Post-selection point and interval estimation of signal sizes in Gaussian samples

We tackle the problem of the estimation of a vector of means from a single vector-valued observation $y$. Whereas previous work reduces the size of the estimates for the largest (absolute) sample elements via shrinkage (like James-Stein) or biases estimated via empirical Bayes methodology, we take a novel approach. We adapt recent developments by Lee et al (2013) in post selection inference for the Lasso to the orthogonal setting, where sample elements have different underlying signal sizes. This is exactly the setup encountered when estimating many means. It is shown that other selection procedures, like selecting the $K$ largest (absolute) sample elements and the Benjamini-Hochberg procedure, can be cast into their framework, allowing us to leverage their results. Point and interval estimates for signal sizes are proposed. These seem to perform quite well against competitors, both recent and more tenured. Furthermore, we prove an upper bound to the worst case risk of our estimator, when combined with the Benjamini-Hochberg procedure, and show that it is within a constant multiple of the minimax risk over a rich set of parameter spaces meant to evoke sparsity.Comment: 27 pages, 13 figure

How to measure mood in nutrition research

© 2014 The Authors. Mood is widely assessed in nutrition research, usually with rating scales. A core assumption is that positive mood reinforces ingestion, so it is important to measure mood well. Four relevant theoretical issues are reviewed: (i) the distinction between protracted and transient mood; (ii) the distinction between mood and emotion; (iii) the phenomenology of mood as an unstable tint to consciousness rather than a distinct state of consciousness; (iv) moods can be caused by social and cognitive processes as well as physiological ones. Consequently, mood is difficult to measure and mood rating is easily influenced by non-nutritive aspects of feeding, the psychological, social and physical environment where feeding occurs, and the nature of the rating system employed. Some of the difficulties are illustrated by reviewing experiments looking at the impact of food on mood. The mood-rating systems in common use in nutrition research are then reviewed, the requirements of a better mood-rating system are described, and guidelines are provided for a considered choice of mood-rating system including that assessment should: have two main dimensions; be brief; balance simplicity and comprehensiveness; be easy to use repeatedly. Also mood should be assessed only under conditions where cognitive biases have been considered and controlled

Cryo-EM structure of the potassium-chloride cotransporter KCC4 in lipid nanodiscs.

Cation-chloride-cotransporters (CCCs) catalyze transport of Cl- with K+ and/or Na+across cellular membranes. CCCs play roles in cellular volume regulation, neural development and function, audition, regulation of blood pressure, and renal function. CCCs are targets of clinically important drugs including loop diuretics and their disruption has been implicated in pathophysiology including epilepsy, hearing loss, and the genetic disorders Andermann, Gitelman, and Bartter syndromes. Here we present the structure of a CCC, the Mus musculus K+-Cl- cotransporter (KCC) KCC4, in lipid nanodiscs determined by cryo-EM. The structure, captured in an inside-open conformation, reveals the architecture of KCCs including an extracellular domain poised to regulate transport activity through an outer gate. We identify binding sites for substrate K+ and Cl- ions, demonstrate the importance of key coordinating residues for transporter activity, and provide a structural explanation for varied substrate specificity and ion transport ratio among CCCs. These results provide mechanistic insight into the function and regulation of a physiologically important transporter family

DNA Sequence Determinants Controlling Affinity, Stability and Shape of DNA Complexes Bound by the Nucleoid Protein Fis.

The abundant Fis nucleoid protein selectively binds poorly related DNA sequences with high affinities to regulate diverse DNA reactions. Fis binds DNA primarily through DNA backbone contacts and selects target sites by reading conformational properties of DNA sequences, most prominently intrinsic minor groove widths. High-affinity binding requires Fis-stabilized DNA conformational changes that vary depending on DNA sequence. In order to better understand the molecular basis for high affinity site recognition, we analyzed the effects of DNA sequence within and flanking the core Fis binding site on binding affinity and DNA structure. X-ray crystal structures of Fis-DNA complexes containing variable sequences in the noncontacted center of the binding site or variations within the major groove interfaces show that the DNA can adapt to the Fis dimer surface asymmetrically. We show that the presence and position of pyrimidine-purine base steps within the major groove interfaces affect both local DNA bending and minor groove compression to modulate affinities and lifetimes of Fis-DNA complexes. Sequences flanking the core binding site also modulate complex affinities, lifetimes, and the degree of local and global Fis-induced DNA bending. In particular, a G immediately upstream of the 15 bp core sequence inhibits binding and bending, and A-tracts within the flanking base pairs increase both complex lifetimes and global DNA curvatures. Taken together, our observations support a revised DNA motif specifying high-affinity Fis binding and highlight the range of conformations that Fis-bound DNA can adopt. The affinities and DNA conformations of individual Fis-DNA complexes are likely to be tailored to their context-specific biological functions

Control of DNA minor groove width and Fis protein binding by the purine 2-amino group.

The width of the DNA minor groove varies with sequence and can be a major determinant of DNA shape recognition by proteins. For example, the minor groove within the center of the Fis-DNA complex narrows to about half the mean minor groove width of canonical B-form DNA to fit onto the protein surface. G/C base pairs within this segment, which is not contacted by the Fis protein, reduce binding affinities up to 2000-fold over A/T-rich sequences. We show here through multiple X-ray structures and binding properties of Fis-DNA complexes containing base analogs that the 2-amino group on guanine is the primary molecular determinant controlling minor groove widths. Molecular dynamics simulations of free-DNA targets with canonical and modified bases further demonstrate that sequence-dependent narrowing of minor groove widths is modulated almost entirely by the presence of purine 2-amino groups. We also provide evidence that protein-mediated phosphate neutralization facilitates minor groove compression and is particularly important for binding to non-optimally shaped DNA duplexes

Diagnosis, investigation and management of hereditary spastic paraplegias in the era of next-generation sequencing.

The hereditary spastic paraplegias (HSPs) are a group of genetic conditions in which spastic paralysis of the legs is the principal clinical feature. This is caused by a relatively selective distal axonal degeneration involving the longest axons of the corticospinal tracts. Consequently, these conditions provide an opportunity to identify genes, proteins and cellular pathways that are critical for axonal health. In this review, we will provide a brief overview of the classification, clinical features and genetics of HSP, highlighting selected HSP subtypes (i.e. those associated with thin corpus callosum or cerebellar ataxia) that are of particular clinical interest. We will then discuss appropriate investigation strategies for HSPs, suggesting how these might evolve with the introduction of next-generation sequencing technology. Finally, we will discuss the management of HSP, an area somewhat neglected by HSP research.We thank Rhys Roberts for reviewing the manuscript. This work was supported by grants from the UK Medical Research Council [MR/M00046X/1]; the Wellcome Trust [082381]; the Tom Wahlig Stiftung; and the UK HSP Support Group. The Cambridge Institute for Medical Research is supported by a Wellcome Trust Strategic Award [100140].This is the final published version. It first appeared at http://link.springer.com/article/10.1007%2Fs00415-014-7598-y