Aberrant location of inhibitory synaptic marker proteins in the hippocampus of dystrophin-deficient mice

Duchenne muscular dystrophy (DMD) is a neuromuscular disease that arises from mutations in the dystrophin-encoding gene. Apart from muscle pathology, cognitive impairment, primarily of developmental origin, is also a significant component of the disorder. Convergent lines of evidence point to an important role for dystrophin in regulating the molecular machinery of central synapses. The clustering of neurotransmitter receptors at inhibitory synapses, thus impacting on synaptic transmission, is of particular significance. However, less is known about the role of dystrophin in influencing the precise expression patterns of proteins located within the pre- and postsynaptic elements of inhibitory synapses. To this end, we exploited molecular markers of inhibitory synapses, interneurons and dystrophin-deficient mouse models to explore the role of dystrophin in determining the stereotypical patterning of inhibitory connectivity within the cellular networks of the hippocampus CA1 region. In tissue from wild-type (WT) mice, immunoreactivity of neuroligin2 (NL2), an adhesion molecule expressed exclusively in postsynaptic elements of inhibitory synapses, and the vesicular GABA transporter (VGAT), a marker of GABAergic presynaptic elements, were predictably enriched in strata pyramidale and lacunosum moleculare. In acute contrast, NL2 and VGAT immunoreactivity was relatively evenly distributed across all CA1 layers in dystrophin-deficient mice. Similar changes were evident with the cannabinoid receptor 1, vesicular glutamate transporter 3, parvalbumin, somatostatin and the GABAA receptor alpha1 subunit. The data show that in the absence of dystrophin, there is a rearrangement of the molecular machinery, which underlies the precise spatio-temporal pattern of GABAergic synaptic transmission within the CA1 sub-field of the hippocampus

AC Stark-shift in CPT-based Cs miniature atomic clocks

We report on studies on the light-shift in caesium miniature atomic clocks based on coherent population trapping (CPT) using a micro-fabricated buffer-gas cell (MEMS cell). The CPT signal is observed on the Cs D1-line by coupling the two hyperfine ground-state Zeeman sublevels involved in the clock transition to a common excited state, using two coherent electromagnetic fields. These light fields are created with a distributed feedback laser and an electro-optical modulator. We study the light-shift phenomena at different cell temperatures and laser wavelengths around 894.6nm. By adjusting the cell temperature, conditions are identified where a miniature CPT atomic clock can be operated with simultaneously low temperature coefficient and suppressed light-shift. The impact of the light-shift on the clock frequency stability is evaluated. These results are relevant for improving the long-term frequency stability of CPT-based Cs vapour-cell clock

On designing observers for time-delay systems with nonlinear disturbances

This is the post print version of the article. The official published version can be obtained from the link below - Copyright 2002 Taylor & Francis LtdIn this paper, the observer design problem is studied for a class of time-delay nonlinear systems. The system under consideration is subject to delayed state and non-linear disturbances. The time-delay is allowed to be time-varying, and the non-linearities are assumed to satisfy global Lipschitz conditions. The problem addressed is the design of state observers such that, for the admissible time-delay as well as non-linear disturbances, the dynamics of the observation error is globally exponentially stable. An effective algebraic matrix inequality approach is developed to solve the non-linear observer design problem. Specifically, some conditions for the existence of the desired observers are derived, and an explicit expression of desired observers is given in terms of some free parameters. A simulation example is included to illustrate the practical applicability of the proposed theory.The work of Z. Wang was supported in part by the University of Kaiserslautern of Germany and the Alexander von Humboldt Foundation of Germany

Impact of P2RX7 ablation on the morphological, mechanical and tissue

Duchenne muscular dystrophy (DMD) is an inherited, lethal disorder characterised by progressive muscle degeneration and associated bone abnormalities. We have previously demonstrated that P2RX7 purinergic receptors contribute to the pathogenesis of DMD, and found that P2RX7 ablation alleviated the severity of the disease. In this work we have used a dystrophic mdx mouse crossed with the global P2RX7 receptor to generate a knockout mouse (mdx/P2X7−/−), and compared its morphometric, mechanical and tissue properties against those of mdx, as well as the wild type (WT) and the P2RX7 knockout (P2X7−/-). Micro-computed tomography (µCT), three-point bending testing, scanning electron microscopy (SEM) and nano-indentation were utilised in the study. The bones were analysed at approximately 4 weeks of age to examine the impact of P2RX7 ablation on the bone properties during the acute disease phase, before muscle wasting is fully developed. The results show that P2RX7 purinoceptor ablation has produced improvement or significant improvement in some of the morphological, the mechanical and the tissue properties of the dystrophic bones examined. Specifically, although the ablation produced smaller bones with significantly lower total cross-section area (Tt.Ar) and Second Moment of Area (SMA), significantly higher cortical bone area (Ct.Ar), cortical area fraction (Ct.Ar/Tt.Ar) and trabecular bone volume fraction (BV/TV) are found in the mdx/P2X7−/− mice than in any other types. Further, the mdx/P2X7−/− bones have relatively higher average flexural strength, work-to-fracture and significantly higher strain to failure compared with those of mdx, suggesting greater resistance to fracture. Indentation modulus, elasticity and creep are also significantly improved in the knockout cortical bones over those of mdx. These findings seem to suggest that specific pharmacological blockade of P2RX7 may improve dystrophic bones, with a potential for therapeutic application in the treatment of the disease

Response Types and Factors Associated with Response Types to Biologic Therapies in Patients with Moderate-to-Severe Plaque Psoriasis from Two Randomized Clinical Trials.

This study aimed to understand treatment response dynamics, including factors associated with favorable response, among patients with moderate-to-severe psoriasis who received guselkumab, adalimumab, or secukinumab. These post hoc analyses used data from the phase III clinical trials ECLIPSE and VOYAGE 1, which were conducted between September 2021 and November 2022. On the basis of absolute Psoriasis Area and Severity Index (aPASI) scores, patients were divided into short-term response types (SRT1-6, based on week 20-48 response) and long-term response types (LRT1-4, based on week 52-252 response). Response types (RTs) were based on aPASI cutoffs deemed clinically relevant by the investigators; SRT1/LRT1 were the most favorable response types. Baseline characteristics were compared across RTs, and logistic regression analyses established factors associated with SRT1/LRT1. Overall, 1045, 662, and 272 patients were included in the ECLIPSE short-term, VOYAGE 1 short-term, and VOYAGE 1 long-term analyses, respectively. Mean age, body mass index (BMI), baseline aPASI score, and body surface area were lower in SRT1 than SRT6. In VOYAGE 1, adalimumab treatment, high BMI, and current/former smoking status resulted in less favorable responses. In the VOYAGE 1 long-term analysis, patients in LRT4 had the highest baseline aPASI score, were older, and were more often obese compared with other LRT groups. Regression analyses showed that SRT1 (both treatments) in VOYAGE 1 and ECLIPSE, and LRT1 (guselkumab group) in the VOYAGE 1 long-term analysis, were associated with week 16 aPASI response. In VOYAGE 1, SRT1 was associated with psoriasis duration and smoking status. Early treatment response and baseline characteristics, including smoking, psoriasis duration, and obesity, may be associated with longer-term response to biologics. ECLIPSE: NCT03090100, VOYAGE 1: NCT02207231

A patient-reported pressure ulcer health-related quality of life instrument for use in prevention trials (PU-QOL-P): psychometric evaluation

Introduction: Pressure ulcer-specific patient-reported outcome (PRO) instruments should be used to inform patient care and provide a strong evidence base for interventions aimed at preventing pressure ulcers. The aim was to carry out a comprehensive evaluation of the psychometric properties of a PRO instrument designed to assess symptoms and functional outcomes in patients at high-risk of developing pressure ulcers, the PU-QOL-P instrument. Methods: We modified the original PU-QOL instrument to be suitable for patients at high risk of pressure ulcer development based on feedback from patients, specialist nurses and PRO methodologists. The modified PU-QOL-P instrument was administered to a sub-set of patients participating in the PRESSURE 2 trial. Patients completed PU-QOL-P and SF12 instruments at baseline, weeks 1 and 3, and 30 days post-treatment. We undertook psychometric evaluation of the modified PU-QOL-P to test scale targeting, scaling assumptions, reliability, validity and responsiveness. Results: The analysis sample consisted of 617 patients that completed both instruments at baseline. We found that the PU-QOL-P instrument, consisting of nine PU-specific outcomes: three symptom and six function scales, meets established criteria for reliability, construct validity, and responsiveness. Internal consistency reliability was high with all scale Cronbach alpha > 0.795 (range 0.795–0.970). The factor analysis mostly supported the six-function scale structure. Scaling assumptions were satisfied; all item-total correlations above 0.30. Convergent validity was confirmed by significant correlations between hypothesized scales as expected. PU-QOL-P scales were responsive to change: mean scale scores from baseline to 30 days post-treatment were statistically significant for all scales apart the daily activities scale (effect sizes ranged from moderate to high). As expected, worse symptoms and functioning was observed in patients who had a category 1 or 2 PU compared to patients who did not have a PU. Conclusions: The PU-QOL-P provides a standardised method for assessing pressure ulcer-specific symptoms and functional outcomes for quantifying the benefits of associated interventions from the patient’s perspective. It can be used in research with adults at risk of pressure ulcer development in all UK healthcare settings

Technology and performances of silicon oxynitride waveguides for optomechanical sensors fabricated by plasma-enhanced chemical vapour deposition

The technology and performances of a micromachined channel waveguides, based on PECVD deposition of silicon oxynitride (SiOxNy) thin films, is presented. The deposition parameters of the PECVD process are studied in connection with their optical, mechanical and chemical properties. Waveguide deign is optimized allowing single mode, low loss propagation and high efficiency of coupling with single mode optical fiber. The proposed technology is applied to fabricate the pigtailed Mach-Zehnder interferometers, where the coupling from optical fiber to waveguide is based on the etch of U-grooves, supporting fibers in the same substrate as the waveguide substrate

Store-operated calcium entry contributes to abnormal Ca²⁺ signalling in dystrophic mdx mouse myoblasts

Sarcolemma damage and activation of various calcium channels are implicated in altered Ca2+ homeostasis in muscle fibres of both Duchenne muscular dystrophy (DMD) sufferers and in the mdx mouse model of DMD. Previously we have demonstrated that also in mdx myoblasts extracellular nucleotides trigger elevated cytoplasmic Ca2+ concentrations due to alterations of both ionotropic and metabotropic purinergic receptors. Here we extend these findings to show that the mdx mutation is associated with enhanced store-operated calcium entry (SOCE). Substantially increased rate of SOCE in mdx myoblasts in comparison to that in control cells correlated with significantly elevated STIM1 protein levels. These results reveal that mutation in the dystrophin-encoding Dmd gene may significantly impact cellular calcium response to metabotropic stimulation involving depletion of the intracellular calcium stores followed by activation of the store-operated calcium entry, as early as in undifferentiated myoblasts. These data are in agreement with the increasing number of reports showing that the dystrophic pathology resulting from dystrophin mutations may be developmentally regulated. Moreover, our results showing that aberrant responses to extracellular stimuli may contribute to DMD pathogenesis suggest that treatments inhibiting such responses might alter progression of this lethal disease

Model development of the Aquistore CO2 storage project

AbstractThe Plains CO2 Reduction (PCOR) Partnership, through the Energy & Environmental Research Center, is collaborating with Petroleum Technology Research Centre in site characterization; risk assessment; public outreach; and monitoring, verification, and accounting activities at the Aquistore project. The PCOR Partnership constructed a static geological model to assess the potential volumetric storage capacity of the Aquistore site and provide the foundation for dynamic simulation for the dynamic CO2 storage capacity. Results of the predictive simulations will be used in the risk assessment process to define an overall monitoring plan and assure stakeholders that the injected CO2 will remain safely stored