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+.

Tetrahydrobiopterin (BHAlthough 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 BH

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.

A new type of very-low Mach number shock in which the primary method of energy re-distribution is the kinematic relaxation of a non-gyrotropic ion population, was discovered at Venus early in the Venus Express mission. This led to the development of an associated theory and numerical analysis. The recent discovery of such a shock at the Earth using THEMIS data experimentally verified this theory using simultaneous magnetic field and plasma data. It also showed that the most favourable conditions for the formation of such a shock is the magnetic cloud phase of an ICME. Venus Express provides an excellent opportunity to study such shocks further. Here we present results from the duration of the mission, which identifies over thirty shock crossings showing evidence of kinematic relaxation. These shock crossings are investigated to understand how the upstream conditions and heavy ions (including pick-up ions) affect their formation.

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.

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.

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.

The mistakes made when attempting tasks often prove to be some of the most invaluable learning experiences. Despite this, outcome and results driven assessment formats largely penalise student performance errors or reward students who succeed by chance. The consequences of this paradigm are visible effects on student relationships with assessment. The student–tutor consensus approach to assessment was introduced to capture student learning achieved ‘from’ assessment to complement the measurement of performance outcomes. This approach parallels student and tutor judgement in a grade negotiation, affording the student an opportunity to share with their assessor what they have learned from the assessment activity. This student self-awareness was then considered alongside the conventional outcome-based score awarded by the tutor to generate a final grade for the assessed activity. Our study evaluated the perceptions of 90 undergraduate students enrolled in the bachelor of paramedic studies, who partic...

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.

This contribution takes the form of a letter from Pope to geographer Dr. Saskia Warren, as part of an ongoing, cross-disciplinary conversation in relation to the author’s artwork Forward Back Together. It asks how our concept of participation is transformed when we consider the materialities of taking part, and in what ways this transforms our understanding of what constitutes a ‘public’ for public art. These themes are discussed in relation to Pope’s research that explores the ways that participatory modes of contemporary art can produce hybrid more-than-human social worlds.

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.

The neuronal ceroid lipofuscinoses (NCLs or Batten disease) are a group of inherited, fatal neurodegenerative disorders of childhood. In these disorders, glial (microglial and astrocyte) activation typically occurs early in disease progression and predicts where neuron loss subsequently occurs. We have found that in the most common juvenile form of NCL (CLN3 disease or JNCL) this glial response is less pronounced in both mouse models and human autopsy material, with the morphological transformation of both astrocytes and microglia severely attenuated or delayed. To investigate their properties, we isolated glia and neurons from Cln3-deficient mice and studied their basic biology in culture. Upon stimulation, both Cln3-deficient astrocytes and microglia also showed an attenuated ability to transform morphologically, and an altered protein secretion profile. These defects were more pronounced in astrocytes, including the reduced secretion of a range of neuroprotective factors, mitogens, chemokines and cytokines, in addition to impaired calcium signalling and glutamate clearance. Cln3-deficient neurons also displayed an abnormal organization of their neurites. Most importantly, using a co-culture system, Cln3-deficient astrocytes and microglia had a negative impact on the survival and morphology of both Cln3-deficient and wildtype neurons, but these effects were largely reversed by growing mutant neurons with healthy glia. These data provide evidence that CLN3 disease astrocytes are functionally compromised. Together with microglia, they may play an active role in neuron loss in this disorder and can be considered as potential targets for therapeutic interventions. Electronic supplementary material The online version of this article (10.1186/s40478-017-0476-y) contains supplementary material, which is available to authorized users.

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.

Polyneuropathies are amongst the most common neurological conditions worldwide affecting over 20 million people. However, 40% of patients with primary polyneuropathies have no disease-causing mutation identified.We investigated patients with gene-negative primary polyneuropathies using a combination of whole genome sequencing, homozigosity mapping and segregation analysis. Pathogenicity was confirmed via enzymatic assays and mass spectroscopy on recombinant protein and patient-derived fibroblasts, plasma and erythrocytes. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the ATP binding.We report that biallelic mutations in human PDXK are associated with primary axonal polyneuropathy and optic atrophy. Pyridoxal kinase (PDXK) is involved in converting vitamin B6 to its active form, pyridoxal 5’-phosphate (PLP). We show that PDXK mutations lead to disease via decreased plasma PLP concentrations. Our functional studies revealed conformational rearrangement in the mutant enzyme around the kinase ATP-binding pocket with impaired PDXK ability to bind ATP and leading to reduced erythrocyte PDXK activity. We show that both the human clinical picture and biochemical profile in PDXK mutations are rescued by PLP supplementation. Patients regained their ability to walk independently. Furthermore, treatment-led normalisation of plasma PLP levels, correlated with reduction of neurofilament light chain concentrations, a biomarker of axonal breakdown.In conclusion, biallelic mutations in human PDXK are associated with a novel disorder leading to treatable primary axonal polyneuropathy and optic atrophy and identifies PLP as therapeutic target.

Elastic and acoustic metamaterials provide an approach to creating materials which possess properties which are not found in natural or conventional materials. This notably includes dynamic effective material properties, i.e. density and modulus, which can become negative in prescribed frequency bands. Elastic and acoustic metamaterials provide alternative solutions to existing problems in acoustics and provide a route to realizing novel new concepts. Novel concepts associated with metamaterials include acoustic invisibility and sub-wavelength imaging. Elastic metamaterials with negative effective parameters can be realized using arrays of local resonators. However the performance of these devices suffers due to a fixed and usually narrow frequency band in which the effective parameters are negative. Active metamaterials provide an alternative approach in which control forces applied to a transmission medium emulate the desired response. Such devices have the benefit of being able to realize a response which is both tunable and not possible with passive components alone. This paper focuses on the development of an experimental demonstration of active elastic metamaterials with negative mass or stiffness across desired frequency bands. The active elastic metamaterial is a one-dimensional structure composed of a series of constrained lumped masses to which control forces are applied through a feedback control. The dynamic effective parameters are extracted from the measured data using a least squares approach to fit the data to an effective system. Comparison of the measured effective parameters to the simulated results verifies the effective response of the active elastic metamaterial in experimentation.

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.

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.

The ability of a material to recover its nominal properties through self-healing is gaininginterest in the research community. However, current approaches remain predominantly passive incounteracting the effect of damage. As a result, healing only begins when the material has occurreddamage and typically there is a mismatch between the healing and damage rate. For applications suchas aircraft, where there is a thin line between functionality and non-functionality, these limitations maybe inherently restrictive. A self-healing system that combines a prognosis unit to predict and estimatethe failure rate and an active self-healing system that matches the healing rate to the estimated failurerate using a feedback loop, has the potential to overcome these limitations. In this paper we proposesuch a system and present results for its application to composite materials.

The term Neurotansmitter disorder, in the area of metabolic disease, focuses particularly on inborn errors affecting monoamine (dopamine & serotonin), pyridoxal phosphate (B6) and folate metabolism. Whilst there has been considerable focus on these disorders with regards to the paediatric population, it is clear that an increasing number of adult patients are being identified. Adult neurologists need to be aware of the clinical presentation of such patients and the appropriate tests that need to be requested to ensure a correct diagnosis is achieved. CSF profiling, by a specialist laboratory, is often required. This has the ability to very often identify the nature of a primary defect with regards to implementation of appropriate treatment. For some of these disorders, treatment can be effective. This may be in the form of monoamine/vitamin replacement. However there are exceptions, e.g. aromatic amino acid decarboxylase and dopamine transporter deficiencies. There also needs also to be an awareness of the growing list of secondary factors that can cause impaired dopamine and serotonin metabolism.

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.

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.

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.

There is currently interest in the metabolism of the various compounds which make up the vitamin E family, especially with regards to the possible use of vitamin E metabolites as markers of oxidative stress and adequate vitamin E supply. A number of vitamin E metabolites have been described to date and we have recently developed a method to extract and quantitate a range of vitamin E metabolites in human urine. During the development of this method a new metabolite of alpha-tocopherol was identified, which we tentatively characterised as 5-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl)-2-methyl-pentanoic acid (alpha-CMBHC).(1) Here we describe the synthesis of alpha-CMBHC as a standard and confirm that it is a metabolite of alpha-tocopherol.

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.

A systematic geometric design methodology to generate a stable controller for simultaneous local and remote attenuation that was previously proposed is experimentally validated on a structure. The local control path transfer function for this experimental system is non-minimum phase due to which the original broadband controller design would yield an unstable controller. Here a modified procedure for systems with local non-minimum phase dynamics is used to generate a stable controller. According to this method, reduction in vibration at local and remote points on a structure can be parameterised in terms of the available design freedom and a controller is realised in terms of the optimal selection of this using the minimum phase counterpart of the local control path transfer function. The modified method results in a controller that is both stable and stabilizing and which achieves the desired vibration attenuation at the local and remote points on the structure. An experimental facility that replicates the vibration transmission through the shaft of a propeller blade rig system is used to demonstrate the method. Vibration for excitation near the first bending mode frequency of the resonating part of this structure is attenuated at the non-resonating part of the system without deteriorating vibration at the resonating end.

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.

The mitochondria-targeted quinone MitoQ protects mitochondria in animal studies of pathologies in vivo and is being developed as a therapy for humans. However, it is unclear whether the protective action of MitoQ is entirely due to its antioxidant properties, because long-term MitoQ administration may alter whole-body metabolism and gene expression. To address this point, we administered high levels of MitoQ orally to wild-type C57BL/6 mice for up to 28 weeks and investigated the effects on whole-body physiology, metabolism, and gene expression, finding no measurable deleterious effects. In addition, because antioxidants can act as pro-oxidants under certain conditions in vitro, we examined the effects of MitoQ administration on markers of oxidative damage. There were no changes in the expression of mitochondrial or antioxidant genes as assessed by DNA microarray analysis. There were also no increases in oxidative damage to mitochondrial protein, DNA, or cardiolipin, and the activities of mitochondrial enzymes were unchanged. Therefore, MitoQ does not act as a pro-oxidant in vivo. These findings indicate that mitochondria-targeted antioxidants can be safely administered long-term to wild-type mice.

Isolated complex I deficiency is the most commonly reported enzyme defect in paediatric mitochondrial disorders, and may arise due to mutations in nuclear-encoded structural or assembly genes, or the mitochondrial genome. We present the clinical, biochemical and molecular genetic data in a young girl whose clinical picture is dominated by chronic renal failure, myopathy and persistent lactic acidosis. An isolated complex I deficiency in muscle was identified due to a novel mutation (m.12425delA) in the MTND5 gene. This single nucleotide deletion is heteroplasmic and detectable in several tissues from the proband but not her mother, suggesting a de novo mutation event. The description of the first frameshift mutation in a mitochondrial complex I gene affirms mitochondrial DNA mutations as an important cause of isolated complex I deficiency in children and the importance of whole mitochondrial genome sequencing in the diagnostic work-up to elucidate the underlying molecular genetic abnormality and provide important genetic advice.

[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] On 10-11 September 2006 the Venus Express magnetometer detected a very strong Interplanetary Coronal Mass Ejection (ICME) event with an average field about 2 times higher than that of a typical ICME at 0.72 AU. While the effective obstacle to the solar wind is compressed to a smaller dimension during this ICME event, the bow shock is located far upstream of its nominal location. The observed shocks are weak and appear very dynamic. The location of the shock crossing can be found all along the Venus Express trajectory, which has an apocenter of 12 R v . We attribute the atypical distant bow shock location as an effect of the extremely low Mach number during the ICME.

The pathogenesis of mitochondrial disorders has largely focused on the impairment of cellular energy metabolism. However, mitochondrial dysfunction has also been implicated as a factor in the initiation of apoptosis due to the translocation of cytochrome c, from mitochondria to the cytosol, and the subsequent cleavage of pro-caspase 3. In this study, we determined the cytochrome c content of cytosols (skeletal muscle) prepared from 22 patients with evidence of compromised mitochondrial electron transport chain enzyme activity and 26 disease controls. The cytochrome c content of the mitochondrial electron transport chain-deficient group was found to be significantly (p < 0.02) elevated when compared with the control group (63.7 +/- 15.5 versus 27.7 +/- 2.5 ng/mg protein). Furthermore, a relationship between the cytosolic cytochrome c content of skeletal muscle and complex I and complex IV activities was demonstrated. Such data raise the possibility that mitochondrial cytochrome c release may be a feature of mitochondrial disorders, particularly for those patients with marked deficiencies of respiratory chain enzymes. Whether initiation of apoptosis occurs as a direct consequence of this cytochrome c release has not been fully evaluated here. However, for one patient with the greatest documented cytosolic cytochrome c content, caspase 3 could be demonstrated in the cytosolic preparation. Further work is required in order to establish whether a relationship also exists between caspase 3 formation and the magnitude of respiratory chain deficiency.

[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.