998,11(5):349-359
Despite the importance of limited proteolysis in biological systems it isoften difficult to rationalize why a proteinase hydrolyses a particularbond, given a simple sequence specificity alone. Understanding of thestructural properties limiting the proteolysis represents a first step onthe pathway to control and manipulation of this phenomena. An expanded setof nick-sites in proteins of known tertiary structure, cut by both narrowand broad specificity proteinases, has been generated yielding a robustdata set of strictly limited sites. A critical evaluation of an expandedset of conformational parameters revealed a strong correlation with limitedproteolytic sites, although they are only modest predictors in isolation.The overall predictive power is significantly improved when theconformational parameters are combined in a weighted predictive scheme thatpermits their relative importance to be compared via a Metropolis searchprotocol. A subset of the parameters performs equally well demonstratingthe key determinants of susceptibility. The derived predictive algorithmhas been made available via the internet. Its utility for predicting othersurface-correlated features is also discussed. 相似文献
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Nagano Nozomi; Porter Craig T.; Thornton Janet M. 《Protein engineering, design & selection : PEDS》2001,14(11):845-855
There are currently at least nine distinct glycosidase sequencefamilies which are all known to adopt a TIM barrel fold [Henrissat,B.and Davies,G. (1997) Curr. Opin. Struct. Biol., 7, 637644].To explore the relationships between these enzymes and theirevolution, comprehensive sequence and structure comparisonswere performed, generating four distinct clusters. The firstcluster, S1, comprises the 相似文献
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