The molecular basis for kinesin functional specificity during mitosis

Microtubule-based motor proteins play key roles dur-ing mitosis to assemble the bipolar spindle, define the cell division axis, and align and segregate the chromo-somes. The majority of mitotic motors are members of the kinesin superfamily. Despite sharing a conserved catalytic core, each kinesin has distinct functions and localization, and is uniquely regulated in time and space. These distinct behaviors and functional specific-ity are generated by variations in the enzymatic domain as well as the non-conserved regions outside of the kinesin motor domain and the stalk. These flanking regions can directly modulate the properties of the kinesin motor through dimerization or self-interactions, and can associate with extrinsic factors, such as microtubule or DNA binding proteins, to pro-vide additional functional properties. This review dis-cusses the recently identified molecular mechanisms that explain how the control and functional specifica-tion of mitotic kinesins is achieved. VC 2013 Wiley Periodicals, Inc. Key Words: mitosis; kinesin; microtubules; motors; regulatio

Reverse engineering of force integration during mitosis in the Drosophila embryo

The mitotic spindle is a complex macromolecular machine that coordinates accurate chromosome segregation. The spindle accomplishes its function using forces generated by microtubules (MTs) and multiple molecular motors, but how these forces are integrated remains unclear, since the temporal activation profiles and the mechanical characteristics of the relevant motors are largely unknown. Here, we developed a computational search algorithm that uses experimental measurements to ‘reverse engineer' molecular mechanical machines. Our algorithm uses measurements of length time series for wild-type and experimentally perturbed spindles to identify mechanistic models for coordination of the mitotic force generators in Drosophila embryo spindles. The search eliminated thousands of possible models and identified six distinct strategies for MT–motor integration that agree with available data. Many features of these six predicted strategies are conserved, including a persistent kinesin-5-driven sliding filament mechanism combined with the anaphase B-specific inhibition of a kinesin-13 MT depolymerase on spindle poles. Such conserved features allow predictions of force–velocity characteristics and activation–deactivation profiles of key mitotic motors. Identified differences among the six predicted strategies regarding the mechanisms of prometaphase and anaphase spindle elongation suggest future experiments

Evaluation of a servo settling algorithm

The aim of this work is to discuss methods of friction identification and provide experimental evaluation of a novel control algorithm that enhances settling after point-to-point motion. This algorithm is called the Nonlinear Integral Action Settling Algorithm or NIASA. As the name suggests, the integral gain is nonlinear, and is based upon a Dahl friction model. The settling resulting from PID + NIASA control is nearly exponential, and governed by a time constant that is specified in the control design. As the NIASA algorithm requires, friction parameters must be identified for the servo under test. Two methods of friction identification (Step Tests and Identification Profile) are contrasted and found to provide comparable results, although the latter can provide advantages. The identified friction parameters are in turn used to perform four sets of control experiments; two PID controllers (standard factory tuning and high performance PID with acceleration feedforward) are tested both with and without NIASA compensation. In the case study with a factory tuned PID controller, servo settling times to within ±3-100 nm, are reduced by between 80.5 and 87.4 when NIASA compensation is added. When the NIASA compensator is added to the high performance PID controller, servo settling time is still reduced by between 50.5 and 73.0. Although the NIASA compensator was designed to increase settling performance for relatively large point-to-point motions, similar positive results are achieved when the method is applied to smaller step motions that do not leave the pre-rolling friction regime. Frequency domain analyses demonstrated the nonlinear loop-gain of the plant, with a clear distinction between the rolling and pre-rolling friction cases. As expected, the nonlinear loop gain was found to lower the bandwidth for smaller motions. Adding NIASA control was observed to increase the bandwidth for small motions by a factor of 3-6, while having little effect for large motions. © 2012 Published by Elsevier Inc. All rights reserved

Nonlinear control algorithm for improving settling time in systems with friction

A nonlinear control algorithm that greatly reduces settling time in precision instruments with rolling element bearings is proposed. Reductions of 80.5%-87.4% in settling time were achieved when settling to within 3-100 nm of the commanded position. Final settling of such systems is typically impacted by the nonlinearity in the pre-rolling friction regime, which manifests as a hysteretic stiffness. Consequently, the integral term in the controller can take a long time to respond. In this paper, a nonlinear integral action settling algorithm is presented. The nonlinear integral gain takes the form of a Dahl friction model. Since the integral gain mimics hysteretic stiffness, the output of the integral control term is instantaneously set to a large value after each direction change, greatly improving settling response. A nearly first-order error dynamic results, which has a user-definable time constant. Before the algorithm can be implemented, the Coulomb friction and initial contact stiffness in the Dahl model must be experimentally determined for the stage. A sensitivity study is performed on the initial contact stiffness, which was found in other works to dictate the stability of the algorithm. © 1993-2012 IEEE

Evaluation of a servo settling algorithm

The aim of this work is to discuss methods of friction identification and provide experimental evaluation of a novel control algorithm that enhances settling after point-to-point motion. This algorithm is called the Nonlinear Integral Action Settling Algorithm or NIASA. As the name suggests, the integral gain is nonlinear, and is based upon a Dahl friction model. The settling resulting from PID + NIASA control is nearly exponential, and governed by a time constant that is specified in the control design. As the NIASA algorithm requires, friction parameters must be identified for the servo under test. Two methods of friction identification (Step Tests and Identification Profile) are contrasted and found to provide comparable results, although the latter can provide advantages. The identified friction parameters are in turn used to perform four sets of control experiments; two PID controllers (standard factory tuning and high performance PID with acceleration feedforward) are tested both with and without NIASA compensation. In the case study with a factory tuned PID controller, servo settling times to within ±3-100 nm, are reduced by between 80.5 and 87.4 when NIASA compensation is added. When the NIASA compensator is added to the high performance PID controller, servo settling time is still reduced by between 50.5 and 73.0. Although the NIASA compensator was designed to increase settling performance for relatively large point-to-point motions, similar positive results are achieved when the method is applied to smaller step motions that do not leave the pre-rolling friction regime. Frequency domain analyses demonstrated the nonlinear loop-gain of the plant, with a clear distinction between the rolling and pre-rolling friction cases. As expected, the nonlinear loop gain was found to lower the bandwidth for smaller motions. Adding NIASA control was observed to increase the bandwidth for small motions by a factor of 3-6, while having little effect for large motions. © 2012 Published by Elsevier Inc. All rights reserved

Chlorpromazine for schizophrenia: a Cochrane systematic review of 50 years of randomised controlled trials

BACKGROUND: Chlorpromazine (CPZ) remains one of the most common drugs used for people with schizophrenia worldwide, and a benchmark against which other treatments can be evaluated. Quantitative reviews are rare; this one evaluates the effects of chlorpromazine in the treatment of schizophrenia in comparison with placebo. METHODS: We sought all relevant randomised controlled trials (RCT) comparing chlorpromazine to placebo by electronic and reference searching, and by contacting trial authors and the pharmaceutical industry. Data were extracted from selected trials and, where possible, synthesised and random effects relative risk (RR), the number needed to treat (NNT) and their 95% confidence intervals (CI) calculated. RESULTS: Fifty RCTs from 1955–2000 were included with 5276 people randomised to CPZ or placebo. They constitute 2008 person-years spent in trials. Meta-analysis of these trials showed that chlorpromazine promotes a global improvement (n = 1121, 13 RCTs, RR 0.76 CI 0.7 to 0.9, NNT 7 CI 5 to 10), although a considerable placebo response is also seen. People allocated to chlorpromazine tended not to leave trials early in both the short (n = 945, 16 RCTs, RR 0.74 CI 0.5 to 1.1) and medium term (n = 1861, 25 RCTs, RR 0.79 CI 0.6 to 1.1). There were, however, many adverse effects. Chlorpromazine is sedating (n = 1242, 18 RCTs, RR 2.3 CI 1.7 to 3.1, NNH 6 CI 5 to 8), increases a person's chances of experiencing acute movement disorders, Parkinsonism and causes low blood pressure with dizziness and dry mouth. CONCLUSION: It is understandable why the World Health Organization (WHO) have endorsed and included chlorpromazine in their list of essential drugs for use in schizophrenia. Low- and middle-income countries may have more complete evidence upon which to base their practice compared with richer nations using recent innovations

The conceptualisation and measurement of DSM-5 Internet Gaming Disorder: the development of the IGD-20 Test

Background: Over the last decade, there has been growing concern about ‘gaming addiction’ and its widely documented detrimental impacts on a minority of individuals that play excessively. The latest (fifth) edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5) included nine criteria for the potential diagnosis of Internet Gaming Disorder (IGD) and noted that it was a condition that warranted further empirical study. Aim: The main aim of this study was to develop a valid and reliable standardised psychometrically robust tool in addition to providing empirically supported cut-off points. Methods: A sample of 1003 gamers (85.2% males; mean age 26 years) from 57 different countries were recruited via online gaming forums. Validity was assessed by confirmatory factor analysis (CFA), criterion-related validity, and concurrent validity. Latent profile analysis was also carried to distinguish disordered gamers from non-disordered gamers. Sensitivity and specificity analyses were performed to determine an empirical cut-off for the test. Results: The CFA confirmed the viability of IGD-20 Test with a six-factor structure (salience, mood modification, tolerance, withdrawal, conflict and relapse) for the assessment of IGD according to the nine criteria from DSM-5. The IGD-20 Test proved to be valid and reliable. According to the latent profile analysis, 5.3% of the total participants were classed as disordered gamers. Additionally, an optimal empirical cut-off of 71 points (out of 100) seemed to be adequate according to the sensitivity and specificity analyses carried

Stabilising Lyme Regis – a strategic approach

Coastal erosion and landslides have been a constant threat to Lyme Regis in West Dorset, UK for over 250 years. By the 1980s, the frequency and scale of coastal erosion and land instability had reached a point whereby the local council realised that a change from the previous ad hoc repair and protection approach was needed to secure the long-term future of the town. An environmental improvements initiative was developed from then onwards to provide a strategic and integrated programme of coast protection and cliff stabilisation measures designed to mitigate the increasing threat of climate change, coastal erosion and landslides, while respecting the site’s unique heritage and environmental interests. This paper outlines the background and principal phases of the project that have been successfully delivered over the period 1990–2015