Tunable few-electron double quantum dots and Klein tunnelling in ultra-clean carbon nanotubes

Quantum dots defined in carbon nanotubes are a platform for both basic scientific studies and research into new device applications. In particular, they have unique properties that make them attractive for studying the coherent properties of single electron spins. To perform such experiments it is necessary to confine a single electron in a quantum dot with highly tunable barriers, but disorder has until now prevented tunable nanotube-based quantum-dot devices from reaching the single-electron regime. Here, we use local gate voltages applied to an ultra-clean suspended nanotube to confine a single electron in both a single quantum dot and, for the first time, in a tunable double quantum dot. This tunability is limited by a novel type of tunnelling that is analogous to that in the Klein paradox of relativistic quantum mechanics.Comment: 21 pages including supplementary informatio

TMEM106B a Novel Risk Factor for Frontotemporal Lobar Degeneration

Recently, the first genome-wide association (GWA) study in frontotemporal lobar degeneration (FTLD) identified common genetic variability at the TMEM106B gene on chromosome 7p21.3 as a potential important risk-modifying factor for FTLD with pathologic inclusions of TAR DNA-binding protein (FTLD-TDP), the most common pathological subtype in FTLD. To gather additional evidence for the implication of TMEM106B in FTLD risk, multiple replication studies in geographically distinct populations were set up. In this review, we revise all recent replication and follow-up studies of the FTLD-TDP GWA study and summarize the growing body of evidence that establish TMEM106B as a bona fide risk factor for FTLD. With the TMEM106B gene, a new player has been identified in the pathogenic cascade of FTLD which could hold important implications for the future development of disease-modifying therapies

DNA strand break repair and neurodegeneration.

A number of DNA repair disorders are known to cause neurological problems. These disorders can be broadly characterised into early developmental, mid-to-late developmental or progressive. The exact developmental processes that are affected can influence disease pathology, with symptoms ranging from early embryonic lethality to late-onset ataxia. The category these diseases belong to depends on the frequency of lesions arising in the brain, the role of the defective repair pathway, and the nature of the mutation within the patient. Using observations from patients and transgenic mice, we discuss the importance of double strand break repair during neuroprogenitor proliferation and brain development and the repair of single stranded lesions in neuronal function and maintenance

Mid-Pleistocene thin-skinned glaciotectonic thrusting of the Aberdeen Ground Formation, Central Graben region, central North Sea

This paper presents the results of a high-resolution 2D seismic survey of mid-Pleistocene glaciogenic sediments in the Central Graben region of the central North Sea. Sediments have undergone major glaciotectonic thrusting and folding associated with the repeated southerly advance of a mid-Pleistocene ice sheet. The total observed length of the thrust-stacked section is approximately 5–6 km, comprising a series of discrete thrust slices, which range in length from  700 m. The basal detachment of the thrust complex occurs at a depth of ca. 220 m below the sea bed within the upper Aberdeen Ground Formation. A thin-skinned glaciotectonic model involving proglacial to ice-marginal glaciotectonic thrusting followed by post-tectonic deposition is proposed. Initial ice advance led to the over-pressurizing of groundwater within a laterally extensive sand sheet in the upper Aberdeen Ground Formation, promoting the formation of a major décollement surface at the base of the developing thrust-stack. Over-pressurization of the groundwater system is thought to have occurred in response to rapid ice advance, suggesting that the development of large-scale thrust complexes may be associated with surge-type behaviour. The proposed model evidences complex dynamics of mid-Pleistocene ice sheets within the central North Sea

Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features

An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of familial frontotemporal lobar degeneration and motor neuron disease, including cases previously identified as linked to chromosome 9. Here we present a detailed retrospective clinical, neuroimaging and histopathological analysis of a C9ORF72 mutation case series in relation to other forms of genetically determined frontotemporal lobar degeneration ascertained at a specialist centre. Eighteen probands (19 cases in total) were identified, representing 35% of frontotemporal lobar degeneration cases with identified mutations, 36% of cases with clinical evidence of motor neuron disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 cases had no identified relevant family history. Families showed wide variation in clinical onset (43–68 years) and duration (1.7–22 years). The most common presenting syndrome (comprising a half of cases) was behavioural variant frontotemporal dementia, however, there was substantial clinical heterogeneity across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical features consistent with motor neuron disease during the period of follow-up. Anxiety and agitation and memory impairment were prominent features (between a half to two-thirds of cases), and dominant parietal dysfunction was also frequent. Affected individuals showed variable magnetic resonance imaging findings; however, relative to healthy controls, the group as a whole showed extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile of the C9ORF72 expansion was significantly more symmetrical than progranulin mutations with significantly less temporal lobe involvement than microtubule-associated protein tau mutations. Neuropathological examination in six cases with C9ORF72 mutation from the frontotemporal lobar degeneration series identified histomorphological features consistent with either type A or B TAR DNA-binding protein-43 deposition; however, p62-positive (in excess of TAR DNA-binding protein-43 positive) neuronal cytoplasmic inclusions in hippocampus and cerebellum were a consistent feature of these cases, in contrast to the similar frequency of p62 and TAR DNA-binding protein-43 deposition in 53 control cases with frontotemporal lobar degeneration–TAR DNA-binding protein. These findings corroborate the clinical importance of the C9ORF72 mutation in frontotemporal lobar degeneration, delineate phenotypic and neuropathological features that could help to guide genetic testing, and suggest hypotheses for elucidating the neurobiology of a culprit subcortical network

Definition and classification of hyperkinetic movements in childhood

Hyperkinetic movements are unwanted or excess movements that are frequently seen in children with neurologic disorders. They are an important clinical finding with significant implications for diagnosis and treatment. However, the lack of agreement on standard terminology and definitions interferes with clinical treatment and research. We describe definitions of dystonia, chorea, athetosis, myoclonus, tremor, tics, and stereotypies that arose from a consensus meeting in June 2008 of specialists from different clinical and basic science fields. Dystonia is a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. Chorea is an ongoing random-appearing sequence of one or more discrete involuntary movements or movement fragments. Athetosis is a slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture. Myoclonus is a sequence of repeated, often nonrhythmic, brief shock-like jerks due to sudden involuntary contraction or relaxation of one or more muscles. Tremor is a rhythmic back-and-forth or oscillating involuntary movement about a joint axis. Tics are repeated, individually recognizable, intermittent movements or movement fragments that are almost always briefly suppressible and are usually associated with awareness of an urge to perform the movement. Stereotypies are repetitive, simple movements that can be voluntarily suppressed. We provide recommended techniques for clinical examination and suggestions for differentiating between the different types of hyperkinetic movements, noting that there may be overlap between conditions. These definitions and the diagnostic recommendations are intended to be reliable and useful for clinical practice, communication between clinicians and researchers, and for the design of quantitative tests that will guide and assess the outcome of future clinical trials. © 2010 Movement Disorder SocietyPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77973/1/23088_ftp.pd

SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms

Clinical Reasoning Assessment Methods

© by the Association of American Medical Colleges. Purpose An evidence-based approach to assessment is critical for ensuring the development of clinical reasoning (CR) competence. The wide array of CR assessment methods creates challenges for selecting assessments fit for the purpose; thus, a synthesis of the current evidence is needed to guide practice. A scoping review was performed to explore the existing menu of CR assessments. Method Multiple databases were searched from their inception to 2016 following PRISMA guidelines. Articles of all study design types were included if they studied a CR assessment method. The articles were sorted by assessment methods and reviewed by pairs of authors. Extracted data were used to construct descriptive appendixes, summarizing each method, including common stimuli, response formats, scoring, typical uses, validity considerations, feasibility issues, advantages, and disadvantages. Results A total of 377 articles were included in the final synthesis. The articles broadly fell into three categories: non-workplace-based assessments (e.g., multiple-choice questions, extended matching questions, key feature examinations, script concordance tests); assessments in simulated clinical environments (objective structured clinical examinations and technology-enhanced simulation); and workplace-based assessments (e.g., direct observations, global assessments, oral case presentations, written notes). Validity considerations, feasibility issues, advantages, and disadvantages differed by method. Conclusions There are numerous assessment methods that align with different components of the complex construct of CR. Ensuring competency requires the development of programs of assessment that address all components of CR. Such programs are ideally constructed of complementary assessment methods to account for each method\u27s validity and feasibility issues, advantages, and disadvantages