Phospholipid flippases attenuate LPS-induced TLR4 signaling by mediating endocytic retrieval of Toll-like receptor 4

P4-ATPases are lipid flippases that catalyze the transport of phospholipids to create membrane phospholipid asymmetry and to initiate the biogenesis of transport vesicles. Here we show, for the first time, that lipid flippases are essential to dampen the inflammatory response and to mediate the endotoxin-induced endocytic retrieval of Toll-like receptor 4 (TLR4) in human macrophages. Depletion of CDC50A, the β-subunit that is crucial for the activity of multiple P4-ATPases, resulted in endotoxin-induced hypersecretion of proinflammatory cytokines, enhanced MAP kinase signaling and constitutive NF-κB activation. In addition, CDC50A-depleted THP-1 macrophages displayed reduced tolerance to endotoxin. Moreover, endotoxin-induced internalization of TLR4 was strongly reduced and coincided with impaired endosomal MyD88-independent signaling. The phenotype of CDC50A-depleted cells was also induced by separate knockdown of two P4-ATPases, namely ATP8B1 and ATP11A. We conclude that lipid flippases are novel elements of the innate immune response that are essential to attenuate the inflammatory response, possibly by mediating endotoxin-induced internalization of TLR4.     

What if We were Already in the In-Between? Further Ventures into the Ontologies of Science and Politics

What follows from the suggestion to pay attention to what is in-between science and politics? Karen François’s paper “In-between science and politics” follows Latour in arguing for the need for political theory to get out of the Platonic cave that it still inhabits. Political theory needs to be brought into the wild through empirical studies of how science and politics in fact intermix. And the Latourian proposition needs to be strengthened by focusing on the embodied knowledges that enable situated objectivities to emerge. Though worthwhile, these arguments are weakened by a superficial treatment of political theory and by a lack of attention to the difficulties involved in combining Latourian actor-network theory with the “strong objectivity” of standpoint theory. Most problematically the paper purports to define as an agenda (exploring the in-between of science and politics) what whole fields of inquiry have already been in full swing exploring for quite a while. The ‘turn to ontology’ in STS and social anthropology and the development of ‘empirical philosophy’ suggests what might be at stake in such explorations.     

Influence of prenatal X-radiation on brain lipid and cerebroside content in developing rats

Résumé Lorsque des rats sont irradiés par des rayons X au 14e jour de la gestation, le contenu en cérébrosides du cortex cérébral et du diencéphale est plus élevé que chez les témoins. Or il est bien connu que ce traitement entraîne d'une part une prolifération gliale et d'autre part une augmentation de la sensibilité du système nerveux central à une stimulation électrique. La possibilité d'une relation entre ces phénomènes est discutée.

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USPHS HD-101 fellow.     

Canonical Analysis: Ranks,Ratios and Fits

Measurements of p variables for n samples are collected into a n×p matrix X, where the samples belong to one of k groups. The group means are separated by Mahalanobis distances. CVA optimally represents the group means of X in an r-dimensional space. This can be done by maximizing a ratio criterion (basically one- dimensional) or, more flexibly, by minimizing a rank-constrained least-squares fitting criterion (which is not confined to being one-dimensional but depends on defining an appropriate Mahalanobis metric). In modern n < p problems, where W is not of full rank, the ratio criterion is shown not to be coherent but the fit criterion, with an attention to associated metrics, readily generalizes. In this context we give a unified generalization of CVA, introducing two metrics, one in the range space of W and the other in the null space of W, that have links with Mahalanobis distance. This generalization is computationally efficient, since it requires only the spectral decomposition of a n×n matrix.     

Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice

Williams syndrome is a neurodevelopmental disorder caused by the hemizygous deletion of 1.6 Mb on human chromosome 7q11.23. This region comprises the gene CYLN2, encoding CLIP-115, a microtubule-binding protein of 115 kD. Using a gene-targeting approach, we provide evidence that mice with haploinsufficiency for Cyln2 have features reminiscent of Williams syndrome, including mild growth deficiency, brain abnormalities, hippocampal dysfunction and particular deficits in motor coordination. Absence of CLIP-115 also leads to increased levels of CLIP-170 (a closely related cytoplasmic linker protein) and dynactin at the tips of growing microtubules. This protein redistribution may affect dynein motor regulation and, together with the loss of CLIP-115-specific functions, underlie neurological alterations in Williams syndrome.     

Forecast covariances in the linear multiregression dynamic model

The linear multiregression dynamic model (LMDM) is a Bayesian dynamic model which preserves any conditional independence and causal structure across a multivariate time series. The conditional independence structure is used to model the multivariate series by separate (conditional) univariate dynamic linear models, where each series has contemporaneous variables as regressors in its model. Calculating the forecast covariance matrix (which is required for calculating forecast variances in the LMDM) is not always straightforward in its current formulation. In this paper we introduce a simple algebraic form for calculating LMDM forecast covariances. Calculation of the covariance between model regression components can also be useful and we shall present a simple algebraic method for calculating these component covariances. In the LMDM formulation, certain pairs of series are constrained to have zero forecast covariance. We shall also introduce a possible method to relax this restriction. Copyright © 2008 John Wiley & Sons, Ltd.