Lamin Mutations Cause Increased YAP Nuclear Entry in Muscle Stem Cells

Mutations in the LMNA gene, encoding the nuclear envelope A-type lamins, are responsible for muscular dystrophies, the most severe form being the LMNA-related congenital muscular dystrophy (L-CMD), with severe defects in myonucleus integrity. We previously reported that L-CMD mutations compromise the ability of muscle stem cells to modulate the yes-associated protein (YAP), a pivotal factor in mechanotransduction and myogenesis. Here, we investigated the intrinsic mechanisms by which lamins influence YAP subcellular distribution, by analyzing different conditions affecting the balance between nuclear import and export of YAP. In contrast to wild type (WT) cells, LMNADK32 mutations failed to exclude YAP from the nucleus and to inactivate its transcriptional activity at high cell density, despite activation of the Hippo pathway. Inhibiting nuclear pore import abolished YAP nuclear accumulation in confluent mutant cells, thus showing persistent nuclear import of YAP at cell confluence. YAP deregulation was also present in congenital myopathy related to nesprin-1KASH mutation, but not in cells expressing the LMNAH222P mutation, the adult form of lamin-related muscle dystrophy with reduced nuclear deformability. In conclusion, our data showed that L-CMD mutations increased YAP nuclear localization via an increased nuclear import and implicated YAP as a pathogenic contributor in muscle dystrophies caused by nuclear envelop defects

Exact Solution Methods for the kk-item Quadratic Knapsack Problem

The purpose of this paper is to solve the 0-1 $k$-item quadratic knapsack problem $(kQKP)$, a problem of maximizing a quadratic function subject to two linear constraints. We propose an exact method based on semidefinite optimization. The semidefinite relaxation used in our approach includes simple rank one constraints, which can be handled efficiently by interior point methods. Furthermore, we strengthen the relaxation by polyhedral constraints and obtain approximate solutions to this semidefinite problem by applying a bundle method. We review other exact solution methods and compare all these approaches by experimenting with instances of various sizes and densities.Comment: 12 page

A cost effectiveness and capacity analysis for the introduction of universal rotavirus vaccination in Kenya : comparison between Rotarix and RotaTeq vaccines

Background Diarrhoea is an important cause of death in the developing world, and rotavirus is the single most important cause of diarrhoea associated mortality. Two vaccines (Rotarix and RotaTeq) are available to prevent rotavirus disease. This analysis was undertaken to aid the decision in Kenya as to which vaccine to choose when introducing rotavirus vaccination. Methods Cost-effectiveness modelling, using national and sentinel surveillance data, and an impact assessment on the cold chain. Results The median estimated incidence of rotavirus disease in Kenya was 3015 outpatient visits, 279 hospitalisations and 65 deaths per 100,000 children under five years of age per year. Cumulated over the first five years of life vaccination was predicted to prevent 34% of the outpatient visits, 31% of the hospitalizations and 42% of the deaths. The estimated prevented costs accumulated over five years totalled US$1,782,761 (direct and indirect costs) with an associated 48,585 DALYs. From a societal perspective Rotarix had a cost-effectiveness ratio of US$142 per DALY (US$5 for the full course of two doses) and RotaTeq US$288 per DALY ($10.5 for the full course of three doses). RotaTeq will have a bigger impact on the cold chain compared to Rotarix. Conclusion Vaccination against rotavirus disease is cost-effective for Kenya irrespective of the vaccine. Of the two vaccines Rotarix was the preferred choice due to a better cost-effectiveness ratio, the presence of a vaccine vial monitor, the requirement of fewer doses and less storage space, and proven thermo-stability

Response to Comment on "following Molecular Mobility during Chemical Reactions: No Evidence for Active Propulsion" and "molecular Diffusivity of Click Reaction Components: The Diffusion Enhancement Question"

In their Comment (DOI: 10.1021/jacs.2c02965) on two related publications by our groups (J. Am. Chem. Soc. 2021, 143, 20884-20890; DOI: 10.1021/jacs.1c09455) and another (J. Am. Chem. Soc. 2022, 144, 1380-1388; DOI: 10.1021/jacs.1c11754), Huang and Granick discuss the diffusion NMR measurements of molecules during a copper-catalyzed azide-alkyne cycloaddition (CuAAC) "click"reaction. Here we respond to these comments and maintain that no diffusion enhancement was observed for any species during the reaction. We show that the relaxation agent does not interfere with the CuAAC reaction kinetics nor the diffusion of the molecules involved. Similarly, the gradient pulse length and diffusion time do not affect the diffusion coefficients. Peak overlap was completely removed in our study with the use of hydrazine as the reducing agent. The steady-state assumption does not hold for these diffusion measurements that take several minutes, which is the reason monotonic gradient orders are not suitable. Finally, we discuss the other reactions where similar changes in diffusion have been claimed. Our conclusions are fully supported by the results represented in our original JACS Article and the corresponding Supporting Information

Estimation of transient increases in bleeding risk associated with physical activity in children with haemophilia

BACKGROUND: Although it is widely appreciated that vigorous physical activity can increase the risk of bleeding episodes in children with haemophilia, the magnitude of the increase in risk is not known. Accurate risk estimates could inform decisions made by children with haemophilia and their parents about participation in physical activity and aid the development of optimal prophylactic schedules. The aim of this study is to provide an accurate estimate of the risks of bleeding associated with vigorous physical activity in children with haemophilia. METHODS/DESIGN: The study will be a case-crossover study nested within a prospective cohort study. Children with moderate or severe haemophilia A or B, recruited from two paediatric haematology departments in Australia, will participate in the study. The child, or the child's parent or guardian, will report bleeding episodes experienced over a 12-month period. Following a bleeding episode, the participant will be interviewed by telephone about exposures to physical activity in the case period (8 hours before the bleed) and 2 control periods (an 8 hour period at the same time on the day preceding the bleed and an 8 hour period two days preceding the bleed). Conditional logistic regression will be used to estimate the risk of participating in vigorous physical activity from measures of exposure to physical activity in the case and control periods. DISCUSSION: This case-control study will provide estimates of the risk of participation in vigorous physical activity in children with haemophilia

The Social context of motorcycle riding and the key determinants influencing rider behavior: A qualitative investigation

Objective: Given the increasing popularity of motorcycle riding and heightened risk of injury or death associated with being a rider, this study explored rider behaviour as a determinant of rider safety and, in particular, key beliefs and motivations which influence such behaviour. To enhance the effectiveness of future education and training interventions, it is important to understand riders’ own views about what influences how they ride. Specifically, this study sought to identify key determinants of riders’ behaviour in relation to the social context of riding including social and identity-related influences relating to the group (group norms and group identity) as well as the self (moral/personal norm and self-identity). ----- ----- Method: Qualitative research was undertaken via group discussions with motorcycle riders (n = 41). Results: The findings revealed that those in the group with which one rides represent an important source of social influence. Also, the motorcyclist (group) identity was associated with a range of beliefs, expectations, and behaviours considered to be normative. Exploration of the construct of personal norm revealed that riders were most cognizant of the “wrong things to do” when riding; among those issues raised was the importance of protective clothing (albeit for the protection of others and, in particular, pillion passengers). Finally, self-identity as a motorcyclist appeared to be important to a rider’s self-concept and was likely to influence their on-road behaviour. ----- ----- Conclusion: Overall, the insight provided by the current study may facilitate the development of interventions including rider training as well as public education and mass media messages. The findings suggest that these interventions should incorporate factors associated with the social nature of riding in order to best align it with some of the key beliefs and motivations underpinning riders’ on-road behaviours

Spatially valid proprioceptive cues improve the detection of a visual stimulus

Vision and proprioception are the main sensory modalities that convey hand location and direction of movement. Fusion of these sensory signals into a single robust percept is now well documented. However, it is not known whether these modalities also interact in the spatial allocation of attention, which has been demonstrated for other modality pairings. The aim of this study was to test whether proprioceptive signals can spatially cue a visual target to improve its detection. Participants were instructed to use a planar manipulandum in a forward reaching action and determine during this movement whether a near-threshold visual target appeared at either of two lateral positions. The target presentation was followed by a masking stimulus, which made its possible location unambiguous, but not its presence. Proprioceptive cues were given by applying a brief lateral force to the participant’s arm, either in the same direction (validly cued) or in the opposite direction (invalidly cued) to the on-screen location of the mask. The d′ detection rate of the target increased when the direction of proprioceptive stimulus was compatible with the location of the visual target compared to when it was incompatible. These results suggest that proprioception influences the allocation of attention in visual spac

A survey of opinion: When to start oral anticoagulants in patients with acute ischaemic stroke and atrial fibrillation?

Introduction: There is uncertainty regarding the optimal timing for initiation of oral anticoagulant treatment in patients with recent ischaemic stroke and atrial fibrillation. We surveyed the current UK practice and assessed clinician’s opinions of when to use oral anticoagulant in recent stroke patients with atrial fibrillation. Patients and methods: An online survey was sent to stroke physicians within the United Kingdom via their national societies. Results: One hundred and twenty-one clinicians responded to the survey. Ninety-five percent of responders agreed that there was uncertainty regarding timing of oral anticoagulant initiation after atrial fibrillation-related ischaemic stroke. Thirty-six percent of responders followed the ‘1–3–6–12’ European Society of Cardiology guidelines recommendation. Uncertainty was greater in cases of moderate stroke than in cases of transient ischaemic attack (TIA), mild or severe stroke. Eighty-eight percent of responders would be willing to participate in a clinical trial of early versus later initiation of oral anticoagulant after stroke. Direct-acting oral anticoagulants were the preferred oral anticoagulant of choice. Discussion and Conclusion: There is a lack of consensus amongst stroke physicians for when to initiate oral anticoagulant to prevent recurrence in stroke patients with atrial fibrillation. There is little uncertainty regarding TIA. A clinical trial assessing the use of early versus later initiation of direct-acting oral anticoagulant in patients with recent ischaemic stroke and atrial fibrillation would be beneficial

Structural efficiency of percolation landscapes in flow networks

Complex networks characterized by global transport processes rely on the presence of directed paths from input to output nodes and edges, which organize in characteristic linked components. The analysis of such network-spanning structures in the framework of percolation theory, and in particular the key role of edge interfaces bridging the communication between core and periphery, allow us to shed light on the structural properties of real and theoretical flow networks, and to define criteria and quantities to characterize their efficiency at the interplay between structure and functionality. In particular, it is possible to assess that an optimal flow network should look like a "hairy ball", so to minimize bottleneck effects and the sensitivity to failures. Moreover, the thorough analysis of two real networks, the Internet customer-provider set of relationships at the autonomous system level and the nervous system of the worm Caenorhabditis elegans --that have been shaped by very different dynamics and in very different time-scales--, reveals that whereas biological evolution has selected a structure close to the optimal layout, market competition does not necessarily tend toward the most customer efficient architecture.Comment: 8 pages, 5 figure