Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system characterized by focal and then generalized weakness leading to paralysis and death from respiratory failure. Symptoms arise from the loss of corticospinal (upper) and brainstem and spinal (lower) motor neurons. The cause of sporadic ALS (sALS) is unknown. Investigations of the 10% of cases that are familial (fALS) have identified over 30 genes whose mutations predispose to ALS. Expression of mutant ALS genes in rodents and cells has generated models that facilitate identification of molecular pathways in ALS. Three pathological processes appear to be central in this disease: (1) conformational instability and aberrant trafficking of critical proteins; (2) perturbations of processing of RNA and RNA-binding proteins; and (3) disruption of homeostasis. Related events include protein aggregation and disturbances of mitochondria, neuronal excitability and axonal transport. Elucidation of these pathways and events provides targets for treatment development.
Excitation identification has received considerable attention because of its importance in safety assessment and structural design. This paper proposed a power spectral density (PSD) identification method for stationary stochastic excitations considering multi-source uncertainties in load fluctuations, material dispersions and measurement noises. Based on the traditional inverse pseudo-excitation method, a two-step weighting regularization strategy is creatively developed to reduce the amplification effects of the uncertainties in the transfer matrix and measurements on reconstructed results near natural frequencies. Especially, to enhance the generalizability of regularization operations, a weighting matrix is defined based on the interval-quantized deviation analysis of pseudo excitations and then an improved Tikhonov regularizing operator is defined given the features of the weighting transfer matrix and pseudo responses. Next, the response superposition-decomposition principle is performed to determine the boundaries of excitation PSD and two uncertainty propagation methods are developed. To guarantee the accuracy and efficiency of uncertainty analysis, the adaptive reduced-dimension Chebyshev model is adopted to characterize the nonlinear response-parameter relationships, and the first-order Taylor series approximation is used to describe the linear response-excitation relationships. Eventually, two numerical examples and one experimental example are discussed to demonstrate the feasibility of the developed approach. The results suggest its promising applications in complicated structures and loading conditions.
Topoisomerase (IIB) inhibitors have been involved in the therapies of tumour progression and have become a major focus for the development of anticancer agents. New three-component hybridised ligands, 1,4-disubstituted-1,2,3-triazoles (8–17), were synthesised via a 1,3-dipolar cycloaddition reaction of 9-azidoacridine/3-azidocoumarin with N/O-propargyl small molecules under click reaction conditions. Cancer cell growth inhibition of the synthesised triazoles was tested against human cell-lines in the NCI-60-cell-panel, and the most active compounds tested against topoisomerase (IIB)-enzymes. The acridinyl ligands (8–10) revealed 60–97% cell growth inhibition in six cancer cell-panels. Cell-cycle analysis of MCF7 and DU-145 cells treated with the active acridinyl ligands exhibited cell-cycle arrest at G2/M phase and proapoptotic activity. In addition, compound 8 displayed greater inhibitory activity against topoisomerase (IIB) (IC50 0.52 µM) compared with doxorubicin (IC50 0.83 µM). Molecular dynamics simulation studies showed the acridine–triazole–pyrimidine hybrid pharmacophore was optimal with respect to protein–ligand interaction and fit within the binding site, with optimal orientation to allow for intercalation with the DNA bases (DG13, DC14, and DT9).
Background: The 11th revision of the International Classification of Diseases (ICD-11) includes a new diagnosis of complex posttraumatic stress disorder (CPTSD). The International Trauma Interview (ITI) is a novel clinician-administered diagnostic interview for the assessment of ICD-11 PTSD and CPTSD. Objective: The aim of this study was to evaluate the psychometric properties of the ITI in a Lithuanian sample in relation to interrater agreement, latent structure, internal reliability, as well as convergent and discriminant validity. Method: In total, 103 adults with a history of various traumatic experiences participated in the study. The sample was predominantly female (83.5%), with a mean age of 32.64 years (SD = 9.36). For the assessment of ICD-11 PTSD and CPTSD, the ITI and the self-report International Trauma Questionnaire (ITQ) were used. Mental health indicators, such as depression, anxiety, and dissociation, were measured using self-report questionnaires. The latent structure of the ITI was evaluated using confirmatory factor analysis (CFA). In order to test the convergent and discriminant validity of the ITI we conducted a structural equation model (SEM). Results: Overall, based on the ITI, 18.4% of participants fulfilled diagnostic criteria for PTSD and 21.4% for CPTSD. A second-order two-factor CFA model of the ITI PTSD and disturbances in self-organization (DSO) symptoms demonstrated a good fit. The associations with various mental health indicators supported the convergent and discriminant validity of the ITI. The clinician-administered ITI and self-report ITQ had poor to moderate diagnostic agreement across different symptom clusters. Conclusion: The ITI is a reliable and valid tool for assessing and diagnosing ICD-11 PTSD and CPTSD.
Background: The psychological treatment of comorbid post-traumatic stress disorder (PTSD) and substance use disorder (SUD) is clinically challenging, and outcomes are often poor. Objective: This paper describes a systematic review and meta-analysis which sought to establish the current efficacy for a number of established psychological approaches for adults and adolescents, in comparison to interventions for SUD alone, or other active approaches, following a pre-registered protocol. Method: This review followed PRISMA and Cochrane Collaboration guidelines. Data extraction and risk of bias judgements using Cochrane criteria were undertaken by all authors. Primary outcomes were PTSD severity and substance use post-treatment. The quality of findings was assessed using GRADE. Following a comprehensive search, conducted to 13 September 2021, 27 studies were included. Results: We found a relatively high level of dropout across studies. In our main comparisons, we found no benefits for present-focused treatment approaches aimed at improving coping skills beyond those for SUD-only interventions. We found modest benefits for trauma-focused intervention plus SUD intervention post-treatment for PTSD (standardized mean difference (SMD) = -0.36, 95% confidence interval (CI) -0.64, -0.08), and at 6-13 months for PTSD (SMD = -0.48, 95% CI -0.81, -0.15) and alcohol use (SMD = -0.23, 95% CI -0.44, -0.02). There were no benefits for cognitive restructuring interventions as a group, but we found a modest effect for integrated cognitive behavioural therapy (ICBT) for PTSD post-treatment (SMD = -0.33, 95% CI -0.62, -0.04). There was evidence of some benefit for trauma-focused intervention over present-focused intervention for PTSD from a single study and for reduction in dropout for incentivized attendance for trauma-focused intervention from another single study. Most findings were of very low quality. Conclusion: There is evidence that trauma-focused therapy and ICBT can improve PTSD for some individuals, but many patients do not fully engage with treatment and average treatment effects are modest. Highlights: For PTSD, evidence was strongest for trauma-focused CBT-based approaches, but effects were modest.There was little evidence of any added benefit on substance use, beyond that of standard addiction treatments, for any included intervention.Dropout from treatment was high.
We compared self-reported parenting beliefs about caring for infants with observed parenting behaviours during play interactions between 32 parents and their infants. We measured parenting beliefs about the value of attunement and structure in caring for infants using the Baby Care Questionnaire (BCQ) (Winstanley & Gattis, 2013; Winstanley, Sperotto, Putnick, Cherian, Bornstein & Gattis, 2014). We used a micro-coding approach to distinguish between responsive parenting behaviours (maintaining infant attention) and demanding parenting behaviours (introducing or redirecting infant attention) (Landry, Garner, Swank & Baldwin, 1996). Attunement beliefs were positively related to responsive parenting behaviours and negatively related to demanding parenting behaviours. Structure beliefs were weakly related to demanding parenting behaviours. These results are an important first step toward identifying relations between self-reported parenting beliefs about attunement and structure and observed parenting behaviours.
Background: Social cognitive impairments, specifically in facial emotion processing and mental state attribution, are common in post-traumatic stress disorder. However few studies so far have examined whether social cognitive ability impacts on PTSD recovery. Objective: To examine whether baseline social cognitive abilities are associated with treatment outcomes following trauma-focused therapy for PTSD. Method: This is a cohort study that will relate treatment outcomes post-discharge to baseline measures of social cognition (five tasks: Emotion Odd-One-Out Task (Oddity), Reading the Mind in the Eyes Task (RMET), Social Shapes Test (SST), Spontaneous Theory of Mind Protocol (STOMP), and Reflective Functioning Questionnaire (RFQ-8)) in people starting a course of psychological therapy for PTSD (target N = 60). The primary outcome will be pre- to post-treatment change in PTSD symptom severity (assessed using the PTSD Checklist for DSM-5). Secondary outcomes include functional impairment (assessed using the Work and Social Adjustment Scale), drop-out rate, and analyses differentiating participants with DSM-5 PTSD and ICD-11 PTSD and CPTSD. Regression models will be used to examine associations between baseline social cognitive performance and outcome measures while adjusting for potential confounders. Two pilot studies informed the development of our study protocol. The first involved qualitative analysis of interviews with nine participants with lived experience of mental health problems to inform our research questions and study protocol. The second involved trialling social cognitive tasks on 20 non-clinical participants to refine our test battery. Discussion: This study will address a gap in the literature about whether abilities in social cognition in people living with PTSD are associated with treatment-related recovery. Highlights: Impairments in social cognition are recognised in people with PTSD.Few studies have examined whether social cognitive ability is associated with recovery from PTSD.We present a study protocol, developed after pilot testing, to address this question.
Background: Self-stigma refers to the internalisation of negative societal views and stereotypes. Self-stigma has been well-characterised in the context of mental disorders such as schizophrenia but has received little attention in relation to post-traumatic stress disorder (PTSD). Objective: This work aimed to determine the prevalence of self-stigma in a sample of adults with PTSD and to establish factors associated with the internalisation of stigma in this population. Method: Participants were 194 adults (mean age 46.07 (SD = 12.39); 64.4% female; 96.6% white Caucasian; residing in the UK), who self-reported a diagnosis of PTSD and currently screened positive for the disorder according to the PTSD Checklist for DSM-5 (PCL-5). Structured interviews and validated self-report questionnaires were used to ascertain clinical and sociodemographic information for analysis. Results: The prevalence of self-stigma measured by the Internalized Stigma of Mental Illness Scale (ISMIS) was 41.2% (95% CI 34.24-48.22). There was no evidence of an association between self-stigma and gender (β = -2.975 (95% CI -7.046-1.097) p = .151), age (β = 0.007 (95% CI -0.152-0.165) p = .953), sexual trauma (β = 0.904 (95% CI -3.668-5.476) p = .697), military trauma (β = -0.571 (95% CI -4.027-7.287) p = .571). Self-stigma was associated with lower income and higher levels of anxiety (β = 5.722 (95% CI 2.922-8.522) p = <.001), depression (β = 6.937 (95% CI 4.287-9.588) p = <.000), and traumatic stress symptoms (β = 3.880 (95% CI 1.401-6.359) p = .002). Conclusions: The results indicate that self-stigma may be a significant issue among people with a diagnosis of PTSD. Further work is needed to understand the long-term impact and to develop interventions to address the internalisation of stigma in this population. Highlights: The prevalence of self-stigma among a sample of participants with PTSD was 41.2%.There was no evidence of an association between self-stigma and gender, age or sexual / military trauma.Self-stigma was associated with lower income and higher levels of anxiety, depression, and traumatic stress symptoms.
Hateful individuals and groups have increasingly been using the Internet to express their ideas, spread their beliefs, and recruit new members. Under- standing the network characteristics of these hateful groups could help understand individuals’ exposure to hate and derive intervention strategies to mitigate the dangers of such networks by disrupting communications. This article analyses two hateful followers net- works and three hateful retweet networks of Twitter users who post content subsequently classified by hu- man annotators as containing hateful content. Our analysis shows similar connectivity characteristics between the hateful followers networks and likewise between the hateful retweet networks. The study shows that the hateful networks exhibit higher connectivity characteristics when compared to other ”risky” networks, which can be seen as a risk in terms of the likelihood of expo- sure to, and propagation of, online hate. Three network performance metrics are used to quantify the hateful content exposure and contagion: giant component (GC) size, density and average shortest path. In order to efficiently identify nodes whose removal reduced the flow of hate in a network, we propose a range of structured node-removal strategies and test their effectiveness. Results show that removing users with a high degree is most effective in reducing the hateful followers network connectivity (GC, size and density), and therefore reducing the risk of exposure to cyberhate and stemming its propagation.
Colonization of terrestrial environments by filamentous fungi relies on their ability to form networks that can forage for and connect resource patches. Despite the importance of these networks, ecologists rarely consider network features as functional traits because their measurement and interpretation are conceptually and methodologically difficult. To address these challenges, we have developed a pipeline to translate images of fungal mycelia, from both micro- and macro-scales, to weighted network graphs that capture ecologically relevant fungal behaviour. We focus on four properties that we hypothesize determine how fungi forage for resources, specifically: connectivity; relative construction cost; transport efficiency; and robustness against attack by fungivores. Constrained ordination and Pareto front analysis of these traits revealed that foraging strategies can be distinguished predominantly along a gradient of connectivity for micro- and macro-scale mycelial networks that is reminiscent of the qualitative ‘phalanx’ and ‘guerilla’ descriptors previously proposed in the literature. At one extreme are species with many inter-connections that increase the paths for multidirectional transport and robustness to damage, but with a high construction cost; at the other extreme are species with an opposite phenotype. Thus, we propose this approach represents a significant advance in quantifying ecological strategies for fungi using network information.
A comparison of the relative merits of video-assisted pulmonary metastasectomy versus thoracotomy is predicated on the assumption that removal of asymptomatic lung metastases favourably influences survival and that it does so by a large degree. Recently published but long-awaited evidence from a prospective cohort study and a randomised trial of Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) challenges that assumption.
Because of COVID-19 in the world, enterprises and consumers pay more and more attention to environmental protection, food safety and health issues. The purpose of this paper is to take China's food company as an example to study the impact of CSR on customer loyalty, mediating effects of company image and customer satisfaction, and moderating effects of COVID-19. The result shows that during COVID-19, company image and customer satisfaction have significant mediating effects, and COVID-19 positively moderate the impact of CSR on customer satisfaction.
There are many factors that contribute to the reproducibility and replicability of scientific research. There is a need to understand the research ecosystem, and improvements will require combined efforts across all parts of this ecosystem. National structures can play an important role in coordinating these efforts, working collaboratively with researchers, institutions, funders, publishers, learned societies and other sectoral organisations, and providing a monitoring and reporting function. Whilst many new ways of working and emerging innovations hold a great deal of promise, it will be important to invest in meta-research activity to ensure that these approaches are evidence based, work as intended, and do not have unintended consequences. Addressing reproducibility will require working collaboratively across the research ecosystem to share best practice and to make the most effective use of resources. The UK Reproducibility Network (UKRN) brings together Local Networks of researchers, Institutions, and External Stakeholders (funders, publishers, learned societies and other sectoral organisations), to coordinate action on reproducibility and work to ensure the UK retains its place as a centre for world-leading research. This activity is coordinated by the UKRN Steering Group. We consider this structure as valuable, bringing together a range of voices at a range of levels to support the combined efforts required to enact change.
Background The phylogenetic ecology of the Afro-Asian dragonfly genus Trithemis has been investigated previously by Damm et al. (in Mol Phylogenet Evol 54:870–882, 2010) and wing ecomorphology by Outomuro et al. (in J Evol Biol 26:1866–1874, 2013). However, the latter investigation employed a somewhat coarse sampling of forewing and hindwing outlines and reported results that were at odds in some ways with expectations given the mapping of landscape and water-body preference over the Trithemis cladogram produced by Damm et al. (in Mol Phylogenet Evol 54:870–882, 2010). To further explore the link between species-specific wing shape variation and habitat we studied a new sample of 27 Trithemis species employing a more robust statistical test for phylogenetic covariation, more comprehensive representations of Trithemis wing morphology and a wider range of morphometric data-analysis procedures. Results Contrary to the Outomuro et al. (in J Evol Biol 26:1866–1874, 2013) report, our results indicate that no statistically significant pattern of phylogenetic covariation exists in our Trithemis forewing and hindwing data and that both male and female wing datasets exhibit substantial shape differences between species that inhabit open and forested landscapes and species that hunt over temporary/standing or running water bodies. Among the morphometric analyses performed, landmark data and geometric morphometric data-analysis methods yielded the worst performance in identifying ecomorphometric shape distinctions between Trithemis habitat guilds. Direct analysis of wing images using an embedded convolution (deep learning) neural network delivered the best performance. Bootstrap and jackknife tests of group separations and discriminant-function stability confirm that our results are not artifacts of overtrained discriminant systems or the “curse of dimensionality” despite the modest size of our sample. Conclusion Our results suggest that Trithemis wing morphology reflects the environment’s “push” to a much greater extent than phylogeny’s “pull”. In addition, they indicate that close attention should be paid to the manner in which morphologies are sampled for morphometric analysis and, if no prior information is available to guide sampling strategy, the sample that most comprehensively represents the morphologies of interest should be obtained. In many cases this will be digital images (2D) or scans (3D) of the entire morphology or morphological feature rather than sparse sets of landmark/semilandmark point locations.
Catalysis is inherently driven by the interaction of reactants, intermediates and formed products with the catalyst’s surface. In order to reach the desired transition state and to overcome the kinetic barrier, elevated temperatures or electrical potentials are employed to increase the rate of reaction. Despite immense efforts in the last decades, research in thermo- and electrocatalysis has often preceded in isolation, even for similar reactions. Conceptually, any heterogeneous surface process that involves changes in oxidation states, redox processes, adsorption of charged species (even as spectators) or heterolytic cleavage of small molecules should be thought of as having parallels with electrochemical processes occurring at electrified interfaces. Herein, we compare current trends in thermo- and electrocatalysis and elaborate on the commonalities and differences between both research fields, with a specific focus on the production of hydrogen peroxide as case study. We hope that interlinking both fields will be inspiring and thought-provoking, eventually creating synergies and leverage towards more efficient decentralized chemical conversion processes. Research in thermo- and electrocatalysis have often preceded in isolation, even for similar reactions. Here, the authors compare current trends in both fields and elaborate on the commonalities and differences with a specific focus on the production of hydrogen peroxide.
The last decade has seen renewed concern within the scientific community over the reproducibility and transparency of research findings. This paper outlines some of the various responsibilities of stakeholders in addressing the systemic issues that contribute to this concern. In particular, this paper asserts that a united, joined-up approach is needed, in which all stakeholders, including researchers, universities, funders, publishers, and governments, work together to set standards of research integrity and engender scientific progress and innovation. Using two developments as examples: the adoption of Registered Reports as a discrete initiative, and the use of open data as an ongoing norm change, we discuss the importance of collaboration across stakeholders.
Intratumoral heterogeneity is caused by genomic instability and phenotypic plasticity, but how these features co-evolve remains unclear. SOX10 is a neural crest stem cell (NCSC) specifier and candidate mediator of phenotypic plasticity in cancer. We investigated its relevance in breast cancer by immunophenotyping 21 normal breast and 1860 tumour samples. Nuclear SOX10 was detected in normal mammary luminal progenitor cells, the histogenic origin of most TNBCs. In tumours, nuclear SOX10 was almost exclusive to TNBC, and predicted poorer outcome amongst cross-sectional ( p = 0.0015, hazard ratio 2.02, n = 224) and metaplastic ( p = 0.04, n = 66) cases. To understand SOX10’s influence over the transcriptome during the transition from normal to malignant states, we performed a systems-level analysis of co-expression data, de-noising the networks with an eigen-decomposition method. This identified a core module in SOX10’s normal mammary epithelial network that becomes rewired to NCSC genes in TNBC. Crucially, this reprogramming was proportional to genome-wide promoter methylation loss, particularly at lineage-specifying CpG-island shores. We propose that the progressive, genome-wide methylation loss in TNBC simulates more primitive epigenome architecture, making cells vulnerable to SOX10-driven reprogramming. This study demonstrates potential utility for SOX10 as a prognostic biomarker in TNBC and provides new insights about developmental phenotypic mimicry—a major contributor to intratumoral heterogeneity.
Background Majority of research and commercial efforts have focussed on use of artificial intelligence (AI) for fracture detection in adults, despite the greater long-term clinical and medicolegal implications of missed fractures in children. The objective of this study was to assess the available literature regarding diagnostic performance of AI tools for paediatric fracture assessment on imaging, and where available, how this compares with the performance of human readers. Materials and methods MEDLINE, Embase and Cochrane Library databases were queried for studies published between 1 January 2011 and 2021 using terms related to ‘fracture’, ‘artificial intelligence’, ‘imaging’ and ‘children’. Risk of bias was assessed using a modified QUADAS-2 tool. Descriptive statistics for diagnostic accuracies were collated. Results Nine eligible articles from 362 publications were included, with most (8/9) evaluating fracture detection on radiographs, with the elbow being the most common body part. Nearly all articles used data derived from a single institution, and used deep learning methodology with only a few (2/9) performing external validation. Accuracy rates generated by AI ranged from 88.8 to 97.9%. In two of the three articles where AI performance was compared to human readers, sensitivity rates for AI were marginally higher, but this was not statistically significant. Conclusions Wide heterogeneity in the literature with limited information on algorithm performance on external datasets makes it difficult to understand how such tools may generalise to a wider paediatric population. Further research using a multicentric dataset with real-world evaluation would help to better understand the impact of these tools.
Background Thyroid hormone responsive protein (THRSP) is a lipogenic nuclear protein that is highly expressed in murine adipose tissue, but its role in humans remains unknown. Methods We characterized the insulin regulation of THRSP in vivo in human adipose tissue biopsies and in vitro in Simpson-Golabi-Behmel syndrome (SGBS) adipocytes . To this end, we measured whole-body insulin sensitivity using the euglycemic insulin clamp technique in 36 subjects [age 40 ± 9 years, body mass index (BMI) 27.3 ± 5.0 kg/m ² ]. Adipose tissue biopsies were obtained at baseline and after 180 and 360 min of euglycemic hyperinsulinemia for measurement of THRSP mRNA concentrations. To identify functions affected by THRSP, we performed a transcriptomic analysis of THRSP-silenced SGBS adipocytes. Mitochondrial function was assessed by measuring mitochondrial respiration as well as oxidation and uptake of radiolabeled oleate and glucose. Lipid composition in THRSP silencing was studied by lipidomic analysis. Results We found insulin to increase THRSP mRNA expression 5- and 8-fold after 180 and 360 min of in vivo euglycemic hyperinsulinemia. This induction was impaired in insulin-resistant subjects, and THRSP expression was closely correlated with whole-body insulin sensitivity. In vitro, insulin increased both THRSP mRNA and protein concentrations in SGBS adipocytes in a phosphoinositide 3-kinase (PI3K)-dependent manner. A transcriptomic analysis of THRSP-silenced adipocytes showed alterations in mitochondrial functions and pathways of lipid metabolism, which were corroborated by significantly impaired mitochondrial respiration and fatty acid oxidation. A lipidomic analysis revealed decreased hexosylceramide concentrations, supported by the transcript concentrations of enzymes regulating sphingolipid metabolism. Conclusions THRSP is regulated by insulin both in vivo in human adipose tissue and in vitro in adipocytes, and its expression is downregulated by insulin resistance. As THRSP silencing decreases mitochondrial respiration and fatty acid oxidation, its downregulation in human adipose tissue could contribute to mitochondrial dysfunction. Furthermore, disturbed sphingolipid metabolism could add to metabolic dysfunction in obese adipose tissue.
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