Motor domain phosphorylation and regulation of the Drosophila kinesin 13, KLP10A

Microtubule (MT)-destabilizing kinesin 13s perform fundamental roles throughout the cell cycle. In this study, we show that the Drosophila melanogaster kinesin 13, KLP10A, is phosphorylated in vivo at a conserved serine (S573) positioned within the α-helix 5 of the motor domain. In vitro, a phosphomimic KLP10A S573E mutant displays a reduced capacity to depolymerize MTs but normal affinity for the MT lattice. In cells, replacement of endogenous KLP10A with KLP10A S573E dampens MT plus end dynamics throughout the cell cycle, whereas a nonphosphorylatable S573A mutant apparently enhances activity during mitosis. Electron microscopy suggests that KLP10A S573 phosphorylation alters its association with the MT lattice, whereas molecular dynamics simulations reveal how KLP10A phosphorylation can alter the kinesin–MT interface without changing important structural features within the motor’s core. Finally, we identify casein kinase 1α as a possible candidate for KLP10A phosphorylation. We propose a model in which phosphorylation of the KLP10A motor domain provides a regulatory switch controlling the time and place of MT depolymerization

Empirical analysis of the relationship between CC and SLOC in a large corpus of Java methods and C functions

Measuring the internal quality of source code is one of the traditional goals of making software development into an engineering discipline. Cyclomatic Complexity (CC) is an often used source code quality metric, next to Source Lines of Code (SLOC). However, the use of the CC metric is challenged by the repeated claim that CC is redundant with respect to SLOC due to strong linear correlation. We conducted an extensive literature study of the CC/SLOC correlation results. Next, we tested correlation on large Java (17.6 M methods) and C (6.3 M functions) corpora. Our results show that linear correlation between SLOC and CC is only moderate as caused by increasingly high variance. We further observe that aggregating CC and SLOC as well as performing a power transform improves the correlation. Our conclusion is that the observed linear correlation between CC and SLOC of Java methods or C functions is not strong enough to conclude that CC is redundant with SLOC. This conclusion contradicts earlier claims from literature, but concurs with the widely accepted practice of measuring of CC next to SLOC

A doublecortin containing microtubule-associated protein is implicated in mechanotransduction in Drosophila sensory cilia

Mechanoreceptors are sensory cells that transduce mechanical stimuli into electrical signals and mediate the perception of sound, touch and acceleration. Ciliated mechanoreceptors possess an elaborate microtubule cytoskeleton that facilitates the coupling of external forces to the transduction apparatus. In a screen for genes preferentially expressed in Drosophila campaniform mechanoreceptors, we identified DCX-EMAP, a unique member of the EMAP family (echinoderm–microtubule-associated proteins) that contains two doublecortin domains. DCX-EMAP localizes to the tubular body in campaniform receptors and to the ciliary dilation in chordotonal mechanoreceptors in Johnston's organ, the fly's auditory organ. Adult flies carrying a piggyBac insertion in the DCX-EMAP gene are uncoordinated and deaf and display loss of mechanosensory transduction and amplification. Electron microscopy of mutant sensilla reveals loss of electron-dense materials within the microtubule cytoskeleton in the tubular body and ciliary dilation. Our results establish a catalogue of candidate genes for Drosophila mechanosensation and show that one candidate, DCX-EMAP, is likely to be required for mechanosensory transduction and amplification

Bayesian Computation with Intractable Likelihoods

This article surveys computational methods for posterior inference with intractable likelihoods, that is where the likelihood function is unavailable in closed form, or where evaluation of the likelihood is infeasible. We review recent developments in pseudo-marginal methods, approximate Bayesian computation (ABC), the exchange algorithm, thermodynamic integration, and composite likelihood, paying particular attention to advancements in scalability for large datasets. We also mention R and MATLAB source code for implementations of these algorithms, where they are available.Comment: arXiv admin note: text overlap with arXiv:1503.0806

Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase, leading to progressive accumulation of glycosaminoglycans in nearly all cell types, tissues and organs. Clinical manifestations include severe airway obstruction, skeletal deformities, cardiomyopathy and, in most patients, neurological decline. Death usually occurs in the second decade of life, although some patients with less severe disease have survived into their fifth or sixth decade. Until recently, there has been no effective therapy for MPS II, and care has been palliative. Enzyme replacement therapy (ERT) with recombinant human iduronate-2-sulphatase (idursulfase), however, has now been introduced. Weekly intravenous infusions of idursulfase have been shown to improve many of the signs and symptoms and overall wellbeing in patients with MPS II. This paper provides an overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS II and provides recommendations for the use of ERT. The issue of treating very young patients and those with CNS involvement is also discussed. ERT with idursulfase has the potential to benefit many patients with MPS II, especially if started early in the course of the disease

Signaling Mechanisms of Vav3, a Guanine Nucleotide Exchange Factor and Androgen Receptor Coactivator, in Physiology and Prostate Cancer Progression

The Rho GTPase guanine nucleotide exchange factor (GEF) Vav3 is the third member of the Vavfamily of GEFS and is activated by tyrosine phosphorylation. Through stimulation of Rho GTPaseactivity, Vav3 promotes cell migration, invasion, and other cellular processes. Work from our laboratory first established that Vav3 is upregulated in models of castration-resistant prostate cancer progression and enhances androgen receptor as well as androgen receptor splice variant activity. Recent analysis of clinical specimens supports Vav3 as a potential biomarker of aggressive prostate cancer. Consistent with a role in promoting castration-­resistant disease, Vav3 is a versatile enhancer of androgen receptor by both ligand-dependent and ligand-independent mechanisms and as such impacts established pathways of androgen receptor reactivation in advanced prostate cancer. Distinct Vav3 domains and mechanisms participate in ligand-dependent and -independent androgen receptor coactivation. To provide a physiologic context, we review Vav3 actions elucidated by gene knockout studies. This chapter describes the pervasive role of Vav3 in progression of prostate cancer to castration resistance. We discuss the mechanisms by which prostate cancer cells exploit Vav3 signaling to promote androgen receptor activity under different hormonal milieus, which are relevant to clinical prostate cancer. Lastly, we review the data on the emerging role for Vav3 in other cancers ranging from leukemias to gliomas.https://nsuworks.nova.edu/hpd_medsci_faculty_books/1002/thumbnail.jp

A 10 year case study on the changing determinants of University student satisfaction in the UK

Higher Education (HE), once the prerogative of a tiny elite, is now accessible to larger numbers of people around the world than ever before yet despite the fact that an understanding of student satisfaction has never been more important for today’s universities, the concept remains poorly understood. Here we use published data from the UK’s National Student Survey (NSS), representing data from 2.3 million full-time students collected from 2007 to 2016, as a case study of the benefits and limitations of measuring student satisfaction that might have applicability for other countries, particularly those that, like the UK, have experienced significant growth in student numbers. The analyses showed that the factor structure of the NSS remained generally stable and that the ability of the NSS to discriminate between different subjects at different universities actually improved over the ten-year sample period. The best predictors of overall satisfaction were 'Teaching Quality' and 'Organisation & Management', with 'Assessment & Feedback' having relatively weak predictive ability, despite the sector's tangible efforts to improve on this metric. The tripling of student fees in 2012 for English students (but not the rest of the UK) was used as a ‘natural experiment’ to investigate the sensitivity of student satisfaction ratings to the real economic costs of HE. The tuition fee increase had no identifiable negative effect, with student satisfaction steadily improving throughout the decade. Although the NSS was never designed to measure perceived value-for money, its insensitivity to major changes in the economic costs of HE to the individual suggest that the conventional concept of student satisfaction is incomplete. As such we propose that the concept of student satisfaction: (i) needs to be widened to take into account the broader economic benefits to the individual student by including measures of perceived value-for-money and (ii) should measure students’ level of satisfaction in the years post-graduation, by which time they may have a greater appreciation of the value of their degree in the workplace

Nighttime assaults: using a national emergency department monitoring system to predict occurrence, target prevention and plan services

Background: Emergency department (ED) data have the potential to provide critical intelligence on when violence is most likely to occur and the characteristics of those who suffer the greatest health impacts. We use a national experimental ED monitoring system to examine how it could target violence prevention interventions towards at risk communities and optimise acute responses to calendar, holiday and other celebration-related changes in nighttime assaults. Methods: A cross-sectional examination of nighttime assault presentations (6.01 pm to 6.00 am; n = 330,172) over a three-year period (31st March 2008 to 30th March 2011) to English EDs analysing changes by weekday, month, holidays, major sporting events, and demographics of those presenting. Results: Males are at greater risk of assault presentation (adjusted odds ratio [AOR] 3.14, 95% confidence intervals [CIs] 3.11-3.16; P < 0.001); with male:female ratios increasing on more violent nights. Risks peak at age 18 years. Deprived individuals have greater risks of presenting across all ages (AOR 3.87, 95% CIs 3.82-3.92; P < 0.001). Proportions of assaults from deprived communities increase midweek. Female presentations in affluent areas peak aged 20 years. By age 13, females from deprived communities exceed this peak. Presentations peak on Friday and Saturday nights and the eves of public holidays; the largest peak is on New Year’s Eve. Assaults increase over summer with a nadir in January. Impacts of annual celebrations without holidays vary. Some (Halloween, Guy Fawkes and St Patrick’s nights) see increased assaults while others (St George’s and Valentine’s Day nights) do not. Home nation World Cup football matches are associated with nearly a three times increase in midweek assault presentation. Other football and rugby events examined show no impact. The 2008 Olympics saw assaults fall. The overall calendar model strongly predicts observed presentations (R2 = 0.918; P < 0.001). Conclusions: To date, the role of ED data has focused on helping target nightlife police activity. Its utility is much greater; capable of targeting and evaluating multi-agency life course approaches to violence prevention and optimising frontline resources. National ED data are critical for fully engaging health services in the prevention of violence