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The human DDX52 protein is a nucleic acid helicase and strand annealase that promotes cell migration
Get PDFDExD-box (DDX) proteins are essential for RNA metabolism and are targets for treatment of cancers and neurodevelopmental disorders. The biochemical mechanisms of many DDX proteins remain unclear, including human DDX52. DDX52 is essential for cell survival and is an emerging biomarker for the onset of metastatic melanoma. In this work, we identified that human DDX52 is an ATP-dependent translocase with 3'-5' polarity, which can unwind DNA duplexes and DNA/RNA hybrids. Further, DDX52 is a nucleic acid annealase, an activity that requires an N-terminal intrinsically disordered protein region. DDX52 becomes hyperactive at DNA annealing if DDX52 helicase activity is inactivated by mutagenesis. Using CRISPR-Cas9 genetic editing, we generated U2OS cell lines heterozygous for DDX52 (DDX52+/-), which exhibit growth defects and impaired cell migration, providing direct support for previous suggestions that DDX52 may promote cancer cell metastasis and C-myc regulation
The impact of derivative use on default probability among non-financial firms: Evidence from European firms
Get PDFThis paper examines how institutional environments shape the effectiveness of derivative hedging in reducing corporate default risk. Using hand-collected data from non-financial firms across nine European countries and various econometric methods to control for endogeneity, we provide novel evidence that the risk-reducing benefits of derivative usage are significantly enhanced in stronger creditor rights settings. Additionally, we document that the default risk-reducing effect of derivatives diminishes in countries with lower economic risk. We also find that for firms in severe financial distress, hedging does not reduce default likelihood. Regarding types of derivatives, we show that interest rate derivatives have a stronger default risk reducing effect than foreign exchange and commodity derivatives
The Ontogeny of the Generalization of Avoidance Behavior
No full textThe developmental trajectory of the generalization of avoidance has received limited research attention, despite generalization and avoidance being key features of anxiety disorders. This study used a gamified avoidance task to investigate generalization in 96 children aged 5–11years old.The task was an adaptation of the classic “Space Invaders” video game, in which participants have to shoot at spaceships to win points while also avoiding being shot by a large spaceship (i.e., aversive outcome). The appearance of the large spaceship (the outcome; which resulted in loss of points) was signaled by colored sensors at the top of the screen. One sensor predicted the outcome (CS+; an aqua-colored sensor), and a second did not (CS−; red). Participants could avoid the loss of points by moving into the safe areas of the screen in anticipation of the large spaceship. Following avoidance training, we then presented six generalization stimuli varying along the blue–green dimension of the CS+ to assess generalization. Our findings revealed that age significantly influenced generalization gradients, with younger children (5–8) exhibiting broader gradients compared to older children (9–11). Regression analyses indicated that age was a significant predictor of generalization. These results underscore the impact of ontogenetic changes on the generalization of avoidance behavior and highlight the importance of including young children in research to better understand the mechanisms underlying generalization and factors leading to anxiety disorders
Exploring the effects of pH, ionic strength, and temperature on bisulfide sorption onto bentonite via experiments and numerical modelling
Get PDFThe long-term performance of the Canadian deep geologic repository (DGR) relies significantly on bentonite clay, as sealing materials intended for use in the engineered barrier system (EBS). One particular safety concern is microbiologically influenced corrosion of the used fuel containers (UFCs) which may occur if bisulfide (HS−) transports through the bentonite buffer to reach the UFC surface and corrode the copper coating. Understanding HS− sorption onto bentonite is therefore an important aspect of this problem, as HS− sorption can reduce the extent of copper corrosion. However, sorption dynamics onto bentonite are not yet well-understood. As such, this study performed laboratory batch experiments to investigate HS− sorption onto bentonite slurries as a function of temperature (10–40 °C), pH (9–11), and ionic strength (0.01 M–1 M NaCl). These conditions were aimed to reflect the range of possible DGR geochemical conditions. The experimental results showed that HS− sorption onto bentonite increased with increasing temperature but decreased with increasing pH and ionic strength. A 3-way ANOVA (analysis of variance) showed that the variables' individual and 2-way interaction effects are statistically significant, which implies that they should be incorporated into a sorption mechanism. A thermodynamic-based sorption model was also developed in PHREEQC assuming that sorption was driven by three key processes: (i) redox reaction with the structural Fe3+ sites, (ii) surface precipitation as FeS (mackinawite), and (iii) surface complexation reactions with surface hydroxyl group (OH) at the edge sites of montmorillonite. The model successfully described the main experimental trends and provided valuable insights into the relative contribution of these processes to the total HS− sorption mechanism. Altogether, this study provides novel insights from experimental and numerical modelling findings that enhance the understanding of HS− sorption onto bentonite, in the context of Canadian DGR design as well as other nuclear repositories worldwide
Geriatric oncology in 2040: Exploring potential realities and challenges. A diverse perspective
Get PDFThe average global life expectancy is predicted to increase to approximately 80 years by 2040 [1]. Cancer is an ageing-related disease, and its prevalence will also increase with this ageing of the population [2]. This rise in older adults living with cancer will demand innovation in service delivery, multidisciplinary collaboration, and a renewed focus on compassionate, patient-centred care. We are therefore compelled to rethink how we approach cancer diagnosis, treatment, and survivorship. This white paper explores the potential realities and challenges through a multidimensional lens, addressing the intersection of demographic shifts, rapid technological advancements, and the evolving needs of older adults living with cancer. Key areas examined include the integration of precision medicine and digital health tools, the adaptation of healthcare delivery models, and the implications for workforce training and resource allocation.The discussion highlights disparities in care, the importance of personalised interventions, and strategies to enhance quality of life for older adults with cancer. By anticipating these developments, the paper offers critical insights for policymakers (who set the rules and goals and allocate funding), health system leaders (who manage the day-to-day operations), clinicians and allied health professionals (who are patient-facing), and patients and caregivers, aiming to promote equity, innovation, quality and resilience in the care of older adults with cancer as we approach the next decade.The paper seeks to consolidate and clarify the diverse issues and opportunities that will emerge as the global population ages and the burden of cancer among older adults rises. With average life expectancy predicted to approach 80 years by 2040, and cancer recognised as a disease closely linked to ageing [3], the paper brings together expert perspectives to provide a sector-wide synthesis of the impending challenges. Its purpose is not to offer a conventional systematic review, but rather to serve as a strategic resource for policymakers, health system leaders, clinicians, allied health professionals, patients, and caregivers, informing the response to demographic shifts, technological advances and evolving patient needs. By consolidating insights on disparities in care, the necessity for personalised interventions, and strategies to enhance quality of life, the paper aims to inform and inspire innovation, equity and resilience in geriatric oncology as we approach the next decade
Squeaking at soft–rigid frictional interfaces
Get PDFSqueaking is a constant companion in various aspects of our daily lives, whether we slide rubber-soled shoes across hardwood floors , scrape chalk on a blackboard, engage the brakes on a bicycle or walk with a hip replacement. When two rigid bodies slide over each other, squeaking is widely understood to result from self-excited stick–slip oscillations, triggered by a decrease in the friction coefficient with increasing slip velocity. However, sliding of extended interfaces can involve crack or slip-pulse propagation . This distinction is amplified when a soft body slides on a rigid one, in which large deformations and material mismatch can cause detachment by opening slip pulses. Previous studies focused mainly on slow sliding, in which pulses are slow and squeaking is absent. Although squeaking at soft–rigid interfaces has been linked to stick–slip oscillations, the mechanisms remain unclear. Here we experimentally investigate soft–rigid interfaces sliding at velocities that produce squeaking. High-speed imaging and acoustic analysis show that opening pulses propagate at approximately the shear wave speed of the soft material, mediating local slip across diverse materials. In flat samples, these pulses are irregular and generate broadband acoustic emissions. Introducing thin surface ridges confines pulse propagation, yielding a consistent repetition frequency matching the first shear mode of the sliding block and squeaking at that frequency. These findings show a structure-driven mechanism that stabilizes rupture in bimaterial friction. Geometric confinement suppresses competing modes, transforming irregular two-dimensional dynamics into coherent one-dimensional pulse trains, offering new insights into frictional rupture from engineered surfaces to geological faults
Tailoring cariprazine for dual disorders via secondary pharmacophore optimization
Get PDFCariprazine is an approved drug used to treat schizophrenia, bipolar disorder, and (more recently) major depression. These serious mental illnesses are often comorbid with psychostimulant use disorders, for which no pharmacotherapeutic is currently approved. Based on preclinical data and multiple case studies, cariprazine demonstrates significant potential as a treatment for such dual disorders. Notably, this drug acts as a high-affinity (Ki = 0.22 nM) partial agonist (Emax = 45.1%) of the dopamine D3 receptor (D3R), a molecular target implicated in a variety of substance use disorders. Unlike other atypical antipsychotics, cariprazine is 3.6-fold more selective for D3R than the homologous dopamine D2 receptor (D2R). Because patients with psychostimulant use disorders may be more susceptible to D2R-related side effects, we hypothesized that compounds with a higher D3R selectivity may offer a therapeutic advantage over cariprazine. By modifying part of the parent drug structure (i.e., secondary pharmacophore), analogues were developed that bind to D3R with similar affinity (Ki = 0.248–2.97 nM) and improved selectivity over D2R (5.0- to 39-fold). Compared to cariprazine, these derivatives behaved functionally as D3R partial agonists and retained a similar off-target profile; however, the most promising compounds also exhibited improved metabolic stability in rat liver microsomes (t1/2 ≥ 61.3 min). Taken together, our findings support further study of the lead candidate (8) for treating dual disorders that may have a reduced side effect profile
Exploring the experiences and wellbeing of competitive women, transgender, and gender diverse gamers
Get PDFVideo gaming offers various benefits, such as social connections and improved wellbeing. However, as competitive video gaming continues to grow, gender-related harassment of women and transgender and gender diverse (TGD) gamers in competitive gaming environments persists. This study explored the experiences of gamers in gaming communities, their mental health, and gaming imposter syndrome. The study also explored women and TGD gamers’ experiences of gender-related harassment. Findings showed that ~87% of women and TGD gamers reported gender-related harassment and employed a range of avoidance action to minimise harassment. They also reported more worries about engaging in gaming communities, more gaming imposter syndrome, and poorer mental health. The findings highlight the pervasiveness of gender-related harassment in competitive video gaming and the reliance of short-term coping strategies among women and TGD gamers. While identity-specific communities may offer support, structural and cultural changes are needed to foster inclusive competitive gaming spaces
Public and Patient Involvement and Engagement in Clinical Trials: A Multi‐Perspective Mixed‐Methods Evaluation of the ROWTATE Programme
Get PDFBackground: Patient and public involvement and engagement (PPIE) has many benefits for the design, delivery and dissemination of health research, but this can be difficult to achieve. Systematic reporting and evaluation of PPIE in multi‐year, multisite and complex clinical trials is very limited. Methodology: This evaluation presents a multi‐perspective description and evaluation of patient and public involvement within a large‐scale, multisite, longitudinal research programme focused on developing and evaluating a vocational rehabilitation and clinical psychology intervention for individuals recovering from traumatic injury. Conducted as part of the NIHR‐funded ROWTATE research programme (2019–2026), the evaluation explores the scope, impact, and lived experiences of PPIE group members across all phases of the study, from development of the intervention, feasibility study and trial design to intervention delivery, data collection, analysis and dissemination. Employing multiple methods, including open‐ended surveys with PPIE group members and researchers, a ‘You Said, We Did’ activity log, and minute taking, the study identifies key patterns related to PPIE group members' motivations, contributions, personal impact and barriers and facilitators to engagement. Results: Findings highlight the significant value of PPIE in enhancing study relevance, improving data collection and communication strategies, informing rehabilitation, clinical psychology and health economics components, and shaping intervention delivery. PPIE group members reported a strong sense of purpose and intellectual engagement, despite challenges including communication gaps and role clarity. Researchers valued PPIE contribution to the research, and the positive and enriching experience of working with PPIE group members. Both groups reflected on the barriers and facilitators to PPIE. Conclusion: The evaluation highlights the importance of inclusive, well‐supported, and transparent PPIE practices and contributes novel insights into the PPIE role in under‐researched domains such as clinical psychology and health economics. Patient or Public Contribution: Traumatic injury survivors were involved in all processes of this evaluation. This includes research design, funding acquisition, data collection, data analysis and interpretation and the write‐up of this manuscript. Five traumatic injury survivors are co‐authors of this manuscript
Offline Reconstruction of Diffusion MRI Acquisitions for Comparison Between Complex PCA-based and AI-based Denoising
Get PDFPurpose: Optimal diffusion MRI (dMRI) data for image denoising is often unavailable from scanner reconstruction. In this work, we make available an offline reconstruction pipeline for GE dMRI acquisitions, giving access to complex dMRI data. Furthermore, we compare the efficacy of GE HealthCare’s AIR-Recon DLTM (ARDL), a proprietary convolutional neural network-based reconstruction and denoising approach, to patch-based MPPCASVS and NORDIC denoising methods on high-resolution dMRI data.Methods: We developed an end-to-end offline dMRI reconstruction pipeline for GE HealthCare acquisitions, augmenting the Orchestra software development kit, and validated its output against scanner reconstruction. We used it to compare MPPCASVS, NORDIC and ARDL denoising approaches, considering underlying metrics reflecting noise variance and bias, such as the signal profiles in highly anisotropic areas, and secondary downstream measurements, such as fiber orientation estimation and white matter tractography.Results: Our validated offline reconstruction supports various in-plane/out-of-plane accelerations and partial Fourier reconstruction methods. Unlike scanner reconstruction, it provides access to complex dMRI data, enabling denoising in the complex domain, which demonstrated superior noise floor suppression compared to magnitude-constrained denoising. PCA-based denoising methods had improved spatial resolution, contrast-to-noise and more robust fiber orientation estimation compared to ARDL.Conclusion: We found significant gains in dMRI data quality when using the proposed offline reconstruction pipeline, allowing complex-domain denoising to obtain high-quality data at high spatial resolution and b-value, using a wide-bore scanner and a standard PGSE EPI sequence. MPPCASVS and NORDIC (4D PCA-based) outperformed ARDL (2D) in terms of spatial resolution and reduction of noise variance
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