Evaluation and comparison of mammalian subcellular localization prediction methods

BACKGROUND: Determination of the subcellular location of a protein is essential to understanding its biochemical function. This information can provide insight into the function of hypothetical or novel proteins. These data are difficult to obtain experimentally but have become especially important since many whole genome sequencing projects have been finished and many resulting protein sequences are still lacking detailed functional information. In order to address this paucity of data, many computational prediction methods have been developed. However, these methods have varying levels of accuracy and perform differently based on the sequences that are presented to the underlying algorithm. It is therefore useful to compare these methods and monitor their performance. RESULTS: In order to perform a comprehensive survey of prediction methods, we selected only methods that accepted large batches of protein sequences, were publicly available, and were able to predict localization to at least nine of the major subcellular locations (nucleus, cytosol, mitochondrion, extracellular region, plasma membrane, Golgi apparatus, endoplasmic reticulum (ER), peroxisome, and lysosome). The selected methods were CELLO, MultiLoc, Proteome Analyst, pTarget and WoLF PSORT. These methods were evaluated using 3763 mouse proteins from SwissProt that represent the source of the training sets used in development of the individual methods. In addition, an independent evaluation set of 2145 mouse proteins from LOCATE with a bias towards the subcellular localization underrepresented in SwissProt was used. The sensitivity and specificity were calculated for each method and compared to a theoretical value based on what might be observed by random chance. CONCLUSION: No individual method had a sufficient level of sensitivity across both evaluation sets that would enable reliable application to hypothetical proteins. All methods showed lower performance on the LOCATE dataset and variable performance on individual subcellular localizations was observed. Proteins localized to the secretory pathway were the most difficult to predict, while nuclear and extracellular proteins were predicted with the highest sensitivity

Calcium channel blockers for acute traumatic brain injury.

BACKGROUND: Acute traumatic brain injury is a major cause of death and disability. Calcium channel blockers (calcium antagonists) have been used in an attempt to prevent cerebral vasospasm after injury, maintain blood flow to the brain, and so prevent further damage. OBJECTIVES: To estimate the effects of calcium channel blockers in patients with acute traumatic brain injury, and in a subgroup of brain injury patients with traumatic subarachnoid haemorrhage. SEARCH STRATEGY: Handsearching and electronic searching for randomised controlled trials. SELECTION CRITERIA: Randomised controlled trials in patients with all levels of severity of clinically diagnosed acute traumatic brain injury. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the identified studies for eligibility and extracted data from each study. Summary odds ratios were calculated using the Mantel-Haenszel method. MAIN RESULTS: Six RCTs were identified as eligible for inclusion in the systematic review. The effect of calcium channel blockers on the risk of death was reported in five of the RCTs. The pooled odds ratio (OR) for the five studies was 0.91 (95% confidence interval [95%CI] 0.70-1.17). For the four RCTs that reported death and severe disability (unfavourable outcome), the pooled odds ratio was 0.85 (95%CI 0.68-1.07). In the two RCTs which reported the risk of death in a subgroup of traumatic subarachnoid haemorrhage patients, the pooled odds ratio was 0.59 (95%CI 0.37-0.94). Three RCTs reported death and severe disability as an outcome in this subgroup, and the pooled odds ratio was 0.67 (95%CI 0.46-0.98). REVIEWER'S CONCLUSIONS: This systematic review of randomised controlled trials of calcium channel blockers in acute traumatic head injury patients shows that considerable uncertainty remains over their effects. The effect of nimodipine in a subgroup of brain injury patients with subarachnoid haemorrhage shows a beneficial effect, though the increase in adverse reactions suffered by the intervention group may mean that the drug is harmful for some patients

LOCATE: a mouse protein subcellular localization database

We present here LOCATE, a curated, web-accessible database that houses data describing the membrane organization and subcellular localization of proteins from the FANTOM3 Isoform Protein Sequence set. Membrane organization is predicted by the high-throughput, computational pipeline MemO. The subcellular locations of selected proteins from this set were determined by a high-throughput, immunofluorescence-based assay and by manually reviewing >1700 peer-reviewed publications. LOCATE represents the first effort to catalogue the experimentally verified subcellular location and membrane organization of mammalian proteins using a high-throughput approach and provides localization data for ∼40% of the mouse proteome. It is available at

LOCATE: a mammalian protein subcellular localization database

LOCATE is a curated, web-accessible database that houses data describing the membrane organization and subcellular localization of mouse and human proteins. Over the past 2 years, the data in LOCATE have grown substantially. The database now contains high-quality localization data for 20% of the mouse proteome and general localization annotation for nearly 36% of the mouse proteome. The proteome annotated in LOCATE is from the RIKEN FANTOM Consortium Isoform Protein Sequence sets which contains 58 128 mouse and 64 637 human protein isoforms. Other additions include computational subcellular localization predictions, automated computational classification of experimental localization image data, prediction of protein sorting signals and third party submission of literature data. Collectively, this database provides localization proteome for individual subcellular compartments that will underpin future systematic investigations of these regions. It is available at http://locate.imb.uq.edu.au

Parkinson disease-linked Vps35 R524W mutation impairs the endosomal association of retromer and induces α-synuclein aggregation

Endosomal sorting is a highly orchestrated cellular process. Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. The cycling of retromer on and off the endosomal membrane is regulated by a network of retromer-interacting proteins. Here, we find that Parkinson disease-associated Vps35 variant, R524W, but not P316S, is a loss-of-function mutation as marked by a reduced association with this regulatory network and dysregulation of endosomal receptor sorting. Expression of Vps35 R524W-containing retromer results in the accumulation of intracellular α-synuclein-positive aggregates, a hallmark of Parkinson disease. Overall, the Vps35 R524W-containing retromer has a decreased endosomal association, which can be partially rescued by R55, a small molecule previously shown to stabilize the retromer complex, supporting the potential for future targeting of the retromer complex in the treatment of Parkinson disease

A New Solid Deuterium Source of Ultra-Cold Neutrons

In polarized neutron decay, the angular correlation between the neutron spin and the direction of emission of the electron is characterized by the coefficient A. Measuring A involves determining the forward-backward asymmetry of the decay beta with respect to the direction of the neutron polarization. The value of A, when combined with measurements of the neutron lifetime, determines the values of the vector and axial vector weak coupling constants, Gv and GA. The value of Gv can also be determined by measurements of superallowed nuclear beta decay and by requiring that the Cabibo-Kobayashi-Maskawi (CKM) mixing matrix be unitary along with the measured value of other elements of the CKM matrix

The tactical mimicry of social enterprise strategies: acting ‘as if’ in the everyday life of third sector organizations

Using England as a paradigmatic case of the „enterprising up ‟ of the third sector through social enterprise policies and programs, this article sheds light on resistance as enacted through dramaturgical identification with government strategies. Drawing from a longitudinal qualitative research study, which is interpreted via Michel de Certeau‟s theory of the everyday, we present the case study of Teak, a charitable regeneration company, to illustrate how its Chief Executive Liam „acted as ‟ a social entrepreneur in order to gain access to important resources. We establish „tactical mimicry ‟ as a sensitizing concept to suggest that third sector practitioners ‟ identification with the normative premises of „social enterprise ‟ is part of a parasitical prosaics geared toward appropriating public money. While tactical mimicry conforms to strategies only in order to exploit them, its ultimate aim is to increase potentials of collective agency outside the direct influence of power. The contribution we make is threefold: first, we extend the recent debate on productive resistance by highlighting how „playing the game ‟ without changing existing relations of power can nevertheless produce largely favorable outcomes. Second, we suggest that recognition of the productive potential of tactical mimicry requires methodologies which pay attention to the spatial and temporal dynamics of resistance. And third, we argue that explaining „social enterprise‟ without consideration of the non-discursive, mainly financial resources made available to those who identify with it, necessarily risks overlooking a crucial element of the dramaturgical dynamic of discourse

Emotional Complexity and the Neural Representation of Emotion in Motion

According to theories of emotional complexity, individuals low in emotional complexity encode and represent emotions in visceral or action-oriented terms, whereas individuals high in emotional complexity encode and represent emotions in a differentiated way, using multiple emotion concepts. During functional magnetic resonance imaging, participants viewed valenced animated scenarios of simple ball-like figures attending either to social or spatial aspects of the interactions. Participant’s emotional complexity was assessed using the Levels of Emotional Awareness Scale. We found a distributed set of brain regions previously implicated in processing emotion from facial, vocal and bodily cues, in processing social intentions, and in emotional response, were sensitive to emotion conveyed by motion alone. Attention to social meaning amplified the influence of emotion in a subset of these regions. Critically, increased emotional complexity correlated with enhanced processing in a left temporal polar region implicated in detailed semantic knowledge; with a diminished effect of social attention; and with increased differentiation of brain activity between films of differing valence. Decreased emotional complexity was associated with increased activity in regions of pre-motor cortex. Thus, neural coding of emotion in semantic vs action systems varies as a function of emotional complexity, helping reconcile puzzling inconsistencies in neuropsychological investigations of emotion recognition

Mindfulness as a General Ingredient of Successful Psychotherapy

In this chapter I present a psychological conceptualization of mindfulness based on constructs in common therapeutic parlance. Taking a functional approach based on the skills and recognitions patients gain from the exercises commonly used in mindfulness training and avoiding exotic and cryptic language, it makes apparent both the commonality mindfulness has with modalities therapists will be already using in their clinical practice and the ways in which it may add something new and therapeutically useful. It also describes the evolutionary pressures that have shaped the biological imperatives driving the default movements of attention that result in day-to-day experience being experienced as less than pleasant; defaults that result in both the need for, and the challenge of cultivating mindfulness. So, while the instructions and narrative within which these principles are introduced into therapy will need to be adapted to the patient’s background and circumstances, an understanding and grounding in the principles enables the therapist both to skillfully make these adaptations to the training exercises and to make them immediately sensible to the patient, including the challenges they will meet in getting started