Search

Aromatic l-amino acid decarboxylase (AADC) deficiency is a complex inherited neurological disorder of monoamine synthesis which results in dopamine and serotonin deficiency. The majority of affected individuals have variable, though often severe cognitive and motor delay, with a complex movement disorder and high risk of premature mortality. For most, standard pharmacological treatment provides only limited clinical benefit. Promising gene therapy approaches are emerging, though may not be either suitable or easily accessible for all patients. To characterize the underlying disease pathophysiology and guide precision therapies, we generated a patient-derived midbrain dopaminergic neuronal model of AADC deficiency from induced pluripotent stem cells. The neuronal model recapitulates key disease features, including absent AADC enzyme activity and dysregulated dopamine metabolism. We observed developmental defects affecting synaptic maturation and neuronal electrical properties, which were improved by lentiviral gene therapy. Bioinformatic and biochemical analyses on recombinant AADC predicted that the activity of one variant could be improved by l-3,4-dihydroxyphenylalanine (l-DOPA) administration; this hypothesis was corroborated in the patient-derived neuronal model, where l-DOPA treatment leads to amelioration of dopamine metabolites. Our study has shown that patient-derived disease modelling provides further insight into the neurodevelopmental sequelae of AADC deficiency, as well as a robust platform to investigate and develop personalized therapeutic approaches., Rossignoli et al. develop the first humanized neuronal model of AADC deficiency. They use this patient-derived neuronal system to elucidate disease mechanisms, and in particular to better define neurodevelopmental features, as well as to test precision therapy approaches.

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.

Collisionless shocks are one of the most effective particle accelerators in the known universe. Even low Mach number shocks could have a significant role in particle heating and acceleration. Theory suggests that kinematic collisionless relaxation, the process whereby a downstream nongyroptopic ion population becomes thermalized through collisionless gyrophase mixing, is the dominant energy redistribution mechanism in quasi‐perpendicular, low Mach number, and low β shocks. However, there have only been a limited number of observations of these shocks using in situ measurements at Venus, Earth and in interplanetary space. This paper presents the results of the first detailed study using in situ measurements, of the effect of fundamental parameters on the formation of these shocks. All low Mach number shocks occurring during the magnetic cloud phase of an interplanetary coronal mass ejection are identified in Venus Express magnetic field data over the duration of the mission. From the 92 shock crossings identified, 38 show clear evidence of kinematic relaxation. It is shown that kinematic relaxation is dominant at Venus when the angle between the local shock normal and upstream magnetic field is greater 50° and the Alfven Mach number is less than 1.4. These shocks are also observed across a range of solar‐zenith‐angles indicating that it is likely that any location on the Venus bow shock could form such a structure. Venus Express plasma measurements are used to verify the parameters estimated from the magnetic field and indicate the importance of heavy ions, including potential pickup O+.

BACKGROUND: Juvenile forms of parkinsonism are rare conditions with onset of bradykinesia, tremor and rigidity before the age of 21 years. These atypical presentations commonly have a genetic aetiology, highlighting important insights into underlying pathophysiology. Genetic defects may affect key proteins of the endocytic pathway and clathrin-mediated endocytosis (CME), as in DNAJC6-related juvenile parkinsonism. OBJECTIVE: To report on a new patient cohort with juvenile-onset DNAJC6 parkinsonism-dystonia and determine the functional consequences on auxilin and dopamine homeostasis. METHODS: Twenty-five children with juvenile parkinsonism were identified from a research cohort of patients with undiagnosed pediatric movement disorders. Molecular genetic investigations included autozygosity mapping studies and whole-exome sequencing. Patient fibroblasts and CSF were analyzed for auxilin, cyclin G-associated kinase and synaptic proteins. RESULTS: We identified 6 patients harboring previously unreported, homozygous nonsense DNAJC6 mutations. All presented with neurodevelopmental delay in infancy, progressive parkinsonism, and neurological regression in childhood. (123) I-FP-CIT SPECT (DaTScan) was performed in 3 patients and demonstrated reduced or absent tracer uptake in the basal ganglia. CSF neurotransmitter analysis revealed an isolated reduction of homovanillic acid. Auxilin levels were significantly reduced in both patient fibroblasts and CSF. Cyclin G-associated kinase levels in CSF were significantly increased, whereas a number of presynaptic dopaminergic proteins were reduced. CONCLUSIONS: DNAJC6 is an emerging cause of recessive juvenile parkinsonism-dystonia. DNAJC6 encodes the cochaperone protein auxilin, involved in CME of synaptic vesicles. The observed dopamine dyshomeostasis in patients is likely to be multifactorial, secondary to auxilin deficiency and/or neurodegeneration. Increased patient CSF cyclin G-associated kinase, in tandem with reduced auxilin levels, suggests a possible compensatory role of cyclin G-associated kinase, as observed in the auxilin knockout mouse. DNAJC6 parkinsonism-dystonia should be considered as a differential diagnosis for pediatric neurotransmitter disorders associated with low homovanillic acid levels. Future research in elucidating disease pathogenesis will aid the development of better treatments for this pharmacoresistant disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

This paper discusses some of the reasons for producing take home laboratory kits. This is then supplemented by detailed presentation of three different types of take home kit, alongside the motivations for their design and an evaluation of their efficacy with students.

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.

BackgroundTetrahydrobiopterin (BH4) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH4deficiencies.ConclusionAlthough the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH4deficient patients.

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.

Typically multi-spacecraft missions are ideally suited to the study of shock spatial scales due to the separation of temporal and spatial variations. These missions are not possible at all locations and therefore in-situ multi-spacecraft measurements are not available beyond the Earth. The present paper presents a study of shock spatial scales using single spacecraft measurements made by the Venus Express spacecraft. The scales are determined based on previous knowledge of shock overshoot scales measured by the ISEE and Cluster missions. The study encompasses around 60 crossings of the Venusian bow shock from 2006 to 2009. The statistical relationship between the shock ramp spatial scales, overshoot and upstream shock parameters are investigated. We find that despite somewhat different solar wind conditions our results are comparable with those based on multi-spacecraft missions at the terrestrial bow shock.

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.

Hereditary folate malabsorption is a rare autosomal recessive disorder caused by impaired active folate transport across membranes and into the central nervous system due to loss-of-function mutations in proton-coupled folate transporter (PCFT). Newborns with this condition have initially normal folate stores, but as they are unable to absorb dietary folate and use rapidly their stores because of their growth demands, symptoms appear in the early infancy. Significant neurological morbidity usually follows the initial non-specific clinical presentation and delayed initiation of treatment. High dose oral and parenteral folinic acid treatment have been previously reported in literature to improve the clinical outcome without achieving optimal cerebrospinal fluid (CSF) folate levels though. The active isomer of 5-formyltetrahydrofolate, also known as levofolinic acid, is available for administration. We report our experience in achieving normal (age dependent) CSF 5-Methyltetrahydrofolate (5-MTHF) levels following daily intramuscular administration of levofolinic acid in three patients with HFM. Follow-up assessment with repeated lumbar punctures has shown a stabilization of 5-MTHF levels within normal range. Clinical features and brain MRI findings had as well either improvement or stabilization. To the best of our knowledge, we provide as well for the first time data in regard to the im levofolinate treatment dosage.

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.

Previous studies into solid elastic metamaterials which have a simultaneously negative effective bulk modulus and density have proposed designs for materials with relatively narrow bandwidths, because of the reliance on resonators to provide the dispersive material properties. Some of the proposed novel applications for metamaterials, such as invisibility cloaks and sub-wavelength lenses, generally require materials with inherently larger bandwidths for practical exploitation. In this paper, a well-known electromagnetic metamaterial design is used together with the electrical-mechanical circuit analogies to propose a simultaneously double negative elastic metamaterial design which does not suffer from the narrow bandwidth constraints of previous designs. An interesting consequence of the proposed design is that it has an effective wavelength which asymptotically goes to infinity with frequency.

Brown-Vialetto-Van Laere syndrome (BVVLS) represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter (RFVT) genes, SLC52A2 and SLC52A3, have recently been linked to BVVLS. However, the genetic frequency, neuropathology and downstream consequences of RFVT mutations have previously been undefined. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between RFVT mutations and BVVLS, identifying twenty-two pathogenic mutations in SLC52A2 and SLC52A3, fourteen of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column-medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain (ETC), we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. ETC complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila RFVT homologue revealed reduced levels of riboflavin, downstream metabolites, and ETC complex I activity. RFVT knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings indicate mitochondrial dysfunction as a downstream consequence of RFVT gene defects in BVVLS and validate riboflavin esters as a potential therapeutic strategy.

Item does not contain fulltext Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.

Intrinsic and extrinsic self-healing approaches through which materials can be healed generally suffer from several problems. One key problem is that to ensure effective healing and to minimise the propagation of a fault, the healing rate needs to be matched to the damage rate. This requirement is usually not met with passive approaches. An alternative to passive healing is active self-healing, whereby the healing mechanism and in particular the healing rate, is controlled in the face of uncertainty and varying conditions. Active self-healing takes advantage of sensing and added external energy to achieve a desired healing rate. To demonstrate active self-healing, an electrochemical material based on the principles of piezoelectricity and electrolysis is modelled and adaptive feedback control is implemented. The adaptive feedback control compensates for the insufficient piezo-induced voltage and guarantees a response that meets the desired healing rate. Importantly, fault propagation can be eliminated or minimised by attaining a match between the healing and damage rate quicker than can be achieved with the equivalent passive system. The desired healing rate is a function of the fault propagation and is assumed known in this paper, but can be estimated in practice through established prognostic techniques.\ud

A geometric-based methodology that was recently proposed provides a systematic controller design approach for controlling remote vibration at multiple points using only a restricted number of sensors and actuators. Valuable physical insight into the existence of control solutions for vibration attenuation at multiple locations is retained with this approach in contrast to alternatives, such as $\mathcal {H}_{2}$ and $\mathcal {H}_{\infty }$ methods. A drawback of the existing geometric design approach is that the controller implementation for the broadband case incorporates an inverted local control path transfer function. When the sensor and actuator are noncollocated or when there is significant latency or phase lag in the system, the local control path model will have nonminimum phase characteristics. Therefore, the resulting controller for this situation will itself be unstable due to the inclusion of an inverted nonminimum phase transfer function. In this brief paper, a systematic procedure is presented, which extends the previous work and which yields both a stable and stabilizing controller without requiring a minimum phase control path assumption. Furthermore, robustness against control spillover at out-of-band frequencies is incorporated within this modified design procedure without deteriorating controller performance within the design bandwidth. The detailed control design procedure is illustrated using a simulated beam vibration problem. Finally, the design approach is experimentally validated using a test rig that replicates the problem of vibration transmission in rotary propulsion systems.

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).

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.

We report here a clinical case of a patient with a novel mutation (Arg347→Gly) in the gene encoding aromatic amino acid decarboxylase (AADC) that is associated with AADC deficiency. The variant R347G in the purified recombinant form exhibits, similarly to the pathogenic mutation R347Q previously studied, a 475-fold drop of kcat compared to the wild-type enzyme. In attempting to unravel the reason(s) for this catalytic defect, we have carried out bioinformatics analyses of the crystal structure of AADC-carbidopa complex with the modelled catalytic loop (residues 328-339). Arg347 appears to interact with Phe103, as well as with both Leu333 and Asp345. We have then prepared and characterized the artificial F103L, R347K and D345A mutants. F103L, D345A and R347K exhibit about 13-, 97-, and 345-fold kcat decrease compared to the wild-type AADC, respectively. However, unlike F103L, the R347G, R347K and R347Q mutants as well as the D345A variant appear to be more defective in catalysis than in protein folding. Moreover, the latter mutants, unlike the wild-type protein and the F103L variant, share a peculiar binding mode of dopa methyl ester consisting of formation of a quinonoid intermediate. This finding strongly suggests that their catalytic defects are mainly due to a misplacement of the substrate at the active site. Taken together, our results highlight the importance of the Arg347-Leu333-Asp345 hydrogen-bonds network in the catalysis of AADC and reveal the molecular basis for the pathogenicity of the variants R347. Following the above results, a therapeutic treatment for patients bearing the mutation R347G is proposed.

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiencies of lysosomal enzymes catalyzing degradation of glycosaminoglycans (GAGs). Previously, we reported a secondary plasma coenzyme Q10 (CoQ) deficiency in MPS patients. For this study, nine MPS patients were recruited in the Hospital Sant Joan de Deu (HSJD, Barcelona) and two patients in the Neurometabolic Unit, National Hospital (NMU, London), to explore the nutritional status of MPS type III patients by analyzing several vitamins and micronutrients in blood and in cerebrospinal fluid. Plasma CoQ and plasma and cerebrospinal fluid pyridoxal phosphate (PLP) content were analyzed by high-pressure liquid chromatography (HPLC) with electrochemical and fluorescence detection, respectively. We found that most MPS-III patients disclosed low plasma pyridoxal phosphate (PLP) values (seven out of nine) and also low plasma CoQ concentrations (eight out of nine). We observed significantly lower median values of PLP, tocopherol, and CoQ (Mann–Whitney U test, p = 0.006, p = 0.004, and p = 0.001, respectively) in MPS patients when compared with age-matched controls. Chi-square test showed a significant association between the fact of having low plasma PLP and CoQ values in the whole cohort of patients. Cerebrospinal fluid PLP values were clearly deficient in the two patients studied. In conclusion, we report a combined CoQ and PLP deficiency in MPS-III patients. These observations could be related to the complexity of the physiopathology of the disease. If our results are confirmed in larger series of patients, CoQ and PLP therapy could be trialed as coadjuvant therapy with the current MPS treatments.

Nat. Genet. 49, 223–237 (2017); published online 19 December 2016; corrected after print 20 April 2017 Following publication of this article, the authors were asked to remove a clinical image and some video footage of one of the affected individuals. Although consent was obtained, in keeping with their ethical consent framework, the authors allow for withdrawal of consent and are carrying out the wishes of the research subjects under their consent process.

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiencies of lysosomal enzymes catalyzing degradation of glycosaminoglycans (GAGs). Previously, we reported a secondary plasma coenzyme Q10 (CoQ) deficiency in MPS patients. For this study, nine MPS patients were recruited in the Hospital Sant Joan de Déu (HSJD, Barcelona) and two patients in the Neurometabolic Unit, National Hospital (NMU, London), to explore the nutritional status of MPS type III patients by analyzing several vitamins and micronutrients in blood and in cerebrospinal fluid. Plasma CoQ and plasma and cerebrospinal fluid pyridoxal phosphate (PLP) content were analyzed by high-pressure liquid chromatography (HPLC) with electrochemical and fluorescence detection, respectively. We found that most MPS-III patients disclosed low plasma pyridoxal phosphate (PLP) values (seven out of nine) and also low plasma CoQ concentrations (eight out of nine). We observed significantly lower median values of PLP, tocopherol, and CoQ (Mann–Whitney U test, p = 0.006, p = 0.004, and p = 0.001, respectively) in MPS patients when compared with age-matched controls. Chi-square test showed a significant association between the fact of having low plasma PLP and CoQ values in the whole cohort of patients. Cerebrospinal fluid PLP values were clearly deficient in the two patients studied. In conclusion, we report a combined CoQ and PLP deficiency in MPS-III patients. These observations could be related to the complexity of the physiopathology of the disease. If our results are confirmed in larger series of patients, CoQ and PLP therapy could be trialed as coadjuvant therapy with the current MPS treatments.

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.

Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies.

Unlike most other cell types, neurons preferentially metabolize glucose via the pentose phosphate pathway (PPP) to maintain their antioxidant status. Inhibiting the PPP in neuronal cell models causes cell death. In rodents, inhibition of this pathway causes selective dopaminergic cell death leading to motor deficits resembling parkinsonism. Using postmortem human brain tissue, we characterized glucose metabolism via the PPP in sporadic Parkinson's disease (PD), Alzheimer's disease (AD), and controls. AD brains showed increased nicotinamide adenine dinucleotide phosphate (NADPH) production in areas affected by disease. In PD however, increased NADPH production was only seen in the affected areas of late-stage cases. Quantifying PPP NADPH-producing enzymes glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase by enzyme-linked immunosorbent assay, showed a reduction in the putamen of early-stage PD and interestingly in the cerebellum of early and late-stage PD. Importantly, there was no decrease in enzyme levels in the cortex, putamen, or cerebellum of AD. Our results suggest that down-regulation of PPP enzymes and a failure to increase antioxidant reserve is an early event in the pathogenesis of sporadic PD.

Elastic metamaterials provide a new approach to solving existing problems in vibration and acoustics. They have also been associated with novel concepts such as acoustic invisibility and subwavelength imaging. To be applied to many of the proposed applications a metamaterial would need to have the desired mass density and elastic moduli over a prescribed frequency band. Importantly active metamaterials provide a degree of adaptability. This paper will focus on extending a previous theoretical concept to a more realistic experimental design. This will include a consideration of the problems which arise when the theory and simulation are developed into an experimental demonstration, including the role which the control system dynamics play in the achievable performance. The adaptability of the bandwidth in which the properties achieve their desired values will also be investigated.

Chronic hypoxia decreases cardiomyocyte respiration, yet the mitochondrial mechanisms remain largely unknown. We investigated the mitochondrial metabolic pathways and enzymes that were decreased following in vivo hypoxia, and questioned whether hypoxic adaptation was protective for the mitochondria. Wistar rats were housed in hypoxia (7 days acclimatisation and 14 days at 11% oxygen), while control rats were housed in normoxia. Chronic exposure to physiological hypoxia increased haematocrit and cardiac vascular endothelial growth factor, in the absence of weight loss and changes in cardiac mass. In both subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria isolated from hypoxic hearts, state 3 respiration rates with fatty acid were decreased by 17-18%, and with pyruvate were decreased by 29-15%, respectively. State 3 respiration rates with electron transport chain (ETC) substrates were decreased only in hypoxic SSM, not in hypoxic IFM. SSM from hypoxic hearts had decreased activities of ETC complexes I, II and IV, which were associated with decreased reactive oxygen species generation and protection against mitochondrial permeability transition pore (MPTP) opening. In contrast, IFM from hypoxic hearts had decreased activity of the Krebs cycle enzyme, aconitase, which did not modify ROS production or MPTP opening. In conclusion, cardiac mitochondrial respiration was decreased following chronic hypoxia, associated with downregulation of different pathways in the two mitochondrial populations, determined by their subcellular location. Hypoxic adaptation was not deleterious for the mitochondria, in fact, SSM acquired increased protection against oxidative damage under the oxygen-limited conditions.

[1] Within the Venusian magnetosheath, Venus Express has observed the existence of high-amplitude, nonlinear waves which have been interpreted as large-scale nonlinear rotational structures within the magnetic field. A number of mechanisms have been proposed that can be used to explain their origin. Venus Express data have been searched for other examples of the similar structures. It appears that such structures are quite rare, being observed during only 8 of the dayside magnetosheath crossings among 676 that took place between April 2006 and February 2008. All together, only 50 such waves have been identified during these 8 crossings. The properties of these structures were studied. After considering a number of possible generation mechanisms, it is concluded that the most probable generation mechanism is the Kelvin-Helmholtz Instability; however, other mechanisms such as shock-related processes cannot be completely discounted.

AIMS: The chronically infarcted rat heart has multiple defects in metabolism, yet the location of the primary metabolic abnormality arising after myocardial infarction is unknown. Therefore, we investigated cardiac mitochondrial metabolism shortly after infarction. METHODS AND RESULTS: Myocardial infarctions (n = 11) and sham operations (n = 9) were performed on Wistar rats, at 2 weeks cardiac function was assessed using echocardiography, and rats were grouped into failing (ejection fraction < or =45%), moderately impaired (46-60%), and sham-operated (>60%). Respiration rates were decreased by 28% in both subsarcolemmal and interfibrillar mitochondria isolated from failing hearts, compared with sham-operated controls. However, respiration rates were not impaired in mitochondria from hearts with moderately impaired function. The mitochondrial defect in the failing hearts was located within the electron transport chain (ETC), as respiration rates were suppressed to the same extent when fatty acids, ketone bodies, or glutamate were used as substrates. Complex III protein levels were decreased by 46% and complex III activity was decreased by 26%, in mitochondria from failing hearts, but all other ETC complexes were unchanged. Decreased complex III activity was accompanied by a three-fold increase in complex III-derived H(2)O(2) production, decreased cardiolipin content, and a 60% decrease in mitochondrial cytochrome c levels from failing hearts. Respiration rates, complex III activity, cardiolipin content, and reactive oxygen species generation rates correlated with ejection fraction. CONCLUSION: In conclusion, a specific defect in complex III occurred acutely after myocardial infarction, which increased oxidative damage and impaired mitochondrial respiration. The extent of mitochondrial dysfunction in the failing heart was proportional to the degree of cardiac dysfunction induced by myocardial infarction.

[1] The interaction of the solar wind with Venus has a significant influence on the evolution of its atmosphere. Due to the lack of an intrinsic planetary magnetic field, there is direct contact between the fast flowing solar wind and the Venusian ionosphere. This leads to a number of different types of atmospheric escape process. Using Venus Express observations, we show that such contact leads to the formation of global vortices downstream of the Venusian bow shock. These vortices accelerate heavy ionospheric ions such as oxygen, leading to their escape. We argue that these vortices are the result of the Kelvin-Helmholtz instability excited by the shear velocity profile at the boundary between the solar wind and ionospheric plasma. These vortices also help to repopulate the night-side ionosphere during solar minimum, when the ionospheric flow from day to night is restricted by the lowered ionopause altitude at the terminator.

[1] Magnetometer data from two Venus years of the Venus Express mission in orbit are investigated for the occurrence of ion cyclotron waves. Proton cyclotron waves were recently detected in the upstream region of Venus by the spacecraft, indicating pickup of planetary protons from Venus's exosphere by the solar wind and loss of hydrogen to interplanetary space. A study of representative cases illustrates the waveform, spectrum, duration, and higher-order resonances of the transverse waves with left-hand circular polarization and propagation nearly along the magnetic field; their properties in the magnetic field principal axes system are determined. A statistical approach studies the wave properties as a function of the angle between the solar wind and magnetic field direction, as a function of their occurrence in space, and with respect to the motional solar wind electric field. Proton cyclotron waves are found up to 9 Venus radii from the planet, for a large range of angles between the solar wind and magnetic field direction, independent from foreshock geometry and independent from the direction of the motional electric field. This reveals that cyclotron wave generation from local pickup of neutral hydrogen is efficient over a large volume of space upstream of the planet and imposes the existence of an extended reservoir of planetary neutral hydrogen at Venus.

[1] Collisionless shocks are present in the vicinity of many astrophysical objects such as supernova remnants, space jets, stars and planets immersed in the supersonic flow of stellar winds. Understanding the shock structure is crucial for understanding the processes of the redistribution of the upstream flow energy into accelerated particles and formation of downstream thermalized distribution. We report first observations (by Venus Express) of subcritical shocks that do not fit into the well-established classical structure classification. It is shown that its abnormal structure is due to kinematical collisionless relaxation of downstream ions. The spatial gyrophase mixing leads to formation of a downstream thermalized distribution, instead of various instabilities. This type of subcritical shock with kinematic relaxation has never been discussed before in theoretical models (e.g., C. F. Kennel et al., 1985).

Trust propagation is the principle by which new trust relationships can be derived from pre-existing trust relationship. Trust transitivity is the most explicit form of trust propagation, meaning for example that if Alice trusts Bob, and Bob trusts Claire, then by transitivity, Alice will also trust Claire. This assumes that Bob recommends Claire to Alice. Trust fusion is also an important element in trust propagation, meaning that Alice can combine Bob's recommendation with her own personal experience in dealing with Claire, or with other recommendations about Claire, in order to derive a more reliable measure of trust in Claire. These simple principles, which are essential for human interaction in business and everyday life, manifests itself in many different forms. This paper investigates possible formal models that can be implemented using belief reasoning based on subjective logic. With good formal models, the principles of trust propagation can be ported to online communities of people, organisations and software agents, with the purpose of enhancing the quality of those communities.

Neutrophil leukocytes have a pivotal function in innate immunity. Dogma dictates that the lethal blow is delivered to microbes by reactive oxygen species (ROS) and halogens, products of the NADPH oxidase, whose impairment causes immunodeficiency. However, recent evidence indicates that the microbes might be killed by proteases, activated by the oxidase through the generation of a hypertonic, K+-rich and alkaline environment in the phagocytic vacuole. Here we show that K+ crosses the membrane through large-conductance Ca2+-activated K+ (BK(Ca)) channels. Specific inhibitors of these channels, iberiotoxin and paxilline, blocked oxidase-induced 86Rb+ fluxes and alkalinization of the phagocytic vacuole, whereas NS1619, a BK(Ca) channel opener, enhanced both. Characteristic outwardly rectifying K+ currents, reversibly inhibited by iberiotoxin, were demonstrated in neutrophils and eosinophils and the expression of the alpha-subunit of the BK channel was confirmed by western blotting. The channels were opened by the combination of membrane depolarization and elevated Ca2+ concentration, both consequences of oxidase activity. Remarkably, microbial killing and digestion were abolished when the BK(Ca) channel was blocked, revealing an essential and unexpected function for this K+ channel in the microbicidal process.

The authors wish to retract this Letter after the report of an inability to reproduce their results1, later confirmed by another2. The studies the authors then conducted led to an internal investigation by University College London, please see the accompanying Supplementary Information for details.

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.

A popular approach for active noise control problems has been the use of the adaptive filtered-X least mean square algorithm. A fundamental problem with feedforward design is that it requires both reference and error sensors. In order to reduce the size, cost and physical complexity of the control system, a feedback controller can be utilised. In contrast to filtered-X least mean square, a feedback controller utilises local acceleration measurements of a sound-absorbing surface instead of global pressure measurements. Most control problems, including active noise control, can be formulated in the general control configuration architecture. This type of architecture allows for the systematic representation of the process and simplifies the design of a vast number of controllers that include [Formula: see text] and controllers. Such controllers are considered ideal candidates for active noise control problems as they can combine near-optimal performance with good robustness characteristics. This article investigates the problem of reflected noise suppression in acoustic ducts and the possibilities and trade-offs of applying [Formula: see text] control strategies. Hence, by controlling locally the reflecting boundary structure, a global cancellation of the undesired noise can be accomplished. In this article, the [Formula: see text] local feedback control strategy and performance are investigated using an experimental pulse tube. The [Formula: see text] design was chosen because it was able to provide consistently a stable response in contrast to the design.