Novel TBK1 truncating mutation in a familial amyotrophic lateral sclerosis patient of Chinese origin

Missense and frameshift mutations in TRAF family member-associated NF-kappa-B activator (TANK)-binding kinase 1 (TBK1) have been reported in European sporadic and familial amyotrophic lateral sclerosis (ALS) cohorts. To assess the role of TBK1 in ALS patient cohorts of wider ancestry, we have analyzed whole-exome sequence data from an Australian cohort of familial ALS (FALS) patients and controls. We identified a novel TBK1 deletion (c.1197delC) in a FALS patient of Chinese origin. This frameshift mutation (p.L399fs) likely results in a truncated protein that lacks functional domains required for adapter protein binding, as well as protein activation and structural integrity. No novel or reported TBK1 mutations were identified in FALS patients of European ancestry. This is the first report of a TBK1 mutation in an ALS patient of Asian origin and indicates that sequence variations in TBK1 are a rare cause of FALS in Australia. © 2015 Elsevier Inc.

Tonic current through GABAA receptors and hyperpolarization-activated cyclic nucleotide-gated channels modulate resonance properties of rat subicular pyramidal neurons

The subiculum, considered to be the output structure of the hippocampus, modulates information flow from the hippocampus to various cortical and sub-cortical areas such as the nucleus accumbens, lateral septal region, thalamus, nucleus gelatinosus, medial nucleus and mammillary nuclei. Tonic inhibitory current plays an important role in neuronal physiology and pathophysiology by modulating the electrophysiological properties of neurons. While the alterations of various electrical properties due to tonic inhibition have been studied in neurons from different regions, its influence on intrinsic subthreshold resonance in pyramidal excitatory neurons expressing hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is not known. Using pharmacological agents, we show the involvement of alpha 5 beta gamma GABA(A) receptors in the picrotoxin-sensitive tonic current in subicular pyramidal neurons. We further investigated the contribution of tonic conductance in regulating subthreshold electrophysiological properties using current clamp and dynamic clamp experiments. We demonstrate that tonic GABAergic inhibition can actively modulate subthreshold properties, including resonance due to HCN channels, which can potentially alter the response dynamics of subicular pyramidal neurons in an oscillating neuronal network.

Lateral motion and departure of vapor bubbles in nucleate pool boiling on thin wires in microgravity

A space experiment on bubble behavior and heat transfer in subcooled pool boiling phenomenon has been performed utilizing the temperature-controlled pool boiling (TCPB) device both in normal gravity in the laboratory and in microgravity aboard the 22(nd) Chinese recoverable satellite. The fluid is R113 at 0.1 MPa and subcooled by 26 degrees C nominally. A thin platinum wire of 60 mu m in diameter and 30mm in length is simultaneously used as heater and thermometer. Only the lateral motion and the departure of discrete vapor bubbles in nucleate pool boiling are reported and analyzed in the present paper. A scale analysis on the Marangoni convection surrounding a bubble in the process of subcooled nucleate pool boiling leads to formulas of the characteristic velocity of the lateral motion and its observability. The predictions consist with the experimental observations. Considering the Marangoni effect, a new qualitative model is proposed to reveal the mechanism underlying the bubble departure processes and a quantitative agreement can also be acquired.

CONTROLLED FORMATION AND CHARACTERISTICS OF INTERFACES IN GAAS/ALGAAS SINGLE QUANTUM-WELLS

The influence of heterostructure quality on transport and optical properties of GaAs/AlGaAs single quantum wells with different qualities was studied. In a conventional sample-A, the transport scattering time and the quantum scattering time are small and close to each other. The interface roughness scattering is a dominant scattering mechanism. From comparison between theory and experiment, interface roughness with fluctuation height 2.5 Angstrom and the lateral size of 50-70 Angstrom were estimated. For samples introducing superlattices instead of AlGaAs layers or by utilizing growth interruption, both the transport and PL measurements showed that interfaces were rather smooth in the samples. The two scattering times are much longer. The interface roughness scattering is relegated to an unimportant position. Results demonstrated that it is important to control the formation of heterostructures in order to improve the interface quality.

Development of multi-channel gated integrator and PXI-DAQ system for nuclear detector arrays

A multi-channel gated integrator and PXI based data acquisition system have been developed for nuclear detector arrays with hundreds of detector units. The multi-channel gated integrator can be controlled by a programmable Cl controller. The PXI-DAQ system consists of NI PXI-1033 chassis with several PXI-DAQ cards. The system software has a user-friendly GUI which is written in C language using LabWindows/CVI under Windows XP operating system. The performance of the PXI-DAQ system is very reliable and capable of handling event rate up to 40 kHz. (C) 2010 Elsevier B.V. All rights reserved.

Advanced polymer membrane development in pervaporation dehydration and lateral flow diagnostics

The work in this thesis concerns the advanced development of polymeric membranes of two types; pervaporation and lateral-flow. The former produced from a solution casting method and the latter from a phase separation. All membranes were produced from casting lacquers. Early research centred on the development of viable membranes. This led to a supported polymer blend pervaporation membrane. Selective layer: plasticized 4:1 mass ratio sodium-alginate: poly(vinyl-alcohol) polymer blend. Using this membrane, pervaporation separation of ethanol/water mixtures was carefully monitored as a function of film thickness and time. Contrary to literature expectations, these films showed increased selectivity and decreased flux as film thickness was reduced. It is argued that morphology and structure of the polymer blend changes with thickness and that these changes define membrane efficiency. Mixed matrix membrane development was done using spherical, discreet, size-monodisperse mesoporous silica particles of 1.8 - 2μm diameter, with pore diameters of ~1.8 nm were incorporated into a poly(vinyl alcohol) [PVA] matrix. Inclusion of silica benefitted pervaporation performance for the dehydration of ethanol, improving flux and selectivity throughout in all but the highest silica content samples. Early lateral-flow membrane research produced a membrane from a basic lacquer composition required for phase inversion; polymer, solvent and non-solvent. Results showed that bringing lacquers to cloud point benefits both the pore structure and skin layers of the membranes. Advancement of this work showed that incorporation of ethanol as a mesosolvent into the lacquer effectively enhances membrane pore structure resulting in an improvement in lateral flow rates of the final membranes. This project details the formation mechanics of pervaporation and lateral-flow membranes and how these can be controlled. The principle methods of control can be applied to the formation of any other flat sheet polymer membranes, opening many avenues of future membrane research and industrial application.

Photocontrolled Binding and Binding-Controlled Photochromism within Anthracene-Modified DNA

Modified DNA strands undergo a reversible light-induced reaction involving the intramolecular photodimerization of two appended anthracene tags. The photodimers exhibit markedly different binding behavior toward a complementary strand that depends on the number of bases between the modified positions. By preforming the duplex, photochromism can be suppressed, illustrating dual-mode gated behavior.

Different frequencies of acupuncture for treatment for chronic low back pain: an-assessor blinded pilot randomised controlled trial.

OBJECTIVES:
To examine the feasibility of a main RCT to compare the effectiveness of two frequencies (2 versus 5 times/week) of acupuncture treatment for chronic low back pain (LBP).
METHODS:
Participants (n=30) with chronic LBP were randomised into two groups to receive 10 acupuncture treatments: Low Frequency Group, 2 times/week for five weeks (n=15); High Frequency Group, 5 times/week for two weeks (n=15). The following outcomes were measured blindly at baseline, 2 weeks, 5 weeks, 3 months and 1 year: pain on a VAS, functional disability using the RMDQ, quality of life using the Measure Yourself Medical Outcome Profile (MYMOP-2), psychological impact with the Coping Strategies Questionnaire (CSQ) and Pain Locus of Control (PLC) questionnaire. Two objective outcomes, the Shuttle Walk Test (SWT) and Lateral Trunk Flexibility (LTF), were also measured.
RESULTS:
The compliance rate was 100% for each group. Some of the measurements were shown to be sensitive (VAS, RMDQ, MYMOP-2 Wellbeing). 66-330 participants would be required for a fully powered non-inferiority trial. The groups were balanced at baseline for LBP and demographic characteristics. There were no significant differences between the groups in terms of any of the outcomes, at each follow-up time point. It was notable however that the clinically important improvement in terms of pain, functional disability, quality of life, and SWT in both groups was achieved within the first two weeks, which was maintained at one year follow-up.
CONCLUSIONS:
It is feasible to conduct a main RCT, to compare different frequencies of acupuncture for LBP, using sensitive measurements. Also the trend for early clinically important improvement within a minimum of four measurements is worthy of further study.

The tectonically controlled emplacement of a vertically sheeted gabbro-pyroxenite intrusion: Feeder-zone of an ocean-island volcano (Fuerteventura, Canary Islands)

The Miocene PX1 gabbro-pyroxenite pluton, Fuerteventura, Canary Islands, is a 3.5 x 5.5 km shallow-level intrusion (0.15-0.2 GPa and 1100-1120 degrees C), interpreted as the feeder-zone to an ocean-island volcano. It displays a vertical magmatic banding expressed in five 50 to 100 metre-wide NNE-SSW trending alkaline gabbro sequences alternating with pyroxenites. This emplacement geometry was controlled by brittle to ductile shear zones, generated by a regional E-W extensional tectonic setting that affected Fuerteventura during the Miocene. At a smaller scale, the PX1 gabbro and pyroxenite bands consist of metre-thick differentiation units, which suggest emplacement by periodic injection of magma pulses as vertical dykes that amalgamated, similarly to a sub-volcanic sheeted dyke complex. Individual dykes underwent internal differentiation following a solidification front parallel to the dyke edges. This solidification front may have been favoured by a significant lateral/horizontal thermal gradient, expressed by the vertical banding in the gabbros, the fractionation asymmetry within individual dykes and the migmatisation of the wall rocks. Pyroxenitic layers result from the fractionation and accumulation of clinopyroxene +/- olivine +/- plagioclase crystals from a mildly alkaline basaltic liquid. They are interpreted as truncated differentiation sequences, from which residual melts were extracted at various stages of their chemical evolution by subsequent dyke intrusions, either next to or within the crystallising unit. Compaction and squeezing of the crystal mush is ascribed to the incoming and inflating magma pulses. The expelled interstitial liquid was likely collected and erupted along with the magma flowing through the newly injected dykes. Clinopyroxene mineral orientation - as evidenced by EBSD and micro X-ray tomography investigations - displays a marked pure-shear component, supporting the interpretation of the role of compaction in the generation of the pyroxenites. Conversely, gabbro sequences underwent minor melt extraction and are believed to represent crystallised coalesced magma batches emplaced at lower rates at the end of eruptive cycles. Clinopyroxene orientations in gabbros record a simple shear component suggesting syn-magmatic deformation parallel to observed NNE-SSW trending shear zones induced by the regional tensional stress field. This emplacement model implies a crystallisation time of 1 to 5 years for individual dykes, consistent with PX1 emplacement over less than 0.5 My. A minimum amount of approximately 150 km(3) of magma is needed to generate the pluton, part of it having been erupted through the Central Volcanic Centre of Fuerteventura. If the regional extensional tectonic regime controls the PX1 feeder-zone initiation and overall geometry, rates and volumes of magma depend on other, source-related factors. High injection rates are likely to induce intrusion growth rates larger than could be accommodated by the regional extension. In this case, dyke intrusion by propagation of a weak tip, combined with the inability of magma to circulate through previously emplaced and crystallised dykes could result in an increase of non-lithostatic pressure on previously emplaced mushy dyke walls; thus generating strong pure-shear compaction within the pluton feeder-zone and interstitial melt expulsion. These compaction-dominated processes are recorded by the cumulitic pyroxenite bands. (C) 2010 Elsevier B.V. All rights reserved.

Towards the nanomechanical actuation and controlled assembly of nanomaterials using charge-transfer reactions in electroactive self-assembled monolayers

Les microcantileviers fonctionnalisés offrent une plateforme idéale pour la nano- et micro-mécanique et pour le développement de (bio-) capteurs tres sensible. Le principe d’opération consiste dans des évènements physicochimiques qui se passent du côté fonctionnalisé du microcantilevier induisant une différence de stress de surface entre les deux côtés du cantilevier qui cause une déflexion verticale du levier. Par contre, les facteurs et les phénomènes interfacials qui régissent la nature et l'intensité du stress de surface sont encore méconnus. Pour éclaircir ce phénomène, la première partie de cette thèse porte sur l'étude des réactions de microcantileviers qui sont recouverts d'or et fonctionnalisés par une monocouche auto-assemblée (MAA) électroactive. La formation d'une MAA de ferrocènylundécanethiol (FcC11SH) à la surface d'or d'un microcantilevier est le modèle utilisé pour mieux comprendre le stress de surface induit par l’électrochimie. Les résultats obtenus démontrent qu'une transformation rédox de la MAA de FcC11SH crée un stress de surface qui résulte dans une déflexion verticale du microcantilevier. Dépendamment de la flexibilité du microcantilevier, cette déflexion peut varier de quelques nanomètres à quelques micromètres. L’oxydation de cette MAA de FcC11SH dans un environnement d'ions perchlorate génère un changement de stress de surface compressive. Les résultats indiquent que la déflexion du microcantilevier est due à une tension latérale provenant d'une réorientation et d'une expansion moléculaire lors du transfért de charge et de pairage d’anions. Pour vérifier cette hypothèse, les mêmes expériences ont été répéteés avec des microcantileviers qui ont été couverts d'une MAA mixte, où les groupements électroactifs de ferrocène sont isolés par des alkylthiols inactifs. Lorsqu’un potentiel est appliqué, un courant est détecté mais le microcantilevier ne signale aucune déflexion. Ces résultats confirment que la déflexion du microcantilevier est due à une pression latérale provenant du ferrocènium qui se réorganise et qui crée une pression sur ses pairs avoisinants plutôt que du couplage d’anions. L’amplitude de la déflexion verticale du microcantilevier dépend de la structure moléculaire de la MAA et du le type d’anion utilisés lors de la réaction électrochimique. Dans la prochaine partie de la thèse, l’électrochimie et la spectroscopie de résonance de plasmon en surface ont été combinées pour arriver à une description de l’adsorption et de l’agrégation des n-alkyl sulfates à l’interface FcC11SAu/électrolyte. À toutes les concentrations de solution, les molécules d'agent tensio-actif sont empilées perpendiculairement à la surface d'électrode sous forme de monocouche condensé entrecroisé. Cependant, la densité du film spécifiquement adsorbé s'est avérée être affectée par l'état d'organisation des agents tensio-actifs en solution. À faible concentration, où les molécules d'agent tensio-actif sont présentes en tant que monomères solvatés, les monomères peuvent facilement s'adapter à l’évolution de la concentration en surface du ferrocènium lors du balayage du potential. Cependant, lorsque les molécules sont présentes en solution en tant que micelles une densité plus faible d'agent tensio-actif a été trouvée en raison de l'incapacité de répondre effectivement à la surface de ferrocenium générée dynamiquement.

Video-based postural sway analysis in a controlled environment

À mesure que la population des personnes agées dans les pays industrialisés augmente au fil de années, les ressources nécessaires au maintien du niveau de vie de ces personnes augmentent aussi. Des statistiques montrent que les chutes sont l’une des principales causes d’hospitalisation chez les personnes agées, et, de plus, il a été démontré que le risque de chute d’une personne agée a une correlation avec sa capacité de maintien de l’équilibre en étant debout. Il est donc d’intérêt de développer un système automatisé pour analyser l’équilibre chez une personne, comme moyen d’évaluation objective. Dans cette étude, nous avons proposé l’implémentation d’un tel système. En se basant sur une installation simple contenant une seule caméra sur un trépied, on a développé un algorithme utilisant une implémentation de la méthode de détection d’objet de Viola-Jones, ainsi qu’un appariement de gabarit, pour suivre autant le mouvement latéral que celui antérieur-postérieur d’un sujet. On a obtenu des bons résultats avec les deux types de suivi, cependant l’algorithme est sensible aux conditions d’éclairage, ainsi qu’à toute source de bruit présent dans les images. Il y aurait de l’intérêt, comme développement futur, d’intégrer les deux types de suivi, pour ainsi obtenir un seul ensemble de données facile à interpréter.

Mixed layer lateral eddy fluxes mediated by air-sea interaction

The modulation of air–sea heat fluxes by geostrophic eddies due to the stirring of temperature at the sea surface is discussed and quantified. It is argued that the damping of eddy temperature variance by such air–sea fluxes enhances the dissipation of surface temperature fields. Depending on the time scale of damping relative to that of the eddying motions, surface eddy diffusivities can be significantly enhanced over interior values. The issues are explored and quantified in a controlled setting by driving a tracer field, a proxy for sea surface temperature, with surface altimetric observations in the Antarctic Circumpolar Current (ACC) of the Southern Ocean. A new, tracer-based diagnostic of eddy diffusivity is introduced, which is related to the Nakamura effective diffusivity. Using this, the mixed layer lateral eddy diffusivities associated with (i) eddy stirring and small-scale mixing and (ii) surface damping by air–sea interaction is quantified. In the ACC, a diffusivity associated with surface damping of a comparable magnitude to that associated with eddy stirring (;500 m2 s21) is found. In frontal regions prevalent in the ACC, an augmentation of surface lateral eddy diffusivities of this magnitude is equivalent to an air–sea flux of 100 W m22 acting over a mixed layer depth of 100 m, a very significant effect. Finally, the implications for other tracer fields such as salinity, dissolved gases, and chlorophyll are discussed. Different tracers are found to have surface eddy diffusivities that differ significantly in magnitude.

Self-assembled arginine-capped peptide bolaamphiphile nanosheets for cell culture and controlled wettability surfaces

The spontaneous assembly of a peptide bolaamphiphile in water, namely, RFL4FR (R, arginine; F, phenylalanine; L, leucine) is investigated, along with its novel properties in surface modification and usage as substrates for cell culture. RFL4FR self-assembles into nanosheets through lateral association of the peptide backbone. The L4 sequence is located within the core of the nanosheets, whereas the R moieties are exposed to the water at the surface of the nanosheets. Kinetic assays indicate that the self-assembly is driven by a remarkable two-step process, where a nucleation phase is followed by fast growth of nanosheets with an autocatalysis process. The internal structure of the nanosheets is formed from ultrathin bolaamphiphile monolayers with a crystalline orthorhombic symmetry with cross-β organization. We show that human corneal stromal fibroblast (hCSF) cells can grow on polystyrene films coated with films dried from RFL4FR solutions. For the first time, this type of amphiphilic peptide is used as a substrate to modulate the wettability of solid surfaces for cell culture applications.

Human skeletal muscle atrophy in amyotrophic lateral sclerosis reveals a reduction in Akt and an increase in atrogin-1

The molecular mechanisms influencing muscle atrophy in humans are poorly understood. Atrogin-1 and MuRF1, two ubiquitin E3-ligases, mediate rodent and cell muscle atrophy and are suggested to be regulated by an Akt/Forkhead (FKHR) signaling pathway. Here we investigated the expression of atrogin-1, MuRF1, and the activity of Akt and its catabolic (FKHR and FKHRL1) and anabolic (p70s6k and GSK-3β) targets in human skeletal muscle atrophy. The muscle atrophy model used was amyotrophic lateral sclerosis (ALS). All measurements were performed in biopsies from 22 ALS patients and 16 healthy controls as well as in G93A ALS mice. ALS patients had a significant increase in atrogin-1 mRNA and protein content, which was associated with a decrease in Akt activity. There was no difference in the mRNA and protein content of FKHR, FKHRL1, p70s6k, and GSK-3β. Similar observations were made in the G93A ALS mice. Human skeletal muscle atrophy, as seen in the ALS model, is associated with an increase in atrogin-1 and a decrease in Akt. The transcriptional regulation of human atrogin-1 may be controlled by an Akt-mediated transcription factor other than FKHR or via another signaling pathway.

Effects of laterally wedged insoles on symptoms and disease progression in medial knee osteoarthritis: a protocol for a randomised, double-blind, placebo controlled trial

Background: Whilst laterally wedged insoles, worn inside the shoes, are advocated as a simple, inexpensive, non-toxic self-administered intervention for knee osteoarthritis (OA), there is currently limited evidence to support their use. The aim of this randomised, double-blind controlled trial is to determine whether laterally wedges insoles lead to greater improvements in knee pain, physical function and health-related quality of life, and slower structural disease progression as well as being more cost-effective, than control flat insoles in people with medial knee OA.

Methods/Design: Two hundred participants with painful radiographic medial knee OA and varus malalignment will be recruited from the community and randomly allocated to lateral wedge or control insole groups using concealed allocation. Participants will be blinded as to which insole is considered therapeutic. Blinded follow up assessment will be conducted at 12 months after randomisation. The outcome measures are valid and reliable measures recommended for OA clinical trials. Questionnaires will assess changes in pain, physical function and health-related quality-of-life. Magnetic resonance imaging will measure changes in tibial cartilage volume. To evaluate cost-effectiveness, participants will record the use of all health-related treatments in a log-book returned to the assessor on a monthly basis. To test the effect of the intervention using an intention-to-treat analysis, linear regression modelling will be applied adjusting for baseline outcome values and other demographic characteristics.

Discussion: Results from this trial will contribute to the evidence regarding the effectiveness of laterally wedged insoles for the management of medial knee OA.

Trial registration: ACTR12605000503628; NCT00415259.