Computational analysis of the LRRK2 interactome.

LRRK2 was identified in 2004 as the causative protein product of the Parkinson's disease locus designated PARK8. In the decade since then, genetic studies have revealed at least 6 dominant mutations in LRRK2 linked to Parkinson's disease, alongside one associated with cancer. It is now well established that coding changes in LRRK2 are one of the most common causes of Parkinson's. Genome-wide association studies (GWAs) have, more recently, reported single nucleotide polymorphisms (SNPs) around the LRRK2 locus to be associated with risk of developing sporadic Parkinson's disease and inflammatory bowel disorder. The functional research that has followed these genetic breakthroughs has generated an extensive literature regarding LRRK2 pathophysiology; however, there is still no consensus as to the biological function of LRRK2. To provide insight into the aspects of cell biology that are consistently related to LRRK2 activity, we analysed the plethora of candidate LRRK2 interactors available through the BioGRID and IntAct data repositories. We then performed GO terms enrichment for the LRRK2 interactome. We found that, in two different enrichment portals, the LRRK2 interactome was associated with terms referring to transport, cellular organization, vesicles and the cytoskeleton. We also verified that 21 of the LRRK2 interactors are genetically linked to risk for Parkinson's disease or inflammatory bowel disorder. The implications of these findings are discussed, with particular regard to potential novel areas of investigation

Anterior cruciate ligament deficiency: rotational instability in the transverse plane. A preliminary laboratory in vivo study

Background. Rotational instability is a major feature of anterior cruciate ligament (ACL) deficiency. Few biomechanical studies have focused on the transverse plane when assessing the function of the ACL. Objective. To analyse the biomechanics of ACL deficient knees in the transverse plane under torsional conditions to detect rotational instability. Methods. Seven subjects (eight ACL deficiency) (ACLd group) and nine recreational athletes (controls) were recruited. Each performed two tasks: crossover and pivoting-jump. Biomechanical data were collected in a movement analysis laboratory. Comparisons were made for torque, rotation and torque curves in transverse plane between ACLd, contralateral knees and controls. Results. Torque curves showed and initial avoidance pattern followed by increased values in crossover task, and lesser values for ACLd group compared to controls in pivoting-jump task. Internal rotation in crossover was 19.8°, 13.7° and 19.1° for ACLd, contralateral and controls respectively (p = 0. 176). In pivoting-jump these values were 18.6°, 13.8° and 18.1° (p = 0.297). Crossover peak torque were 257, 178.4 and 184.8 Nmm for ACLd, contralateral and controls (p = 0.5), while pivoting-jump values were 238.4, 152.2 and 218 Nmm for ACLd, contralateral and controls (p = 0.288). Conclusion. Torque curve analysis identified a distinctive pattern differentiating ACLd and control group. However, no statistically significant differences were found in peak transverse plane parameters between groups

Gait disturbances in football, rugby players and skiers following anterior cruciate ligament reconstruction

Background. Patients who have undergone anterior cruciate ligament (ACL) reconstruction surgery may exhibit post-operative lower limb gait disturbances. Design. Laboratory in vivo controlled study. Kinematics and kinetics parameters of knee motion were measured in post-ACL reconstruction participants (n = 5; m = 4 / f = 1, age 30.6 years, height 179.2 cm, weight 80.4 kg) and control participants (n = 10; m = 6 / f = 4, age 30.3 years, height 173.5 cm, weight 65.3 kg). Kinematics and kinetics were recorded for normal gait, ‘cutting’ gait and ‘weaving’ gait (ẋ = 3 per gait type) using instrumented motion analysis and ground embedded force plates. Between groups, differences in knee joint alignment were determined in the frontal plane for normal gait,and in the coronal plane for cutting and weaving. Five of the subjects were recruited for this study had an ACL reconstruction in the past (at least two years before the test), and ten were part of a control group. Each subject performed three different tasks with both legs on a force plate: normal walking, a weaving movement, and a cutting movement. Kinematic and kinetic data were collected with four optoelectronic cameras and two force plates. Comparisons were made in the frontal plane for walking and in the coronal plane for cutting and weaving between the reconstructed knee and the contralateral, healthy knee in the late stance period. Results. There were no significant differences between the ACL reconstructed knees and the contralateral healthy knees in the walking task (p = 0.27 – 0.49). Knee coronal plane rotation showed between group similarity(cutting = 21.82° vs 11.29°, p = 0.175; weaving = 17.88 vs 21.34°, p = 0.406). Conclusions. There is an increased rotation of the knee during walking and cutting in ACL reconstructed knees when compared to the contralateral knee, although this difference was not statistically significant

Sequential Extensions of Causal and Evidential Decision Theory

Moving beyond the dualistic view in AI where agent and environment are separated incurs new challenges for decision making, as calculation of expected utility is no longer straightforward. The non-dualistic decision theory literature is split between causal decision theory and evidential decision theory. We extend these decision algorithms to the sequential setting where the agent alternates between taking actions and observing their consequences. We find that evidential decision theory has two natural extensions while causal decision theory only has one.Comment: ADT 201

The central image of a gravitationally lensed quasar

A galaxy can act as a gravitational lens, producing multiple images of a background object. Theory predicts there should be an odd number of images but, paradoxically, almost all observed lenses have 2 or 4 images. The missing image should be faint and appear near the galaxy's center. These ``central images'' have long been sought as probes of galactic cores too distant to resolve with ordinary observations. There are five candidates, but in one case the third image is not necessarily a central image, and in the others, the central component might be a foreground source rather than a lensed image. Here we report the most secure identification of a central image, based on radio observations of PMN J1632-0033, one of the latter candidates. Lens models incorporating the central image show that the mass of the lens galaxy's central black hole is less than 2 x 10^8 M_sun, and the galaxy's surface density at the location of the central image is more than 20,000 M_sun per square parsec, in agreement with expectations based on observations of galaxies hundreds of times closer to the Earth.Comment: Nature, in press [7 pp, 2 figs]. Standard media embargo applies before publicatio

Development of a decision aid to inform patients' and families' renal replacement therapy selection decisions.

BACKGROUND: Few educational resources have been developed to inform patients' renal replacement therapy (RRT) selection decisions. Patients progressing toward end stage renal disease (ESRD) must decide among multiple treatment options with varying characteristics. Complex information about treatments must be adequately conveyed to patients with different educational backgrounds and informational needs. Decisions about treatment options also require family input, as families often participate in patients' treatment and support patients' decisions. We describe the development, design, and preliminary evaluation of an informational, evidence-based, and patient-and family-centered decision aid for patients with ESRD and varying levels of health literacy, health numeracy, and cognitive function. METHODS: We designed a decision aid comprising a complementary video and informational handbook. We based our development process on data previously obtained from qualitative focus groups and systematic literature reviews. We simultaneously developed the video and handbook in "stages." For the video, stages included (1) directed interviews with culturally appropriate patients and families and preliminary script development, (2) video production, and (3) screening the video with patients and their families. For the handbook, stages comprised (1) preliminary content design, (2) a mixed-methods pilot study among diverse patients to assess comprehension of handbook material, and (3) screening the handbook with patients and their families. RESULTS: The video and handbook both addressed potential benefits and trade-offs of treatment selections. The 50-minute video consisted of demographically diverse patients and their families describing their positive and negative experiences with selecting a treatment option. The video also incorporated health professionals' testimonials regarding various considerations that might influence patients' and families' treatment selections. The handbook was comprised of written words, pictures of patients and health care providers, and diagrams describing the findings and quality of scientific studies comparing treatments. The handbook text was written at a 4th to 6th grade reading level. Pilot study results demonstrated that a majority of patients could understand information presented in the handbook. Patient and families screening the nearly completed video and handbook reviewed the materials favorably. CONCLUSIONS: This rigorously designed decision aid may help patients and families make informed decisions about their treatment options for RRT that are well aligned with their values

Maternal psychological distress in primary care and association with child behavioural outcomes at age three

Observational studies indicate children whose mothers have poor mental health are at increased risk of socio-emotional behavioural difficulties, but it is unknown whether these outcomes vary by the mothers’ mental health recognition and treatment status. To examine this question, we analysed linked longitudinal primary care and research data from 1078 women enrolled in the Born in Bradford cohort. A latent class analysis of treatment status and self-reported distress broadly categorised women as (a) not having a common mental disorder (CMD) that persisted through pregnancy and the first 2 years after delivery (N = 756, 70.1 %), (b) treated for CMD (N = 67, 6.2 %), or (c) untreated (N = 255, 23.7 %). Compared to children of mothers without CMD, 3-year-old children with mothers classified as having untreated CMD had higher standardised factor scores on the Strengths and Difficulties Questionnaire (d = 0.32), as did children with mothers classified as having treated CMD (d = 0.27). Results were only slightly attenuated in adjusted analyses. Children of mothers with CMD may be at risk for socio-emotional and behavioural difficulties. The development of effective treatments for CMD needs to be balanced by greater attempts to identify and treat women. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00787-015-0777-2) contains supplementary material, which is available to authorized users

MicroRNAs in cardiac arrhythmia: DNA sequence variation of MiR-1 and MiR-133A in long QT syndrome.

Long QT syndrome (LQTS) is a genetic cardiac condition associated with prolonged ventricular repolarization, primarily a result of perturbations in cardiac ion channels, which predisposes individuals to life-threatening arrhythmias. Using DNA screening and sequencing methods, over 700 different LQTS-causing mutations have been identified in 13 genes worldwide. Despite this, the genetic cause of 30-50% of LQTS is presently unknown. MicroRNAs (miRNAs) are small (∼ 22 nucleotides) noncoding RNAs which post-transcriptionally regulate gene expression by binding complementary sequences within messenger RNAs (mRNAs). The human genome encodes over 1800 miRNAs, which target about 60% of human genes. Consequently, miRNAs are likely to regulate many complex processes in the body, indeed aberrant expression of various miRNA species has been implicated in numerous disease states, including cardiovascular diseases. MiR-1 and MiR-133A are the most abundant miRNAs in the heart and have both been reported to regulate cardiac ion channels. We hypothesized that, as a consequence of their role in regulating cardiac ion channels, genetic variation in the genes which encode MiR-1 and MiR-133A might explain some cases of LQTS. Four miRNA genes (miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2), which encode MiR-1 and MiR-133A, were sequenced in 125 LQTS probands. No genetic variants were identified in miR-1-1 or miR-133a-1; but in miR-1-2 we identified a single substitution (n.100A> G) and in miR-133a-2 we identified two substitutions (n.-19G> A and n.98C> T). None of the variants affect the mature miRNA products. Our findings indicate that sequence variants of miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2 are not a cause of LQTS in this cohort

Testing for Network and Spatial Autocorrelation

Testing for dependence has been a well-established component of spatial statistical analyses for decades. In particular, several popular test statistics have desirable properties for testing for the presence of spatial autocorrelation in continuous variables. In this paper we propose two contributions to the literature on tests for autocorrelation. First, we propose a new test for autocorrelation in categorical variables. While some methods currently exist for assessing spatial autocorrelation in categorical variables, the most popular method is unwieldy, somewhat ad hoc, and fails to provide grounds for a single omnibus test. Second, we discuss the importance of testing for autocorrelation in data sampled from the nodes of a network, motivated by social network applications. We demonstrate that our proposed statistic for categorical variables can both be used in the spatial and network setting