Association between dendritic lamellar bodies and complex spike synchrony in the olivocerebellar system

Dendritic lamellar bodies have been reported to be associated with dendrodendritic gap junctions. In the present study we investigated this association at both the morphological and electrophysiological level in the olivocerebellar system. Because cerebellar GABAergic terminals are apposed to olivary dendrites coupled by gap junctions, and because lesions of cerebellar nuclei influence the coupling between neurons in the inferior olive, we postulated that if lamellar bodies and gap junctions are related, then the densities of both structures will change together when the cerebellar input is removed. Lesions of the cerebellar nuclei in rats and rabbits resulted in a reduction of the density of lamellar bodies, the number of lamellae per lamellar body, and the density of gap junctions in the inferior olive, whereas the number of olivary neurons was not significantly reduced. The association between lamellar bodies and electrotonic coupling was evaluated electrophysiologically in alert rabbits by comparing the occurrence of complex spike synchrony in different Purkinje cell zones of the flocculus that receive their climbing fibers from olivary subnuclei with different densities of lamellar bodies. The complex spike synchrony of Purkinje cell pairs, that receive their climbing fibers from an olivary subnucleus with a high density of lamellar bodies, was significantly higher than that of Purkinje cells, that receive their climbing fibers from a subnucleus with a low density of lamellar bodies. To investigate whether the complex spike synchrony is related to a possible synchrony between simple spikes, we recorded simultaneously the complex spike and simple spike responses of Purkinje cell pairs during natural visual stimulation. Synchronous simple spike responses did occur, and this synchrony tended to increase as the synchrony between the complex spikes increased. This relation raises the possibility that synchronously activated climbing fibers evoke their effects in part via the simple spike response of Purkinje cells. The present results indicate that dendritic lamellar bodies and dendrodendritic gap junctions can be downregulated concomitantly, and that the density of lamellar bodies in different olivary subdivisions is correlated with the degree of synchrony of their climbing fiber activity. Therefore these data support the hypothesis that dendritic lamellar bodies can be associated with dendrodendritic gap junctions. Considering that the density of dedritic lamellar bodies in the inferior olive is higher than in any other area of the brain, this conclusion implies that electrotonic coupling is important for the function of the olivocerebellar system

Zonal organization of the climbing fiber projection to the flocculus and nodulus of the rabbit: A combined axonal tracing and acetylcholinesterase histochemical study

The localization and termination of olivocerebellar fibers in the flocculus and nodulus of the rabbit were studied with anterograde axonal transport methods [wheatgerm agglutinin-horseradish peroxidase (WGA-HRP) and tritiated leucine] and correlated with the compartments in the white matter of these lobules delineated with acetylcholinesterase histochemistry (Tan et al. J. Comp. Neurol., 1995, this issue). Olivocerebellar fibers originating from the caudal dorsal cap travel through floccular compartments FC2 and FC4 to terminate as climbing fibers in floccular zones FZII and FZIV. Fibers from the rostral dorsal cap and the ventrolateral outgrowth traverse compartments FC1 and FC3, which are interleaved with compartments FC2 and FC4, and terminate in zones FZI and FZIII. Fibers from the rostral pole of the medial accessory olive traverse the C2 compartment and terminate in the C2 zone. FZI-II

Design and characterization of hybrid III–V concentrator photovoltaic–thermoelectric receivers under primary and secondary optical elements

Lattice-matched monolithic triple-junction Concentrator Photovoltaic (CPV) cells (InGa(0.495)P/GaIn(0.012)As/Ge) were electrically and thermally interfaced to two Thermoelectric (TE) Peltier module designs. An electrical and thermal model of the hybrid receivers was modelled in COMSOL Multiphysics software v5.3 to improve CPV cell cooling whilst increasing photon energy conversion efficiency. The receivers were measured for current-voltage characteristics with the CPV cell only (with sylguard encapsulant), under single secondary optical element (SOE) at x2.5 optical concentration, and under Fresnel lens primary optical element (POE) concentration between x313 and x480. Measurements were taken in solar simulators at Cardiff and Jaén Universities, and on-sun with dual-axis tracking at Jaén University. The hybrid receivers were electrically, thermally and theoretically investigated. The electrical performance data for the cells under variable irradiance and cell temperature conditions were measured using the integrated thermoelectric module as both a temperature sensor and as a solid-state heat pump. The performance of six SOE-CPV-TE hybrid devices were evaluated within two 3-receiver strings under primary optical concentration with measured acceptance angles of 1.00o and 0.89o, similar to commercially sourced CPV modules. A six-parameter one-diode equivalent electrical model was developed for the multi-junction CPV cells with SOE and POE. This was applied to extract six model parameters with the experimental I-V curves of type A receiver at 1, 3 and 500 concentration ratios. Standard test conditions (1000W/m2, 25oC and AM1.5G spectrum) were assumed based on trust-region-reflective least squares algorithm in MATLAB. The model fitted the experimental I-V curves satisfactorily with a mean error of 4.44%, and the optical intensity gain coefficient of SOE and POE is as high as 0.91, in comparison with 0.50-0.86 for crossed compound parabolic concentrators (CCPC). The determined values of diode reverse saturation current, combined series resistance and shunt resistance were similar to those of monocrystalline PV cell/modules in our previous publications. The model may be applicable to performance prediction of multi-junction CPV cells in the future

Visuo-Vestibular Information Processing by Unipolar Brush Cells in the Rabbit Flocculus

The unipolar brush cell (UBC) is a glutamatergic granular layer interneuron that is predominantly located in the vestibulocerebellum and parts of the vermis. In rat and rabbit, we previously found using juxtacellular labeling combined with spontaneous activity recording that cells with highly regular spontaneous activity belong to the UBC category. Making use of this signature, we recorded from floccular UBCs in both anesthetized and awake rabbits while delivering visuo-vestibular stimulation by using sigmoidal rotation of the whole animal. In the anesthetized rabbit, the activity of the presumed UBC units displayed a wide variety of modulation profiles that could be related to aspects of head velocity or acceleration. These modulation profiles could also be found in the awake rabbit where, in addition, they could also carry an eye position signal. Furthermore, units in the awake rabbit could demonstrate rather long response latencies of up to 0.5 s. We suggest that the UBCs recorded in this study mostly belong to the type I UBC category (calretinin-positive) and that they can play diverse roles in floccular visuo-vestibular information processing, such as transformation of velocity-related signals to acceleration-related signals

Tralokinumab provides clinically meaningful responses at week 16 in adults with moderate-to-severe atopic dermatitis who do not achieve IGA 0/1

Background and Objective: Investigator’s Global Assessment of clear/almost clear skin (IGA 0/1) is a difficult endpoint to achieve after short-term treatment of chronic moderate-to-severe atopic dermatitis, and does not fully reflect clinically meaningful changes in other parameters. We assessed the impact of tralokinumab versus placebo on other clinically meaningful parameters in patients not achieving IGA 0/1 at week 16 using pooled data from two monotherapy phase III trials, ECZTRA 1 and 2. Methods: This post hoc analysis included patients (n = 1328) from ECZTRA 1 and 2 who did not achieve the co-primary endpoint, IGA 0/1 at week 16 without rescue medication. Endpoints evaluating atopic dermatitis extent and severity included proportions of patients achieving IGA 0/1, 50%, 75%, and 90% improvement in Eczema Area and Severity Index (EASI-50/75/90); endpoints evaluating patient-reported outcomes included a ≥ 3-point improvement in worst daily pruritus Numerical Rating Scale (NRS), a ≥ 3-point improvement in eczema-related sleep interference (sleep) NRS, a ≥ 4-point improvement in Dermatology Life Quality Index (DLQI), and DLQI ≤ 5. Specifically, clinically meaningful responses were defined as EASI-50, a ≥ 3-point improvement in itch NRS, or a ≥ 4-point improvement in DLQI at week 16. Results: Among ECZTRA 1 and 2 patients who did not achieve IGA 0/1 at week 16 without rescue medication, a significantly greater proportion of patients receiving tralokinumab versus placebo achieved EASI-50 (33.0% vs 13.0%), a ≥ 3-point improvement in itch NRS (22.6% vs 9.4%), or a ≥ 4-point improvement in DLQI (41.2% vs 24.5%) at week 16. In addition, compared with placebo, a numerically greater proportion of tralokinumab-treated patients achieved all three measures of clinically meaningful response (30% vs 18%) or a clinically meaningful change in at least one outcome (48.8% vs 28.5%). Significantly greater proportions of patients receiving tralokinumab versus placebo achieved additional clinician-reported and patient-reported outcomes, such as EASI-75 (13.5% vs 4.1%), EASI-90 (3.5% vs 1.1%), DLQI ≤ 5 (22.5% vs 12.5%), and a ≥ 3-point improvement in sleep NRS (24.5% vs 11.5%). Conclusions: Tralokinumab provided clinically meaningful responses in patients with moderate-to-severe atopic dermatitis who did not achieve IGA 0/1 at week 16 and/or used rescue medication. Using multiple validated outcome measures of both efficacy and quality of life, alongside IGA scores, can better characterize tralokinumab treatment responses in patients with moderate-to-severe atopic dermatitis. [Video abstract available] Clinical Trial Registration: NCT03131648 (ECZTRA 1); study start date: 30 May, 2017; primary completion date: 7 August, 2018; study completion date: 10 October, 2019. NCT03160885 (ECZTRA 2); study start date: 12 June, 2017; primary completion date: 4 September, 2019; study completion date: 14 August, 2019. [MediaObject not available: see fulltext.]

Infections in Dupilumab Clinical Trials in Atopic Dermatitis : A Comprehensive Pooled Analysis

Background: Patients with moderate-to-severe atopic dermatitis (AD) have increased infection risk, including skin infections and systemic infections. Immunomodulators (e.g., anti-tumor necrosis factors, anti-interleukin [anti-IL]-23, anti-IL-17, Janus kinase inhibitors) increase risk of infections. Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma. Objective: The aim was to determine the impact of dupilumab on infection rates in patients with moderate-to-severe AD. Methods: This analysis pooled data from seven randomized, placebo-controlled dupilumab trials in adults with moderate-to-severe AD. Exposure-adjusted analyses assessed infection rates. Results: Of 2932 patients, 1091 received placebo, 1095 dupilumab 300 mg weekly, and 746 dupilumab 300 mg every 2 weeks. Treatment groups had similar infection rates overall per 100 patient-years (placebo, 155; dupilumab weekly, 150; dupilumab every 2 weeks, 156; dupilumab combined, 152), and similar non-skin infection rates. Serious/severe infections were reduced with dupilumab (risk ratio 0.43; p < 0.05), as were bacterial and other non-herpetic skin infections (risk ratio 0.44; p < 0.001). Although herpesviral infection rates overall were slightly higher with dupilumab than placebo, clinically important herpesviral infections (eczema herpeticum, herpes zoster) were less common with dupilumab (risk ratio 0.31; p < 0.01). Systemic anti-infective medication use was lower with dupilumab. Conclusions: Dupilumab is associated with reduced risk of serious/severe infections and non-herpetic skin infections and does not increase overall infection rates versus placebo in patients with moderate-to-severe AD. ClinicalTrials.gov Identifiers: NCT01548404, NCT02210780, NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649

Around the tangent cone theorem

A cornerstone of the theory of cohomology jump loci is the Tangent Cone theorem, which relates the behavior around the origin of the characteristic and resonance varieties of a space. We revisit this theorem, in both the algebraic setting provided by cdga models, and in the topological setting provided by fundamental groups and cohomology rings. The general theory is illustrated with several classes of examples from geometry and topology: smooth quasi-projective varieties, complex hyperplane arrangements and their Milnor fibers, configuration spaces, and elliptic arrangements.Comment: 39 pages; to appear in the proceedings of the Configurations Spaces Conference (Cortona 2014), Springer INdAM serie

Effects of Cooking in Solutions of Varying pH on the Dietary Fiber Components of Vegetables

To study the effect of pH on dietary fiber components of vegetables, beans, cauliflower, potatoes, peas and corn were cooked in buffers of pH 2, 4, 6, and 10. Water-soluble pectin and hemicellulose, water-insoluble pectin and hemicellulose, cellulose and lignin were quantitated in raw, cooked vegetables and cooking medium. Tenderness and pH of raw and cooked vegetables were determined. Texture varied with cooking medium. Cooked vegetables were most firm at pH 4 and softest at pH 10. Dietary components found in cooking medium reflected these textural changes. Vegetables which showed greater pH effects exhibited greater changes in fiber components.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73821/1/j.1365-2621.1984.tb13237.x.pd

Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis.

BACKGROUND Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis. METHODS In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator’s Global Assessment and a reduction of 2 points or more in that score from baseline at week 16. RESULTS We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo (P<0.001 for both comparisons with placebo). The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo (P<0.001 for both comparisons). In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo (P<0.001 for all comparisons). Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups. CONCLUSIONS In two phase 3 trials of identical design involving patients with atopic dermatitis, dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo. Trials of longer duration are needed to assess the long-term effectiveness and safety of dupilumab. (Funded by Sanofi and Regeneron Pharmaceuticals; SOLO 1 ClinicalTrials.gov number, NCT02277743; SOLO 2 ClinicalTrials .gov number, NCT02277769.

Attentive Learning of Sequential Handwriting Movements: A Neural Network Model

Defense Advanced research Projects Agency and the Office of Naval Research (N00014-95-1-0409, N00014-92-J-1309); National Science Foundation (IRI-97-20333); National Institutes of Health (I-R29-DC02952-01)