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Lydia B Munns,1,2,&ast; Harriet Demnitz-King,1,&ast; Claire André,3 Stéphane Rehel,3 Valentin Ourry,3 Vincent de La Sayette,4 Denis Vivien,3,5 Gaël Chételat,3 Géraldine Rauchs,3,&ast; Natalie L Marchant1,&ast; On behalf of the Medit-Ageing Research Group1Division of Psychiatry, University College London, London, UK; 2Department of Psychology, York University, York, UK; 3Normandie Univ, UNICAEN, INSERM, U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Neuropresage Team, GIP Cyceron, Caen, France; 4Service de Neurologie, CHU de Caen-Normandie, Caen, France; 5Département de Recherche Clinique, CHU Caen-Normandie, Caen, France&ast;These authors contributed equally to this workCorrespondence: Natalie L Marchant, Division of Psychiatry, University College London, London, UK, Email n.marchant@ucl.ac.uk Lydia B Munns, Department of Psychology, York University, York, United Kingdom, Email lydbmunns@gmail.comObjective: Poor sleep and high levels of repetitive negative thinking (RNT), including future-directed (ie, worry) and past-directed (ie, brooding) negative thoughts, have been associated with markers of dementia risk. The relationship between RNT and sleep health in older adults is unknown. This study aimed to investigate this association and its specificities including multiple dimensions of objective and subjective sleep.Methods: This study used a cross sectional quantitative design with baseline data from 127 cognitively healthy older adults (mean age 69.4 ± 3.8 years; 63% female) who took part in the Age-Well clinical trial, France. RNT (ie, worry and brooding) levels were measured using the Penn State Worry Questionnaire and the Rumination Response Scale (brooding subscale). Polysomnography was used to assess sleep objectively, and the Pittsburgh Sleep Quality Index and the St. Mary’s Hospital Sleep Questionnaire were used to measure sleep subjectively. In primary analyses the associations between RNT and sleep (ie, objective sleep duration, fragmentation and efficiency and subjective sleep disturbance) were assessed via adjusted regressions.&#x00A0Results: Higher levels of RNT were associated with poorer objective sleep efficiency (worry: β=− 0.32, p< 0.001; brooding: β=− 0.26, p=0.002), but not objective sleep duration, fragmentation, or subjective sleep disturbance. Additional analyses, however, revealed differences in levels of worry between those with short, compared with typical and long objective sleep durations (p < 0.05).Conclusion: In cognitively healthy older adults, RNT was associated with sleep characteristics that have been implicated in increased dementia risk. It will take additional research to ascertain the causal link between RNT and sleep characteristics and how they ultimately relate to the risk of developing dementia.Keywords: perseverative cognition, rumination, sleep, anxiety, ageing

Contractile actomyosin bundles are key force-producing and mechanosensing elements in muscle and non-muscle tissues. Whereas the organization of muscle myofibrils and mechanism regulating their contractility are relatively well-established, the principles by which myosin-II activity and force-balance are regulated in non-muscle cells have remained elusive. We show that Caldesmon, an important component of smooth muscle and non-muscle cell actomyosin bundles, is an elongated protein that functions as a dynamic cross-linker between myosin-II and tropomyosin-actin filaments. Depletion of Caldesmon results in aberrant lateral movement of myosin-II filaments along actin bundles, leading to irregular myosin distribution within stress fibers. This manifests as defects in stress fiber network organization and contractility, and accompanied problems in cell morphogenesis, migration, invasion, and mechanosensing. These results identify Caldesmon as critical factor that ensures regular myosin-II spacing within non-muscle cell actomyosin bundles, and reveal how stress fiber networks are controlled through dynamic cross-linking of tropomyosin-actin and myosin filaments.

Engineered culture substrates have proven invaluable for investigating the role of cell and extracellular matrix geometry in governing cell behavior. While the mechanisms relating geometry to phenotype are complex, it is clear that the actin cytoskeleton plays a key role in integrating geometric inputs and transducing these cues into intracellular signals that drive downstream biology. Here, we review recent progress in elucidating the role of the cell and matrix geometry in regulating actin cytoskeletal architecture and mechanics. We address new developments in traditional two-dimensional culture paradigms and discuss efforts to extend these advances to three-dimensional systems, ranging from nanotextured surfaces to microtopographical systems (e.g. channels) to fully three-dimensional matrices.

The aggressive brain tumor glioblastoma (GBM) is characterized by rapid cellular infiltration of brain tissue, raising the possibility that disease progression could potentially be slowed by disrupting the machinery of cell migration. The LIM kinase isoforms LIMK1 and LIMK2 (LIMK1/2) play important roles in cell polarization, migration, and invasion and are markedly upregulated in GBM and many other infiltrative cancers. Yet, it remains unclear whether LIMK suppression could serve as a viable basis for combating GBM infiltration. In this study, we investigated effects of LIMK1/2 suppression on GBM invasion by combining GBM culture models, engineered invasion paradigms, and mouse xenograft models. While knockdown of either LIMK1 or LIMK2 only minimally influenced invasion in culture, simultaneous knockdown of both isoforms strongly reduced the invasive motility of continuous culture models and human GBM tumor-initiating cells (TIC) in both Boyden chamber and 3D hyaluronic acid spheroid invasion assays. Furthermore, LIMK1/2 functionally regulated cell invasiveness, in part, by disrupting polarized cell motility under confinement and cell chemotaxis. In an orthotopic xenograft model, TICs stably transduced with LIMK1/2 shRNA were implanted intracranially in immunocompromised mice. Tumors derived from LIMK1/2 knockdown TICs were substantially smaller and showed delayed growth kinetics and more distinct margins than tumors derived from control TICs. Overall, LIMK1/2 suppression increased mean survival time by 30%. These findings indicate that LIMK1/2 strongly regulate GBM invasive motility and tumor progression and support further exploration of LIMK1/2 as druggable targets. SIGNIFICANCE: Targeting the actin-binding proteins LIMK1 and LIMK2 significantly diminishes glioblastoma invasion and spread, suggesting the potential value of these proteins as therapeutic targets.

In this study the authors report that Caldesmon controls force-balance and architecture of stress fibers through dynamic cross-linking of actin and myosin filaments. Caldesmon depletion led to consequent problems in cell morphogenesis, motility and mechanosensing.

Dilated cardiomyopathy (DCM) is a leading cause of morbidity and mortality worldwide; yet how genetic variation and environmental factors impact DCM heritability remains unclear. Here, we report that compound genetic interactions between DNA sequence variants contribute to the complex heritability of DCM. By using genetic data from a large family with a history of DCM, we discovered that heterozygous sequence variants in the TROPOMYOSIN 1 (TPM1) and VINCULIN (VCL) genes cose-gregate in individuals affected by DCM. In vitro studies of patient-derived and isogenic human-pluripotent-stem-cell-derived cardio-myocytes that were genome-edited via CRISPR to create an allelic series of TPM1 and VCL variants revealed that cardiomyocytes with both TPM1 and VCL variants display reduced contractility and sarcomeres that are less organized. Analyses of mice genetically engineered to harbour these human TPM1 and VCL variants show that stress on the heart may also influence the variable penetrance and expressivity of DCM-associated genetic variants in vivo. We conclude that compound genetic variants can interact combinatorially to induce DCM, particularly when influenced by other disease-provoking stressors.

Introduction: Late life depression (LLD) is characterized by specific clinical features including a high frequency of vascular form and frequent antidepressant treatment resistance. The expression and functions of the serine protease inhibitor, Plasminogen Activator Inhibitor‐1 (PAI‐1) is known to be altered by aging, vascular damage, insulin levels associated with a sedentary lifestyle, chronic stress leading to hypercortisolemia, and inflammatory changes linked to stress responses. These phenomena would be implicated in LLD like vascular depression. This article thus aims to review the existing literature regarding the association between LLD and plasmatic levels of PAI‐1, a marker of hypofibrinolysis. We hypothesize that increased age would be associated with changes in PAI‐1 plasma level and function which influence LLD pathogenesis and its treatment. Results: Although a large number of studies on PAI‐1 changes in the elderly exist, studies about its implications in LLD are sparse. Despite heterogeneous findings regarding the direction of variation in plasmatic PAI‐1 levels among elderly participants with LLD, all studies demonstrated an association between PAI‐1 levels and current or remitted depressive symptoms. Moreover, disruptions in the concentrations of other biological markers influencing PAI‐1 expression, such as cytokines or adipokines, were also observed, notably an increase in the levels of interleukins 6 and 8. Discussion: LLD genesis appears to be influenced by PAI‐1 regulatory loops which are implicated in senescence or cell death. The resistance to antidepressant treatment appears to be linked to distinct biological profiles involving inflammatory and fibrinolytic factors. Taken together these data suggest that PAI‐1 pathway may be a promising target of treatment development efforts for LLD, and depression in general. [ABSTRACT FROM AUTHOR]

In this paper, we examine the relationship between terrorism and exports at the firm-level. We use a panel data of 301 firms listed on the Pakistan Stock Exchange and records of terrorist attacks in Pakistani cities from 1999 to 2014. By calculating city-level terrorism indices, the study reveals significant variations in the frequency of terrorist incidents both between cities and within cities over different time periods. Our panel regressions show that firm exports are correlated with terrorist attacks in the cities where the firms are located, and these correlations are statistically significant even when terrorism is lagged up to six years. Interregional spillover effects of terrorism are less pronounced. While a negative correlation can be found between firm exports and our terrorism indices, the correlation with domestic sales tends to be statistically insignificant. The findings shed light on the persistent link between local terrorism and firms' international and domestic operations. [ABSTRACT FROM AUTHOR]

The ratio of index finger length to ring finger length (2D:4D) is considered to be a putative biomarker of prenatal androgen exposure (PAE), with previous research suggesting that 2D:4D is associated with human behaviors, especially sex-typical behaviors. This study empirically examines the relationship between 2D:4D and individual competitiveness, a behavioral trait that is found to be sexually dimorphic. We employ two related, but distinct, measures of competitiveness, namely behavioral measures obtained from economic experiments and psychometric self-reported measures. Our analyses are based on two independent data sets obtained from surveys and economic experiments with 461 visitors of a shopping mall (Study I) and 617 university students (Study II). The correlation between behavior in the economic experiment and digit ratios of both hands is not statistically significant in either study. In contrast, we find a negative and statistically significant relationship between psychometric self-reported measures of competitiveness and right hand digit ratios (R2D:4D) in both studies. This relationship is especially strong for younger people. Hence, this study provides some robust empirical evidence for a negative association between R2D:4D and self-reported competitiveness. We discuss potential reasons why digit ratio may relate differently to behaviors in specific economics experiments and to self-reported general competitiveness.