Dynamic walking features and improved walking performance in multiple sclerosis patients treated with fampridine (4-aminopyridine)

Background: Impaired walking capacity is a frequent confinement in Multiple Sclerosis (MS). Patients are affected by limitations in coordination, walking speed and the distance they may cover. Also abnormal dynamic walking patterns have been reported, involving continuous deceleration over time. Fampridine (4-aminopyridine), a potassium channel blocker, may improve walking in MS. The objective of the current study was to comprehensively examine dynamic walking characteristics and improved walking capacity in MS patients treated with fampridine. Methods: A sample of N = 35 MS patients (EDSS median: 4) underwent an electronic walking examination prior to (Time 1), and during treatment with fampridine (Time 2). Patients walked back and forth a distance of 25 ft for a maximum period of 6 min (6-minute 25-foot-walk). Besides the total distance covered, average speed on the 25-foot distance and on turns was determined separately for each test minute, at Time 1 and Time 2. Results: Prior to fampridine administration, 27/35 patients (77 %) were able to complete the entire 6 min of walking, while following the administration, 34/35 patients (97 %) managed to walk for 6 min. In this context, walking distance considerably increased and treatment was associated with faster walking and turning across all six test minutes (range of effect sizes: partial eta squared = .34-.72). Importantly, previously reported deceleration across test minutes was consistently observable at Time 1 and Time 2. Discussion: Fampridine administration is associated with improved walking speed and endurance. Regardless of a treatment effect of fampridine, the previously identified, abnormal dynamic walking feature, i.e. the linear decline in walking speed, may represent a robust feature. Conclusions: The dynamic walking feature might hence be considered as a candidate for a new outcome measure in clinical studies involving interventions other than symptomatic treatment, such as immune-modulating medication. Trial registration: DRKS00009228 (German Clinical Trials Register). Date obtained: 25.08.2015

Disentangling astroglial physiology with a realistic cell model in silico

Electrically non-excitable astroglia take up neurotransmitters, buffer extracellular K+ and generate Ca2+ signals that release molecular regulators of neural circuitry. The underlying machinery remains enigmatic, mainly because the sponge-like astrocyte morphology has been difficult to access experimentally or explore theoretically. Here, we systematically incorporate multi-scale, tri-dimensional astroglial architecture into a realistic multi-compartmental cell model, which we constrain by empirical tests and integrate into the NEURON computational biophysical environment. This approach is implemented as a flexible astrocyte-model builder ASTRO. As a proof-of-concept, we explore an in silico astrocyte to evaluate basic cell physiology features inaccessible experimentally. Our simulations suggest that currents generated by glutamate transporters or K+ channels have negligible distant effects on membrane voltage and that individual astrocytes can successfully handle extracellular K+ hotspots. We show how intracellular Ca2+ buffers affect Ca2+ waves and why the classical Ca2+ sparks-and-puffs mechanism is theoretically compatible with common readouts of astroglial Ca2+ imaging

Kinetic inductance detectors (KIDs) for the SAFARI instrument on SPICA

Kinetic Inductance Detectors (KIDs) with frequency domain read-out are intrinsically very suitable to use as building blocks for very large arrays. KIDs therefore are an attractive detector option for the SAFARI instrument on SPICA, Millimetron and also for large scale ground based imaging arrays. To study the properties of large KID arrays we have fabricated 400 pixels array made from 40 nm thick Al films on high resistivity Si substrates. The array is tested in a dry dilution refrigerator at 100 mK. We present the device design and experimental results. We also present a new design of the array with lithographic air bridges over the coplanar waveguide feedline. The air bridges are designed to suppress the slot line mode in the feedline and that will improve the pixel to pixel reproducibility of large arrays

The Impact of Global Warming and Anoxia on Marine Benthic Community Dynamics: an Example from the Toarcian (Early Jurassic)

The Pliensbachian-Toarcian (Early Jurassic) fossil record is an archive of natural data of benthic community response to global warming and marine long-term hypoxia and anoxia. In the early Toarcian mean temperatures increased by the same order of magnitude as that predicted for the near future; laminated, organic-rich, black shales were deposited in many shallow water epicontinental basins; and a biotic crisis occurred in the marine realm, with the extinction of approximately 5% of families and 26% of genera. High-resolution quantitative abundance data of benthic invertebrates were collected from the Cleveland Basin (North Yorkshire, UK), and analysed with multivariate statistical methods to detect how the fauna responded to environmental changes during the early Toarcian. Twelve biofacies were identified. Their changes through time closely resemble the pattern of faunal degradation and recovery observed in modern habitats affected by anoxia. All four successional stages of community structure recorded in modern studies are recognised in the fossil data (i.e. Stage III: climax; II: transitional; I: pioneer; 0: highly disturbed). Two main faunal turnover events occurred: (i) at the onset of anoxia, with the extinction of most benthic species and the survival of a few adapted to thrive in low-oxygen conditions (Stages I to 0) and (ii) in the recovery, when newly evolved species colonized the re-oxygenated soft sediments and the path of recovery did not retrace of pattern of ecological degradation (Stages I to II). The ordination of samples coupled with sedimentological and palaeotemperature proxy data indicate that the onset of anoxia and the extinction horizon coincide with both a rise in temperature and sea level. Our study of how faunal associations co-vary with long and short term sea level and temperature changes has implications for predicting the long-term effects of “dead zones” in modern oceans

Hadley circulation and precipitation changes control black shale deposition in the Late Jurassic Boreal Seaway

New climate simulations using the HadCM3L model with a paleogeography of the Late Jurassic [155.5 Ma], and proxy-data corroborate that warm and wet tropical-like conditions reached as far north as the UK sector of the Jurassic Boreal Seaway [~35oN]. This is associated with a northern hemisphere Jurassic Hadley cell and an intensified subtropical jet which both extend significantly polewards than in the modern (July-September). Deposition of the Kimmeridge Clay Formation [KCF] occurred in the shallow, storm-dominated, epeiric Boreal Seaway. High resolution paleo-environmental proxy data from the Kimmeridge Clay Formation [KCF; ~155–150 Ma], UK are used to test for the role of tropical atmospheric circulation on meter-scale heterogeneities in black shale deposition. Proxy and model data show that the most organic-rich section [eudoxus to mid-hudlestoni zones] is characterised by a positive δ13Corg excursion and up to 37 wt% total organic carbon [%TOC]. Orbital-modulation of organic carbon burial primarily in the long eccentricity power band combined with a clear positive correlation between %TOC carbonate-free and the kaolinite/illite ratio supports peak organic carbon burial under the influence of very humid climate conditions, similar to the modern tropics. This re-interpretation of large-scale climate relationships, supported by independent modelling and geological data, has profound implications for atmospheric circulation patterns and processes affecting marine productivity and organic carbon burial further north along the Boreal Seaway, including the Arctic

Microphase separation of highly amphiphilic, low N polymers by photoinduced copper-mediated polymerization, achieving sub-2 nm domains at half-pitch

The lower limit of domain size resolution using microphase separation of short poly(acrylic acid) homopolymers equipped with a short fluorinated tail, posing as an antagonist 'A block' in pseudo AB block copolymers has been investigated. An alkyl halide initiator with a fluorocarbon chain was utilized as a first 'A block' in the synthesis of low molecular weight polymers (1400-4300 g mol -1) using photoinduced Cu(ii)-mediated polymerization allowing for very narrow dispersity. Poly(tert-butyl acrylate) was synthesized and subsequently deprotected to give very low degrees of polymerization (N), amphiphilic polymers with low dispersity (D = 1.06-1.13). By exploiting the high driving force for demixing and the well-defined 'block' sizes, we are able to control the nanostructure in terms of domain size (down to 3.4 nm full-pitch) and morphology. This work demonstrates the simple and highly controlled synthesis of polymers to push the boundaries of the smallest achievable domain sizes obtained from polymer self-assembly

Oceanic response to Pliensbachian and Toarcian magmatic events: Implications from an organic-rich basinal succession in the NW Tethys

The Bächental bituminous marls (Bächentaler Bitumenmergel) belonging to the Sachrang Member of the Lower Jurassic Middle Allgäu Formation were investigated using a multidisciplinary approach to determine environmental controls on the formation of organic-rich deposits in a semi-restricted basin of the NW Tethys during the Early Jurassic. The marls are subdivided into three units on the basis of mineralogical composition, source-rock parameters, redox conditions, salinity variations, and diagenetic processes. Redox proxies (e.g., pristane/phytane ratio; aryl isoprenoids; bioturbation; ternary plot of iron, total organic carbon, and sulphur) indicate varying suboxic to euxinic conditions during deposition of the Bächental section. Redox variations were mainly controlled by sea-level fluctuations with the tectonically complex bathymetry of the Bächental basin determining watermass exchange with the Tethys Ocean. Accordingly, strongest anoxia and highest total organic carbon content (up to 13%) occur in the middle part of the profile (upper tenuicostatum and lower falciferum zones), coincident with an increase in surface-water productivity during a period of relative sea-level lowstand that induced salinity stratification in a stagnant basin setting. This level corresponds to the time interval of the lower Toarcian oceanic anoxic event (T-OAE). However, the absence of the widely observed lower Toarcian negative carbon isotope excursion in the study section questions its unrestricted use as a global chemostratigraphic marker. Stratigraphic correlation of the thermally immature Bächental bituminous marls with the Posidonia Shale of SW Germany on the basis of C27/C29 sterane ratio profiles and ammonite data suggests that deposition of organic matter-rich sediments in isolated basins in the Alpine realm commenced earlier (late Pliensbachian margaritatus Zone) than in regionally proximal epicontinental seas (early Toarcian tenuicostatum Zone). The late Pliensbachian onset of reducing conditions in the Bächental basin coincided with an influx of volcaniclastic detritus that was possibly connected to complex rifting processes of the Alpine Tethys and with a globally observed eruption-induced extinction event. The level of maximum organic matter accumulation in the Bächental basin corresponds to the main eruptive phase of the Karoo-Ferrar large igneous province (LIP), confirming its massive impact on global climate and oceanic conditions during the Early Jurassic. The Bächental marl succession is thus a record of the complex interaction of global (i.e., LIP) and local (e.g., redox and salinity variations, basin morphology) factors that caused reducing conditions and organic matter enrichment in the Bächental basin. These developments resulted in highly inhomogeneous environmental conditions in semi-restricted basins of the NW Tethyan domain during late Pliensbachian and early Toarcian time