Functionality of the Crosswise Model for Assessing Sensitive or Transgressive Behavior: A Systematic Review and Meta-Analysis

Tools for reliable assessment of socially sensitive or transgressive behavior warrant constant development. Among them, the Crosswise Model (CM) has gained considerable attention. We systematically reviewed and meta-analyzed empirical applications of CM and addressed a gap for quality assessment of indirect estimation models. Guided by the PRISMA protocol, we identified 45 empirical studies from electronic database and reference searches. Thirty of these were comparative validation studies (CVS) comparing CM and direct question (DQ) estimates. Six prevalence studies exclusively used CM. One was a qualitative study. Behavior investigated were substance use and misuse (k = 13), academic misconduct (k = 8), and corruption, tax evasion, and theft (k = 7) among others. Majority of studies (k = 39) applied the “more is better” hypothesis. Thirty-five studies relied on birthday distribution and 22 of these used P = 0.25 for the non-sensitive item. Overall, 11 studies were assessed as high-, 31 as moderate-, and two as low quality (excluding the qualitative study). The effect of non-compliance was assessed in eight studies. From mixed CVS results, the meta-analysis indicates that CM outperforms DQ on the “more is better” validation criterion, and increasingly so with higher behavior sensitivity. However, little difference was observed between DQ and CM estimates for items with DQ prevalence estimate around 50%. Based on empirical evidence available to date, our study provides support for the superiority of CM to DQ in assessing sensitive/transgressive behavior. Despite some limitations, CM is a valuable and promising tool for population level investigation.publishedVersio

Salbutamol modifies the neuromuscular junction in a mouse model of ColQ myasthenic syndrome.

The β-adrenergic agonists salbutamol and ephedrine have proven to be effective as therapies for human disorders of the neuromuscular junction, in particular many subsets of congenital myasthenic syndromes. However, the mechanisms underlying this clinical benefit are unknown and improved understanding of the effect of adrenergic signalling on the neuromuscular junction is essential to facilitate the development of more targeted therapies. Here, we investigated the effect of salbutamol treatment on the neuromuscular junction in the ColQ deficient mouse, a model of end-plate acetylcholinesterase deficiency. ColQ-/- mice received 7 weeks of daily salbutamol injection, and the effect on muscle strength and neuromuscular junction morphology was analysed. We show that salbutamol leads to a gradual improvement in muscle strength in ColQ-/- mice. In addition, the neuromuscular junctions of salbutamol treated mice showed significant improvements in several postsynaptic morphological defects, including increased synaptic area, acetylcholine receptor area and density, and extent of postjunctional folds. These changes occurred without alterations in skeletal muscle fibre size or type. These findings suggest that β-adrenergic agonists lead to functional benefit in the ColQ-/- mouse and to long-term structural changes at the neuromuscular junction. These effects are primarily at the postsynaptic membrane and may lead to enhanced neuromuscular transmission

Functionality of the Crosswise Model for Assessing Sensitive or Transgressive Behavior: A Systematic Review and Meta-Analysis

Tools for reliable assessment of socially sensitive or transgressive behavior warrant constant development. Among them, the Crosswise Model (CM) has gained considerable attention. We systematically reviewed and meta-analyzed empirical applications of CM and addressed a gap for quality assessment of indirect estimation models. Guided by the PRISMA protocol, we identified 45 empirical studies from electronic database and reference searches. Thirty of these were comparative validation studies (CVS) comparing CM and direct question (DQ) estimates. Six prevalence studies exclusively used CM. One was a qualitative study. Behavior investigated were substance use and misuse (k = 13), academic misconduct (k = 8), and corruption, tax evasion, and theft (k = 7) among others. Majority of studies (k = 39) applied the “more is better” hypothesis. Thirty-five studies relied on birthday distribution and 22 of these used P = 0.25 for the non-sensitive item. Overall, 11 studies were assessed as high-, 31 as moderate-, and two as low quality (excluding the qualitative study). The effect of non-compliance was assessed in eight studies. From mixed CVS results, the meta-analysis indicates that CM outperforms DQ on the “more is better” validation criterion, and increasingly so with higher behavior sensitivity. However, little difference was observed between DQ and CM estimates for items with DQ prevalence estimate around 50%. Based on empirical evidence available to date, our study provides support for the superiority of CM to DQ in assessing sensitive/transgressive behavior. Despite some limitations, CM is a valuable and promising tool for population level investigation

Rare disease research workflow using multilayer networks elucidates the molecular determinants of severity in Congenital Myasthenic Syndromes

\ua9 The Author(s) 2024.Exploring the molecular basis of disease severity in rare disease scenarios is a challenging task provided the limitations on data availability. Causative genes have been described for Congenital Myasthenic Syndromes (CMS), a group of diverse minority neuromuscular junction (NMJ) disorders; yet a molecular explanation for the phenotypic severity differences remains unclear. Here, we present a workflow to explore the functional relationships between CMS causal genes and altered genes from each patient, based on multilayer network community detection analysis of complementary biomedical information provided by relevant data sources, namely protein-protein interactions, pathways and metabolomics. Our results show that CMS severity can be ascribed to the personalized impairment of extracellular matrix components and postsynaptic modulators of acetylcholine receptor (AChR) clustering. This work showcases how coupling multilayer network analysis with personalized -omics information provides molecular explanations to the varying severity of rare diseases; paving the way for sorting out similar cases in other rare diseases

Collagen VI regulates motor circuit plasticity and motor performance by cannabinoid modulation

Collagen VI is a key component of muscle basement membranes, and genetic variants can cause monogenic muscular dystrophies. Conversely, human genetic studies recently implicated collagen VI in central nervous system function, with variants causing the movement disorder dystonia. To elucidate the neurophysiological role of collagen VI, we generated mice with a truncation of the dystonia-related collagen alpha 3 (VI) (COL6A3) C-terminal domain (CTD). These Col6a3(CTT) mice showed a recessive dystonia-like phenotype in both sexes. We found that COL6A3 interacts with the cannabinoid receptor 1 (CB1R) complex in a CTD-dependent manner. Col6a3(CTT) mice of both sexes have impaired homeostasis of excitatory input to the basal pontine nuclei (BPN), a motor control hub with dense COL6A3 expression, consistent with deficient endocannabinoid signaling. Aberrant synaptic input in the BPN was normalized by a CB1R agonist, and motor performance in Col6a3(CTT) mice of both sexes was improved by CB1R agonist treatment. Our findings identify a readily therapeutically addressable synaptic mechanism for motor control

Mitochondrial DNA deletions in muscle satellite cells: implications for therapies.

Progressive myopathy is a major clinical feature of patients with mitochondrial DNA (mtDNA) disease. There is limited treatment available for these patients although exercise and other approaches to activate muscle stem cells (satellite cells) have been proposed. The majority of mtDNA defects are heteroplasmic (a mixture of mutated and wild-type mtDNA present within the muscle) with high levels of mutated mtDNA and low levels of wild-type mtDNA associated with more severe disease. The culture of satellite cell-derived myoblasts often reveals no evidence of the original mtDNA mutation although it is not known if this is lost by selection or simply not present in these cells. We have explored if the mtDNA mutation is present in the satellite cells in one of the commonest genotypes associated with mitochondrial myopathies (patients with single, large-scale mtDNA deletions). Analysis of satellite cells from eight patients showed that the level of mtDNA mutation in the satellite cells is the same as in the mature muscle but is most often subsequently lost during culture. We show that there are two periods of selection against the mutated form, one early on possibly during satellite cell activation and the other during the rapid replication phase of myoblast culture. Our data suggest that the mutations are also lost during rapid replication in vivo, implying that strategies to activate satellite cells remain a viable treatment for mitochondrial myopathies in specific patient groups

Development of good modelling practice for physiologically based pharmacokinetic models for use in risk assessment : the first steps

International audienceThe increasing use of tissue dosimetry estimated using pharmacokinetic models in chemical risk assessments in various jurisdictions necessitates the development of internationally recognized good modelling practice (GMP). These practices would facilitate sharing of models and model evaluations and consistent applications in risk assessments. Clear descriptions of good practices for model development i.e., research and analysis activities, model characterization i.e., methods to describe how consistent the model is with biology and the strengths and limitations of available models and data, such as sensitivity analyses, model documentation, and model evaluation i.e., independent review that will assist risk assessors in their decisions of whether and how to use the models, and also model developers to understand expectations for various purposes e.g., research versus application in risk assessment. Next steps in the development of guidance for GMP and research to improve the scientific basis of the models are described based on a review of the current status of the application of physiologically based pharmacokinetic (PBPK) models in risk assessments in Europe, Canada, and the United States at the International Workshop on the Development of GMP for PBPK

Novel use of untargetted metabolomic profiling of treadmill ultramarathon running

INTRODUCTION: The rising popularity of ultramarathon running over the past few years has seen non-professional runners striving for bigger and tougher extreme physical challenges. Understanding the effects of ultramarathon events and the ultramarathon runners profile provides a unique model to investigate the physiological responses to prolonged physical exertion. The current study determined the metabolic changes induced by extreme exercise through ultra-marathon running in order gain an insight into how metabolism is adapted for endurance performance. Plasma samples were analysed for their metabolomic profiles to determine the metabolic changes. The aim of the current study was to analyse the change in metabolic profile of trained ultramarathon runners in response to an 80.5km simulated treadmill ultramarathon. METHODS: Metabolomic profiling of nine trained male ultramarathon runners was performed in response to an 80.5km self-paced treadmill-based time trial performed in a controlled laboratory environment. Plasma samples were obtained from venous whole blood, collected at rest, half-way (40.25km) and on completion of 80.5km (post-80.5km). Samples were analysed by high resolution mass spectrometry in combination with both hydrophilic interaction (HILIC) and reversed phase (RP) chromatography. The extracted putatively identified features were modelled using Simca P 14.1 software. RESULTS: The runners completed the distance in 09:00:18±01:14:07 (hh:mm:ss), at a running velocity of 9.8±1.3 km.h-1. The exercise induced a large number of metabolic changes with multiple amino acids decreasing in abundance while there were increases in the levels of a number of acylcarnitines, fatty acids and oxidised fatty acids. There were no significant differences observed between the halfway (40.25km) and post-80.5km samples (p>0.05). A large number of amino acids decreased and fatty acid metabolism was affected with an increase in the formation of medium-chain unsaturated and partially oxidised fatty acids and conjugates of fatty acids with carnitines. CONCLUSION: A marked elevation in acylcarnitine levels suggests a source of energy for export into the musculoskeletal mitochondria. The fall in the amino acids used in protein biosynthesis may be due to an increase in protein biosynthesis during exercise. Elevation of oxidised fatty acids may be associated with potent effects on blood vessels promoting either vasodilation or vasoconstriction or as markers of oxidative stress. The pattern of fatty acids and carnitines observed in the current study suggests a large increase in peroxisomal metabolism providing acetyl carnitine as a fuel source. This is the first study to provide evidence of the metabolic profile in response to prolonged ultramarathon running using an untargeted approach. The findings provide an insight into the effects of ultramarathon running on the metabolic specificities and alterations that may demonstrate cardio-protective effects