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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.

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.

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.

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.

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.

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.

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.

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.

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.

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).