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The pursuit of productivity and quality optimization in thin wall machining has given rise to a growing interest in robotic assisted milling. This is the interaction between robot, workpiece and machine tool, in which the robot is used to increase stiffness and damping of the structure during machining, via a controlled supporting force on the structure. In this research, the efficacy of the fixturing method is evaluated in pocket milling applications. Machining test results demonstrated decreased form error on the pocket floor.

Previous missions to Venus have revealed that encounters with plasma irregularities of atmospheric origin outside the atmosphere are not uncommon. A number of mechanisms have been proposed to discuss their origins as well as their roles in the atmospheric evolution of Venus. One such mechanism involves an ionopause with a wavelike appearance. By utilizing the magnetic field and plasma data from Venus Express (VEX), we present the first observational statistical analysis of the ionospheric boundary wave phenomena at Venus using data from 2006 to 2014. Results from the minimum variance analysis of all the photoelectron dropout events in the ionosphere reveal that the ionopause of Venus does not always appear to be smooth, but often exhibits a wavelike appearance. In the northern polar region of Venus, the normal directions of the rippled ionospheric boundary crossings lie mainly in the terminator plane with the largest component predominantly along the dawn‐dusk (YVSO) direction. The average estimated wavelength of the boundary wave is 212 ± 12 km and the average estimated velocity difference across the ionopause is 104 ± 6 km/s. The results suggest that the rippled boundary is a result of Kelvin‐Helmholtz Instability. Analysis reveals a correlation between the normal directions and the locations of the boundary wave with respect to Venus. This indicates the draping of magnetic field lines may play a role in enhancing the plasma flow along the dawn‐dusk direction, which could subsequently set up a velocity shear that favors the excitation of ionospheric boundary wave by the KHI along the dawn‐dusk direction.

Objectives To describe the spectrum of movement disorders and cerebrospinal fluid (CSF) neurotransmitter profiles in paediatric patients withPOLGdisease. Methods We identified children with genetically confirmedPOLGdisease, in whom CSF neurotransmitter analysis had been undertaken. Clinical data were collected retrospectively. CSF neurotransmitter levels were compared to both standardised age‐related reference ranges and to non‐POLGpatients presenting with status epilepticus. Results Forty‐one patients withPOLGdisease were identified. Almost 50% of the patients had documented evidence of a movement disorder, including non‐epileptic myoclonus, choreoathetosis and ataxia. CSF neurotransmitter analysis was undertaken in 15 cases and abnormalities were seen in the majority (87%) of cases tested. In many patients, distinctive patterns were evident, including raised neopterin, homovanillic acid and 5‐hydroxyindoleacetic acid levels. Conclusions Children withPOLGmutations can manifest with a wide spectrum of abnormal movements, which are often prominent features of the clinical syndrome. Underlying pathophysiology is probably multifactorial, and aberrant monoamine metabolism is likely to play a role.

The presence of monoamines and their cofactors (the pterins and vitamin B6 (pyridoxal phosphate (PLP))) in human cerebrospinal fluid (CSF) can be used as indicators of the biosynthesis and turnover of dopamine and serotonin in the brain. In addition, abnormalities in the CSF levels of these molecules are associated with various neurological diseases, including genetic diseases leading to dopamine and serotonin deficiency. Here, we provide a set of quantitative high-performance liquid-chromatography (HPLC) approaches to determine CSF levels of monoamines and their cofactors. This protocol describes step-by-step procedures for CSF sample preparation for the analysis of different molecules, HPLC calibration and analysis, and data quantification and interpretation. Unlike plasma/tissue/blood samples, CSF requires minimal sample preparation: in this protocol, only the analysis of PLP requires mixing with trichloroacetic acid to release the protein-bound vitamin, centrifugation, and mixing of the supernatant with phosphate buffer and sodium cyanide for derivatization in alkaline conditions. Monoamines are analyzed by HPLC with coulometric electrochemical detection (ED), pterins are analyzed by HPLC with coupled coulometric electrochemical and fluorescence detection, and PLP is analyzed by HPLC with fluorescence detection. The quantification of all compounds is achieved by external calibration procedures, and internal quality control and standards are analyzed in each run. We anticipate that investigation of dopamine and serotonin disturbances will be facilitated by measurements of these compounds in human CSF and other biological samples. The estimated time for the different procedures primarily depends on the electrochemical detector stabilization. Overnight stabilization of this detector is advised, and, after that step, preanalytical equilibration rarely exceeds 3 h.

TPK1 mutations are a rare, but potentially treatable, cause of thiamine deficiency. Diagnosis is challenging given the phenotypic overlap that exists with other metabolic and neurological disorders. We report a case of TPK1-related disease presenting with Leigh-like syndrome and review the diagnostic utility of thiamine pyrophosphate (TPP) blood measurement. The proband, a 35-year-old male, presented at four months of age with recurrent episodes of post-infectious encephalopathy. He subsequently developed epilepsy, learning difficulties, sensorineural hearing loss, spasticity, and dysphagia. There was a positive family history for Leigh syndrome in an older brother. Plasma lactate was elevated (3.51 mmol/L) and brain MRI showed bilateral basal ganglia hyperintensities, indicative of Leigh syndrome. Histochemical and spectrophotometric analysis of mitochondrial respiratory chain complexes I, II+III, and IV was normal. Genetic analysis of muscle mitochondrial DNA was negative. Whole exome sequencing of the proband confirmed compound heterozygous variants in TPK1: c. 426G>C (p. Leu142Phe) and c. 258+1G>A (p.?). Blood TPP levels were reduced, providing functional evidence for the deleterious effects of the variants. We highlight the clinical and bioinformatics challenges to diagnosing rare genetic disorders and the continued utility of biochemical analyses, despite major advances in DNA sequencing technology, when investigating novel, potentially disease-causing, genetic variants. Blood TPP measurement represents a fast and cost-effective diagnostic tool in TPK1-related diseases.

Pyridoxal 5′-phosphate (PLP), the active form of vitamin B 6 , functions as a cofactor in humans for more than 140 enzymes, many of which are involved in neurotransmitter synthesis and degradation. A deficiency of PLP can present, therefore, as seizures and other symptoms that are treatable with PLP and/or pyridoxine. Deficiency of PLP in the brain can be caused by inborn errors affecting B 6 vitamer metabolism or by inactivation of PLP, which can occur when compounds accumulate as a result of inborn errors of other pathways or when small molecules are ingested. Whole-exome sequencing of two children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial), PROSC , which encodes a PLP-binding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified four additional children with biallelic PROSC mutations. Pre-treatment cerebrospinal fluid samples showed low PLP concentrations and evidence of reduced activity of PLP-dependent enzymes. However, cultured fibroblasts showed excessive PLP accumulation. An E.coli mutant lacking the PROSC homolog (Δ YggS ) is pyridoxine sensitive; complementation with human PROSC restored growth whereas hPROSC encoding p.Leu175Pro, p.Arg241Gln, and p.Ser78Ter did not. PLP, a highly reactive aldehyde, poses a problem for cells, which is how to supply enough PLP for apoenzymes while maintaining free PLP concentrations low enough to avoid unwanted reactions with other important cellular nucleophiles. Although the mechanism involved is not fully understood, our studies suggest that PROSC is involved in intracellular homeostatic regulation of PLP, supplying this cofactor to apoenzymes while minimizing any toxic side reactions.

Cerebral folate deficiency is typically defined as a deficiency of the major folate species 5-methyltetrahydrofolate in the cerebrospinal fluid (CSF) in the presence of normal peripheral total folate levels. However, it should be noted that cerebral folate deficiency is also often used to describe conditions where CSF 5-MTHF is low, in the presence of low or undefined peripheral folate levels. Known defects of folate transport are deficiency of the proton coupled folate transporter, associated with systemic as well as cerebral folate deficiency, and deficiency of the folate receptor alpha, leading to an isolated cerebral folate deficiency associated with intractable seizures, developmental delay and/or regression, progressive ataxia and choreoathetoid movement disorders. Inborn errors of folate metabolism include deficiencies of the enzymes methylenetetrahydrofolate reductase, dihydrofolate reductase and 5,10-methenyltetrahydrofolate synthetase. Cerebral folate deficiency is potentially a treatable condition and so prompt recognition of these inborn errors and initiation of appropriate therapy is of paramount importance. Secondary cerebral folate deficiency may be observed in other inherited metabolic diseases, including disorders of the mitochondrial oxidative phosphorylation system, serine deficiency, and pyridoxine dependent epilepsy. Other secondary causes of cerebral folate deficiency include the effects of drugs, immune response activation, toxic insults and oxidative stress. This review describes the absorption, transport and metabolism of folate within the body; analytical methods to measure folate species in blood, plasma and CSF; inherited and acquired causes of cerebral folate deficiency; and possible treatment options in those patients found to have cerebral folate deficiency.

We describe neurotransmitter abnormalities in two patients with drug-resistant epilepsy resulting from deleterious de novo mutations in sodium channel genes. Whole exome sequencing identified a de novo SCN2A splice-site mutation (c.2379 +1G>A, p.G1u717Gly.fs*30) resulting in deletion of exon 14, in a 10-year old male with early onset global developmental delay, intermittent ataxia, autism, hypotonia, epileptic encephalopathy and cerebral/cerebellar atrophy. In the cerebrospinal fluid both homovanillic acid and 5-hydroxyindoleacetic acid were significantly decreased; extensive biochemical and genetic investigations ruled out primary neurotransmitter deficiencies and other known inborn errors of metabolism. In an 8-year old female with an early onset intractable epileptic encephalopathy, developmental regression, and progressive cerebellar atrophy, a previously unreported de novo missense mutation was identified in SCN8A (c.5615G>A; p.Arg1872GIn), affecting a highly conserved residue located in the C-terminal of the Na(v)1.6 protein. Aside from decreased homovanillic acid and 5-hydroxyindoleacetic acid, 5-methyltetrahydrofolate was also found to be low. We hypothesize that these channelopathies cause abnormal synaptic mono-amine metabolite secretion/uptake via impaired vesicular release and imbalance in electrochemical ion gradients, which in turn aggravate the seizures. Treatment with oral 5-hydroxytryptophan, L-Dopa/Carbidopa, and a dopa agonist resulted in mild improvement of seizure control in the male case, most likely via dopamine and serotonin receptor activated signal transduction and modulation of glutamatergic, GABA-ergic and glycinergic neurotransmission. Neurotransmitter analysis in other sodium channelopathy patients will help validate our findings, potentially yielding novel treatment opportunities. (C) 2015 Elsevier Inc. All rights reserved

In some applications, vibration control objectives may require reduction of levels at locations where control system components cannot be sited due to space or environmental considerations. Control actuators and error sensors for such a scenario will need to be placed at appropriate locations which are potentially remote from the points where ultimate attenuation is desired. The performance of the closed loop system, therefore, cannot be assessed simply by the measurement obtained at this local error sensor. The control design objective has to take into account the vibration levels at the remote locations as well. A design methodology was recently proposed that tackles such problems using a single-loop feedback control architecture. The work in this paper describes an extension of this control design procedure to enable the systematic design of multiple decentralised control loops. The approach is based upon sequential loop closing and conditions are provided that ensure that closed loop stability is maintained even in the event of failure in some control loops. The design procedure is illustrated through its application to a laboratory scale slab floor that replicates the problems associated with human induced vibration in large open-plan office buildings. The experimental results demonstrate the efficacy of the approach and significant suppression of the dominant low frequency modes in the floor is achieved using two independent acceleration feedback control loops.

Low frequency waves in the foot of a supercritical quasi-perpendicular shock front have been observed since the very early in situ observations of the terrestrial bow shock (Guha et al., 1972). The great attention that has been devoted to these type of waves since the first observations is explained by the key role attributed to them in the processes of energy redistribution in the shock front by various theoretical models. In some models, these waves play the role of the intermediator between the ions and electrons. It is assumed that they are generated by plasma instability that exist due to the counter-streaming flows of incident and reflected ions. In the second type of models, these waves result from the evolution of the shock front itself in the quasi-periodic process of steepening and overturning of the magnetic ramp. However, the range of the observed frequencies in the spacecraft frame are not enough to distinguish the origin of the observed waves. It also requires the determination of the wave vectors and the plasma frame frequencies. Multipoint measurements within the wave coherence length are needed for an ambiguous determination of the wave vectors. In the main multi-point missions such as ISEE, AMPTE, Cluster and THEMIS, the spacecraft separation is too large for such a wave vector determination and therefore only very few case studies are published (mainly for AMPTE UKS AMPTE IRM pair). Here we present the observations of upstream low frequency waves by the Cluster spacecraft which took place on 19 February 2002. The spacecraft separation during the crossing of the bow shock was small enough to determine the wave vectors and allowed the identification of the plasma wave dispersion relation for the observed waves. Presented results are compared with whistler wave dispersion and it is shown that contrary to previous studies based on the AMPTE data, the phase velocity in the shock frame is directed downstream. The consequences of this finding for both types of models that were developed to explain the generation of these waves are discussed.

Dempster’s rule is traditionally interpreted as an operator for fusing belief functions. While there are different types of belief fusion, there has been considerable confusion regarding the exact type of operation that Dempster’s rule performs. Many alternative operators for belief fusion have been proposed, where some are based on the same fundamental principle as Dempster’s rule, and others have a totally different basis, such as the cumulative and averaging fusion operators. In this article, we analyze Dempster’s rule from a statistical and frequentist perspective and compare it with cumulative and averaging belief fusion. We prove, and illustrate by examples on colored balls, that Dempster’s rule in fact represents a method for serial combination of stochastic constraints. Consequently, Dempster’s rule is not a method for cumulative fusion of belief functions under the assumption that subjective beliefs are an extension of frequentist beliefs. Having identified the true nature of Dempster’s rule, appropriate applications of Dempster’s rule of combination are described such as the multiplication of orthogonal belief functions, and the combination of preferences dictated by different parties. © 2012 Wiley Periodicals, Inc.

In situ measurements of the magnetic field are vital to the study of many fundamental problems in planetary research. Therefore the magnetometer experiment is a key element of the payload of Venus Express. In addition to the interaction of the solar wind with Venus, these measurements are crucial for the study of atmospheric escape and detection of lightning. However, the methodology for the magnetic field measurements had to be different to the traditional approach, because Venus Express is not a magnetically clean spacecraft. A technique based on two-point simultaneous measurements of the magnetic field and systems identification software is used to separate the natural magnetic field from the spacecraft generated interference. In this paper an overview of the techniques developed to separate these two field types and the results achieved for 1 Hz Venus Express data are presented. Previous publications suggest that the resulting Venus Express cleaned data is of comparable quality to measurements made from onboard magnetically clean spacecraft (Zhang et al., 2008a, b; Slavin et al., 2009).

A metamaterial that is composed of solid viscoelastic elements with controllable properties is proposed in this Letter. This enables an adaptable and general acoustic metamaterial to be practically realised. An array of masses with a single elastic connection to a supporting viscoelastic structure, such as one that is dynamically equivalent to an array of Helmholtz resonators, only provides a system with negative effective mass. A local active control scheme applied to each of these masses can emulate additional elastic connections to the supporting structure. An array of masses with a suitable local control scheme can provide both the negative effective stiffness and mass required for negative refraction. The tuneable feedback control parameters determine the characteristics of the region of double negativity.

Although there is no intrinsic magnetic field at Venus, the convected interplanetary magnetic field piles up to form a magnetic barrier in the dayside inner magnetosheath. In analogy to the Earth's magnetosphere, the magnetic barrier acts as an induced magnetosphere on the dayside and hence as the obstacle to the solar wind. It consists of regions near the planet and its wake for which the magnetic pressure dominates all other pressure contributions. The initial survey performed with the Venus Express magnetic field data indicates a well-defined boundary at the top of the magnetic barrier region. It is clearly identified by a sudden drop in magnetosheath wave activity, and an abrupt and pronounced field draping. It marks the outer boundary of the induced magnetosphere at Venus, and we adopt the name “magnetopause” to address it. The magnitude of the draped field in the inner magnetosheath gradually increases and the magnetopause appears to show no signature in the field strength. This is consistent with PVO observations at solar maximum. A preliminary survey of the 2006 magnetic field data confirms the early PVO radio occultation observations that the ionopause stands at ∼250 km altitude across the entire dayside at solar minimum. The altitude of the magnetopause is much lower than at solar maximum, due to the reduced altitude of the ionopause at large solar zenith angles and the magnetization of the ionosphere. The position of the magnetopause at solar minimum is coincident with the ionopause in the subsolar region. This indicates a sinking of the magnetic barrier into the ionosphere. Nevertheless, it appears that the thickness of the magnetic barrier remains the same at both solar minimum and maximum. We have found that the ionosphere is magnetized ∼95% of the time at solar minimum, compared with 15% at solar maximum. For the 5% when the ionosphere is un-magnetized at solar minimum, the ionopause occurs at a higher location typically only seen during solar maximum conditions. These have all occurred during extreme solar conditions.

Glutamate is the major excitatory amino acid of the mammalian brain but can be toxic to neurones if its extracellular levels are not tightly controlled. Astrocytes have a key role in the protection of neurones from glutamate toxicity, through regulation of extracellular glutamate levels via glutamate transporters and metabolic and antioxidant support. In this study, we report that cultures of rat astrocytes incubated with high extracellular glutamate (5 mM) exhibit a twofold increase in the extracellular concentration of the tripeptide antioxidant glutathione (GSH) over 4 h. Incubation with glutamate did not result in an increased release of lactate dehydrogenase, indicating that the rise in GSH was not because of membrane damage and leakage of intracellular pools. Glutamate-induced increase in extracellular GSH was also independent of de novo GSH synthesis, activation of NMDA and non-NMDA glutamate receptors or inhibition of extracellular GSH breakdown. Dose-response curves indicate that GSH release from rat astrocytes is significantly stimulated even at 0.1 mM glutamate. The ability of astrocytes to increase GSH release in the presence of extracellular glutamate could be an important neuroprotective mechanism enabling neurones to maintain levels of the key antioxidant, GSH, under conditions of glutamate toxicity.

In this study, magnetic field measurements obtained by the Venus Express spacecraft are used to determine the bow shock position at solar minimum. The best fit of bow shock location from solar zenith angle 20–120° gives a terminator bow shock location of 2.14 RV (1 RV=6052 km) which is 1600 km closer to Venus than the 2.40 RV determined during solar maximum conditions, a clear indication of the solar cycle variation of the Venus bow shock location. The best fit to the subsolar bow shock is 1.32 RV, with the bow shock completely detached. Finally, a global bow shock model at solar minimum is constructed based on our best-fit empirical bow shock in the sunlit hemisphere and an asymptotic limit of the distant bow shock which is a Mach cone under typical Mach number of 5.5 at solar minimum. We also describe our approach to making the measurements and processing the data in a challenging magnetic cleanliness environment. An initial evaluation of the accuracy of measurements shows that the data are of a quality comparable to magnetic field measurements made onboard magnetically clean spacecraft.

Glutathione (GSH) is one of the major antioxidants in the brain. GSH is secreted by astrocytes and this extracellular GSH is used by neurones to maintain and increase their intracellular GSH levels. For efficient GSH trafficking between astrocytes and neurones, GSH needs to be maintained in the reduced form. In model systems, GSH trafficking has been shown to be essential for neuroprotection against a variety of stress conditions. Previously we and others have shown that GSH and thiols are unstable in cell culture media and are easily oxidised. In the present study it is shown that nanomolar concentrations of copper (II) ions can cause decay of GSH in cell culture media. Increased free or redox active copper has been implicated in a variety of diseases and degradation of extracellular GSH is a possible mechanism by which it exerts its harmful effects. Rat astrocytes, a human astrocytoma cell line and astrocyte-conditioned media, in the absence of cells, are able to retard this copper-catalysed decay of GSH and maintain GSH in its reduced form. The protective effect of astrocytes appears to be a combination of copper removing and antioxidant mechanisms. The importance of these protective mechanisms is discussed with regards to neurodegenerative diseases.

Venus has no significant internal magnetic field1, which allows the solar wind to interact directly with its atmosphere2,3. A field is induced in this interaction, which partially shields the atmosphere, but we have no knowledge of how effective that shield is at solar minimum. (Our current knowledge of the solar wind interaction with Venus is derived from measurements at solar maximum3,4,5,6.) The bow shock is close to the planet, meaning that it is possible that some solar wind could be absorbed by the atmosphere and contribute to the evolution of the atmosphere7,8. Here we report magnetic field measurements from the Venus Express spacecraft3 in the plasma environment surrounding Venus. The bow shock under low solar activity conditions seems to be in the position that would be expected from a complete deflection by a magnetized ionosphere9. Therefore little solar wind enters the Venus ionosphere even at solar minimum.

Oxidative stress and subsequent impairment of mitochondrial function is implicated in the neurodegenerative process and hence in diseases such as Parkinson's and Alzheimer's disease. Within the brain, neuronal and astroglial cells can display a differential susceptibility to oxidant exposure. Thus, astrocytes can up regulate glutathione availability and, in response to mitochondrial damage, glycolytic flux. Whilst neuronal cells do not appear to possess such mechanisms, neuronal glutathione status may be enhanced due to the trafficking of glutathione precursors from the astrocyte. However, when antioxidants reserves are not sufficient or the degree of oxidative stress is particularly great, mitochondrial damage occurs, particularly at the level of complex IV (cytochrome oxidase). Whilst the exact mechanism for the loss of activity of this enzyme complex is not know, it is possible that loss and/or oxidative modification of the phospholipid, cardiolipin is a critical factor. Consequently, in this short article, we also consider (a) cardiolipin metabolism and function, (b) the susceptibility of this molecule to undergo oxidative modification following exposure to oxidants such as peroxynitrite, (c) loss of mitochondrial cardiolipin in neurodegenerative disorders, (d) methods of detecting cardiolipin and (e) possible therapeutic strategies that may protect cardiolipin from oxidative degradation.