D-4F, an apoA-1 mimetic, decreases airway hyperresponsiveness, inflammation, and oxidative stress in a murine model of asthma

Asthma is characterized by oxidative stress and inflammation of the airways. Although proinflammatory lipids are involved in asthma, therapies targeting them remain lacking. Ac-DWFKAFYDKVAEKFKEAFNH2 (4F) is an apolipoprotein (apo)A-I mimetic that has been shown to preferentially bind oxidized lipids and improve HDL function. The objective of the present study was to determine the effects of 4F on oxidative stress, inflammation, and airway resistance in an established murine model of asthma. We show here that ovalbumin (OVA) -sensitization increased airway hyperresponsiveness, eosinophil recruitment, and collagen deposition in lungs of C57BL/6J mice by a mechanism that could be reduced by 4F. OVA sensitization induced marked increases in transforming growth factor (TGF)β-1, fibroblast specific protein (FSP)-1, anti-T15 autoantibody staining, and modest increases in 4-hydroxynonenal (4-HNE) Michael\u27s adducts in lungs of OVA-sensitized mice. 4F decreased TGFβ-1, FSP-1, anti-T15 autoantibody, and 4-HNE adducts in the lungs of the OVA-sensitized mice. Eosinophil peroxidase (EPO) activity in bronchial alveolar lavage fluid (BALF), peripheral eosinophil counts, total IgE, and proinflammatory HDL (p-HDL) were all increased in OVA-sensitized mice. 4F decreased BALF EPO activity, eosinophil counts, total IgE, and p-HDL in these mice. These data indicate that 4F reduces pulmonary inflammation and airway resistance in an experimental murine model of asthma by decreasing oxidative stress

Energetics and atomic mechanisms of dislocation nucleation in strained epitaxial layers

We study numerically the energetics and atomic mechanisms of misfit dislocation nucleation and stress relaxation in a two-dimensional atomistic model of strained epitaxial layers on a substrate with lattice misfit. Relaxation processes from coherent to incoherent states for different transition paths are studied using interatomic potentials of Lennard-Jones type and a systematic saddle point and transition path search method. The method is based on a combination of repulsive potential minimization and the Nudged Elastic Band method. For a final state with a single misfit dislocation, the minimum energy path and the corresponding activation barrier are obtained for different misfits and interatomic potentials. We find that the energy barrier decreases strongly with misfit. In contrast to continuous elastic theory, a strong tensile-compressive asymmetry is observed. This asymmetry can be understood as manifestation of asymmetry between repulsive and attractive branches of pair potential and it is found to depend sensitively on the form of the potential.Comment: 11 pages, 9 figures, to appear in Phys. Rev.

Assessment of the reliability of the motor unit size index (MUSIX) in single subject “round-robin” and multi-centre settings

Objective The motor unit size index (MUSIX) is incorporated into the motor unit number index (MUNIX). Our objective was to assess the intra-/inter-rater reliability of MUSIX in healthy volunteers across single subject “round robin” and multi-centre settings. Methods Data were obtained from i). a round-robin assessment in which 12 raters (6 with prior experience and 6 without) assessed six muscles (abductor pollicis brevis, abductor digiti minimi, biceps brachii, tibialis anterior, extensor digitorum brevis and abductor hallucis) and ii). a multi-centre study with 6 centres studying the same muscles in 66 healthy volunteers. Intra/inter-rater data were provided by 5 centres, 1 centre provided only intra-rater data. Intra/inter-rater variability was assessed using the coefficient of variation (COV), Bland-Altman plots, bias and 95% limits of agreement. Results In the round-robin assessment intra-rater COVs for MUSIX ranged from 7.8% to 28.4%. Inter-rater variability was between 7.8% and 16.2%. Prior experience did not impact on MUSIX values. In the multi-centre study MUSIX was more consistent than the MUNIX. Abductor hallucis was the least reliable muscle. Conclusions The MUSIX is a reliable neurophysiological biomarker of reinnervation. Significance MUSIX could provide insights into the pathophysiology of a range of neuromuscular disorders, providing a quantitative biomarker of reinnervation

Head-down tilt bed rest with or without artificial gravity is not associated with motor unit remodeling

© 2020, The Author(s). Purpose: The objective of this study was to assess whether artificial gravity attenuates any long-duration head-down 60 bed rest (HDBR)-induced alterations in motor unit (MU) properties. Methods: Twenty-four healthy participants (16 men; 8 women; 26–54 years) underwent 60-day HDBR with (n = 16) or without (n = 8) 30 min artificial gravity daily induced by whole-body centrifugation. Compound muscle action potential (CMAP), MU number (MUNIX) and MU size (MUSIX) were estimated using the method of Motor Unit Number Index in the Abductor digiti minimi and tibialis anterior muscles 5 days before (BDC-5), and during day 4 (HDT4) and 59 (HDT59) of HDBR. Results: The CMAP, MUNIX, and MUSIX at baseline did not change significantly in either muscle, irrespective of the intervention (p > 0.05). Across groups, there were no significant differences in any variable during HDBR, compared to BDC-5. Conclusion: Sixty days of HDBR with or without artificial gravity does not induce alterations in motor unit number and size in the ADM or TA muscles in healthy individuals

Asymmetric recurrent laryngeal nerve conduction velocities and dorsal cricoarytenoid muscle electromyographic characteristics in clinically normal horses

The dorsal cricoarytenoid (DCA) muscles, are a fundamental component of the athletic horse’s respiratory system: as the sole abductors of the airways, they maintain the size of the rima glottis which is essential for enabling maximal air intake during intense exercise. Dysfunction of the DCA muscle leads to arytenoid collapse during exercise, resulting in poor performance. An electrodiagnostic study including electromyography of the dorsal cricoarytenoid muscles and conduction velocity testing of the innervating recurrent laryngeal nerves (RLn) was conducted in horses with normal laryngeal function. We detected reduced nerve conduction velocity of the left RLn, compared to the right, and pathologic spontaneous activity (PSA) of myoelectrical activity within the left DCA muscle in half of this horse population and the horses with the slowest nerve conduction velocities. The findings in this group of horses are consistent with left sided demyelination and axonal loss, consistent with Recurrent Laryngeal Neuropathy (RLN), a highly prevalent degenerative disorder of the RLn in horses that predominantly affects the left side. The detection of electromyographic changes compatible with RLN in clinically unaffected horses is consistent with previous studies that identified “subclinical” subjects, presenting normal laryngeal function despite neuropathologic changes within nerve and muscle confirmed histologically

Investigating the metabolic capabilities of Mycobacterium tuberculosis H37Rv using the in silico strain iNJ661 and proposing alternative drug targets

<p>Abstract</p> <p>Background:</p> <p><it>Mycobacterium tuberculosis </it>continues to be a major pathogen in the third world, killing almost 2 million people a year by the most recent estimates. Even in industrialized countries, the emergence of multi-drug resistant (MDR) strains of tuberculosis hails the need to develop additional medications for treatment. Many of the drugs used for treatment of tuberculosis target metabolic enzymes. Genome-scale models can be used for analysis, discovery, and as hypothesis generating tools, which will hopefully assist the rational drug development process. These models need to be able to assimilate data from large datasets and analyze them.</p> <p>Results:</p> <p>We completed a bottom up reconstruction of the metabolic network of <it>Mycobacterium tuberculosis </it>H37Rv. This functional <it>in silico </it>bacterium, <it>iNJ</it>661, contains 661 genes and 939 reactions and can produce many of the complex compounds characteristic to tuberculosis, such as mycolic acids and mycocerosates. We grew this bacterium <it>in silico </it>on various media, analyzed the model in the context of multiple high-throughput data sets, and finally we analyzed the network in an 'unbiased' manner by calculating the Hard Coupled Reaction (HCR) sets, groups of reactions that are forced to operate in unison due to mass conservation and connectivity constraints.</p> <p>Conclusion:</p> <p>Although we observed growth rates comparable to experimental observations (doubling times ranging from about 12 to 24 hours) in different media, comparisons of gene essentiality with experimental data were less encouraging (generally about 55%). The reasons for the often conflicting results were multi-fold, including gene expression variability under different conditions and lack of complete biological knowledge. Some of the inconsistencies between <it>in vitro </it>and <it>in silico </it>or <it>in vivo </it>and <it>in silico </it>results highlight specific loci that are worth further experimental investigations. Finally, by considering the HCR sets in the context of known drug targets for tuberculosis treatment we proposed new alternative, but equivalent drug targets.</p

Motor unit potential morphology differences in individuals with non-specific arm pain and lateral epicondylitis

<p>Abstract</p> <p>Background</p> <p>The pathophysiology of non-specific arm pain (NSAP) is unclear and the diagnosis is made by excluding other specific upper limb pathologies, such as lateral epicondylitis or cervical radiculopathy. The purpose of this study was to determine: (i) if the quantitative parameters related to motor unit potential morphology and/or motor unit firing patterns derived from electromyographic (EMG) signals detected from an affected muscle of patients with NSAP are different from those detected in the same muscle of individuals with lateral epicondylitis (LE) and/or control subjects and (ii) if the quantitative EMG parameters suggest that the underlying pathophysiology in NSAP is either myopathic or neuropathic in nature.</p> <p>Methods</p> <p>Sixteen subjects with NSAP, 11 subjects with LE, eight subjects deemed to be at-risk for developing a repetitive strain injury, and 37 control subjects participated. A quantitative electromyography evaluation was completed using decomposition-based quantitative electromyography (DQEMG). Needle- and surface-detected EMG signals were collected during low-level isometric contractions of the extensor carpi radialis brevis (ECRB) muscle. DQEMG was used to extract needle-detected motor unit potential trains (MUPTs), and needle-detected motor unit potential (MUP) and surface detected motor unit potential (SMUP) morphology and motor unit (MU) firing rates were compared among the four groups using one-way analysis of variance (ANOVA). Post hoc analyses were performed using Tukey's pairwise comparisons.</p> <p>Results</p> <p>Significant group differences were found for all MUP variables and for MU firing rate (<it>p</it> < 0.006). The post-hoc analyses revealed that patients with NSAP had smaller MUP amplitude and SMUP amplitude and area compared to the control and LE groups (<it>p </it>< 0.006). MUP duration and AAR values were significantly larger in the NSAP, LE and at-risk groups compared to the control group (<it>p </it>< 0.006); while MUP amplitude, duration and AAR values were smaller in the NSAP compared to the LE group. SMUP duration was significantly shorter in the NSAP group compared to the control group (<it>p </it>< 0.006). NSAP, LE and at-risk subjects had lower mean MU firing rates than the control subjects (<it>p </it>< 0.006).</p> <p>Conclusion</p> <p>The size-related parameters suggest that the NSAP group had significantly smaller MUPs and SMUPs than the control and LE subjects. Smaller MUPs and SMUPs may be indicative of muscle fiber atrophy and/or loss. A prospective study is needed to confirm any causal relationship between smaller MUPs and SMUPs and NSAP as found in this work.</p

Follicular fluid content and oocyte quality: from single biochemical markers to metabolomics

The assessment of oocyte quality in human in vitro fertilization (IVF) is getting increasing attention from embryologists. Oocyte selection and the identification of the best oocytes, in fact, would help to limit embryo overproduction and to improve the results of oocyte cryostorage programs. Follicular fluid (FF) is easily available during oocyte pick-up and theorically represents an optimal source on non-invasive biochemical predictors of oocyte quality. Unfortunately, however, the studies aiming to find a good molecular predictor of oocyte quality in FF were not able to identify substances that could be used as reliable markers of oocyte competence to fertilization, embryo development and pregnancy. In the last years, a well definite trend toward passing from the research of single molecular markers to more complex techniques that study all metabolites of FF has been observed. The metabolomic approach is a powerful tool to study biochemical predictors of oocyte quality in FF, but its application in this area is still at the beginning. This review provides an overview of the current knowledge about the biochemical predictors of oocyte quality in FF, describing both the results coming from studies on single biochemical markers and those deriving from the most recent studies of metabolomic