A family of mammalian Na+-dependent L-ascorbic acid transporters.

Vitamin C (L-ascorbic acid) is essential for many enzymatic reactions, in which it serves to maintain prosthetic metal ions in their reduced forms (for example, Fe2+, Cu+), and for scavenging free radicals in order to protect tissues from oxidative damage. The facilitative sugar transporters of the GLUT type can transport the oxidized form of the vitamin, dehydroascorbic acid, but these transporters are unlikely to allow significant physiological amounts of vitamin C to be taken up in the presence of normal glucose concentrations, because the vitamin is present in plasma essentially only in its reduced form. Here we describe the isolation of two L-ascorbic acid transporters, SVCT1 and SVCT2, from rat complementary DNA libraries, as the first step in investigating the importance of L-ascorbic acid transport in regulating the supply and metabolism of vitamin C. We find that SVCT1 and SVCT2 each mediate concentrative, high-affinity L-ascorbic acid transport that is stereospecific and is driven by the Na+ electrochemical gradient. Despite their close sequence homology and similar functions, the two isoforms of the transporter are discretely distributed: SVCT1 is mainly confined to epithelial systems (intestine, kidney, liver), whereas SVCT2 serves a host of metabolically active cells and specialized tissues in the brain, eye and other organs.     

Dynamics of Drosophila embryonic patterning network perturbed in space and time using microfluidics

Biochemical networks are perturbed both by fluctuations in environmental conditions and genetic variation. These perturbations must be compensated for, especially when they occur during embryonic pattern formation. Complex chemical reaction networks displaying spatiotemporal dynamics have been controlled and understood by perturbing their environment in space and time. Here, we apply this approach using microfluidics to investigate the robust network in Drosophila melanogaster that compensates for variation in the Bicoid morphogen gradient. We show that the compensation system can counteract the effects of extremely unnatural environmental conditions--a temperature step--in which the anterior and posterior halves of the embryo are developing at different temperatures and thus at different rates. Embryonic patterning was normal under this condition, suggesting that a simple reciprocal gradient system is not the mechanism of compensation. Time-specific reversals of the temperature step narrowed down the critical period for compensation to between 65 and 100 min after onset of embryonic development. The microfluidic technology used here may prove useful to future studies, as it allows spatial and temporal regulation of embryonic development.     

Signs, toy models, and the a priori: from Helmholtz to Wittgenstein

The Marburg neo-Kantians argue that Hermann von Helmholtz’s empiricist account of the a priori does not account for certain knowledge, since it is based on a psychological phenomenon, trust in the regularities of nature. They argue that Helmholtz’s account raises the ‘problem of validity’ (Gültigkeitsproblem): how to establish a warranted claim that observed regularities are based on actual relations. I reconstruct Heinrich Hertz’s and Ludwig Wittgenstein’s Bild theoretic answer to the problem of validity: that scientists and philosophers can depict the necessary a priori constraints on states of affairs in a given system, and can establish whether these relations are actual relations in nature. The analysis of necessity within a system is a lasting contribution of the Bild theory. However, Hertz and Wittgenstein argue that the logical and mathematical sentences of a Bild are rules, tools for constructing relations, and the rules themselves are meaningless outside the theory. Carnap revises the argument for validity by attempting to give semantic rules for translation between frameworks. Russell and Quine object that pragmatics better accounts for the role of a priori reasoning in translating between frameworks. The conclusion of the tale, then, is a partial vindication of Helmholtz’s original account.     

Negation scope detection with a conditional random field model

Identifying negation cues and their scope in a text is an important subtask of information extrac-tion that can benefit other natural language processing tasks, including but not limited to medical da-ta mining, relation extraction, question answering and sentiment analysis.The tasks of negation cue and negation scope detection can be treated as sequence labelling problems.In this paper, a system is presented having two components: negation cue detection and negation scope detection.In the first phase, a conditional random field ( CRF) model is trained to detect the negation cues using a lexicon of negation words and some lexical and contextual features.Then, another CRF model is trained to detect the scope of each negation cue identified in the first phase, using basic lexical and contextual features.These two models are trained and tested using the dataset distributed within the*Sem Shared Task 2012 on resolving the scope and focus of negation.Experimental results show that the system outperformed all the systems submitted to this shared task.     

Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus

TREX1 acts in concert with the SET complex in granzyme A-mediated apoptosis, and mutations in TREX1 cause Aicardi-Goutières syndrome and familial chilblain lupus. Here, we report monoallelic frameshift or missense mutations and one 3' UTR variant of TREX1 present in 9/417 individuals with systemic lupus erythematosus but absent in 1,712 controls (P = 4.1 x 10(-7)). We demonstrate that two mutant TREX1 alleles alter subcellular targeting. Our findings implicate TREX1 in the pathogenesis of SLE.     

Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs.     

Stochastic models underlying Croston's method for intermittent demand forecasting

Croston's method is widely used to predict inventory demand when it is intermittent. However, it is an ad hoc method with no properly formulated underlying stochastic model. In this paper, we explore possible models underlying Croston's method and three related methods, and we show that any underlying model will be inconsistent with the properties of intermittent demand data. However, we find that the point forecasts and prediction intervals based on such underlying models may still be useful. Copyright © 2005 John Wiley & Sons, Ltd.