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CD40L plays a major role in immune response and is a major therapeutic target for inflammation. Integrin α5β1 and CD40 simultaneously bind to CD40L. It is unclear if α5β1 and CD40 work together in CD40/CD40L signaling or how α5β1 binds to CD40L. In this article, we describe that the integrin-binding site of human CD40L is predicted to be located in the trimeric interface by docking simulation. Mutations in the predicted integrin-binding site markedly reduced the binding of α5β1 to CD40L. Several CD40L mutants defective in integrin binding were defective in NF-κB activation and B cell activation and suppressed CD40L signaling induced by wild-type CD40L; however, they still bound to CD40. These findings suggest that integrin α5β1 binds to monomeric CD40L through the binding site in the trimeric interface of CD40L, and this plays a critical role in CD40/CD40L signaling. Integrin αvβ3, a widely distributed vascular integrin, bound to CD40L in a KGD-independent manner, suggesting that αvβ3 is a new CD40L receptor. Several missense mutations in CD40L that induce immunodeficiency with hyper-IgM syndrome type 1 (HIGM1) are clustered in the integrin-binding site of the trimeric interface. These HIGM1 CD40L mutants were defective in binding to α5β1 and αvβ3 (but not to CD40), suggesting that the defect in integrin binding may be a causal factor of HIGM1. These findings suggest that α5β1 and αvβ3 bind to the overlapping binding site in the trimeric interface of monomeric CD40L and generate integrin-CD40L-CD40 ternary complex. CD40L mutants defective in integrins have potential as antagonists of CD40/CD40L signaling. [ABSTRACT FROM AUTHOR]

Objective: Clinicians' perceptions of CBT-I Coach, a patient-facing mobile app for cognitive-behavioral therapy for insomnia (CBT-I), are critical to its adoption and integration into practice. Diffusion of innovations theory emphasizes the influence of perceptions, including the relative advantage to current practice, the compatibility to clinicians' needs, the complexity, the innovation's trialability, and observability. This study intended to evaluate the use and perceptions of CBT-I Coach among Veterans Affairs (VA)-trained CBT-I clinicians. Participants and Methods: Clinicians (N = 108) were surveyed about their use, feedback, and perceptions of CBT-I Coach a year after the app became available. Results: Overall perceptions of CBT-I Coach were favorable. Fifty percent of clinicians reported using CBT-I Coach, with 98% intending to continue use. The app was perceived to increase sleep diary completion and homework compliance. Clinicians viewed the app as providing accessibility to helpful tools and improving patient engagement. Of those not using the app, 83% endorsed intention to use it. Reasons for nonuse were lack of patient access to smart phones, not being aware of the app, not having time to learn it, and inability to directly access app data. Those who reported using CBT-I Coach had more favorable perceptions across all constructs (p <.01 – p <.001), except relative advantage, compared to nonusers. Users perceived it as less complex and more compatible with their practice than nonusers. Conclusions: Continued efforts are needed to increase adoption and enhance use of CBT-I Coach, as well as study if reported benefits can be evidenced more directly. [ABSTRACT FROM AUTHOR]

Insomnia affects up to 22% of the U.S. adult population. The use of mobile health applications (mHealth apps) has been posited as one way to increase access to evidence-based interventions for insomnia, such as cognitive behavioral therapy for insomnia (CBT-I). The purpose of the current study was to summarize the availability of mHealth apps that focus on providing users with the behavioral and/or cognitive skills to manage insomnia, assess their adherence to evidence-based principles, and examine their usability. The terms "insomnia," "insomnia treatment," and "sleep treatment" were used to search the Apple iTunes and Google Play stores in November 2016. Social network query within the authors' professional networks was also conducted. Apps that met inclusion criteria for the study were downloaded and reviewed by the research team for their general characteristics,inclusion of CBT-I skills, strategies, and principles,and aesthetics and usability. Of the 357 apps initially found, 12 met criteria for further review. Overall, the apps were moderately adherent to CBT-I principles, with a mean app score of 1.44 out of 3.00, and moderately usable, with a mean usability score of 3.54 out of 5.00. Few apps currently exist that utilize evidence-based principles to help users practice the behavioral and cognitive skills shown to manage insomnia. Thus, there are exciting opportunities for clinicians, researchers, and mHealth experts to develop effective apps that can help ease the public health burden of insomnia. [ABSTRACT FROM AUTHOR]

Motivation Emergent biological dynamics derive from the evolution of lower-level spatial and temporal processes. A long-standing challenge for scientists and engineers is identifying simple low-level rules that give rise to complex higher-level dynamics. High-resolution biological data acquisition enables this identification and has evolved at a rapid pace for both experimental and computational approaches. Simultaneously harnessing the resolution and managing the expense of emerging technologies—e.g. live cell imaging, scRNAseq, agent-based models—requires a deeper understanding of how spatial and temporal axes impact biological systems. Effective emulation is a promising solution to manage the expense of increasingly complex high-resolution computational models. In this research, we focus on the emulation of a tumor microenvironment agent-based model to examine the relationship between spatial and temporal environment features, and emergent tumor properties. Results Despite significant feature engineering, we find limited predictive capacity of tumor properties from initial system representations. However, incorporating temporal information derived from intermediate simulation states dramatically improves the predictive performance of machine learning models. We train a deep-learning emulator on intermediate simulation states and observe promising enhancements over emulators trained solely on initial conditions. Our results underscore the importance of incorporating temporal information in the evaluation of spatio-temporal emergent behavior. Nevertheless, the emulators exhibit inconsistent performance, suggesting that the underlying model characterizes unique cell populations dynamics that are not easily replaced. Availability and implementation All source codes for the agent-based model, emulation, and analyses are publicly available at the corresponding DOIs: 10.5281/zenodo.10622155, 10.5281/zenodo.10611675, 10.5281/zenodo.10621244, respectively. [ABSTRACT FROM AUTHOR]

There is a strong link between integrins and interleukin-1β (IL-1β), but the specifics of the role of integrins in IL-1β signaling are unclear. We describe that IL-1β specifically bound to integrins αvβ3 and α5β1. The E128K mutation in the IL1R-binding site enhanced integrin binding. We studied whether direct integrin binding is involved in IL-1β signaling. We compared sequences of IL-1β and IL-1 receptor antagonist (IL1RN), which is an IL-1β homologue but has no agonistic activity. Several surface-exposed Lys residues are present in IL-1β, but not in IL1RN. A disulfide linkage is present in IL1RN, but is not in IL-1β because of natural C117F mutation. Substitution of the Lys residues to Glu markedly reduced integrin binding of E128K IL-1β, suggesting that the Lys residues mediate integrin binding. The Lys mutations reduced, but did not completely abrogate, agonistic action of IL-1β.Westudied whether the disulfide linkage plays a role in agonistic action of IL-1β. Reintroduction of the disulfide linkage by the F117C mutation did not affect agonistic activity of WT IL-1β, but effectively reduced the remaining agonistic activity of the Lys mutants. Also, deletion of the disulfide linkage in IL1RN by the C116F mutation did not make it agonistic. We propose that the direct binding to IL-1β to integrins is primarily important for agonistic IL-1β signaling, and that the disulfide linkage indirectly affects signaling by blocking conformational changes induced by weak integrin binding to the Lys mutants. The integrin-IL-1β interaction is a potential target for drug discovery. [ABSTRACT FROM AUTHOR]

The structural testing and finite element (FE) analysis described in this paper were part of a major research project undertaken at Imperial College London to investigate the deformation of bolted segmental grey cast iron (GCI) tunnel linings. A key aim was to quantify how joints influence the behaviour of the lining, through a three-path approach comprising physical experiments, finite element modelling, and field instrumentation. The laboratory results have been used to assess the validity of the tunnel assessment methods used by industry. This study examined joint articulation under the serviceability limit state in the absence of hoop force focussing on factors such as applied bolt preload, the loading direction and the freedom of the circumferential flange to deflect. Two half-scale GCI lining segments were bolted together at the longitudinal flanges to form a bolted arch in a similar fashion to the tests performed by Thomas (1977). Modern instrumentation was implemented to gain detailed measurements quantifying changes in global displacements of the two segments, bolt forces and joint opening under applied loading. For the first time, the physical experiments were conducted contemporaneously with the development of a three-dimensional FE model of the joint. The experimental data and the results from the FE analysis indicate a reduction in joint stiffness as the joint articulates under applied load. It is shown that the presence of a joint has far greater influence on the behaviour of the ‘arch’ than the level of preload applied to the bolts in the joint. The FE analysis allowed the deformation behaviour of the joint under positive and negative bending to be investigated: its response under the two modes differs significantly. [ABSTRACT FROM AUTHOR]

Background: Vasopressin is one of the vasopressors used to augment blood pressure in subarachnoid hemorrhage (SAH) patients with clinically significant vasospasm. The purpose of the present study was to determine whether the administration of vasopressin to a population of SAH patients was an independent predictor of developing hyponatremia.Methods: A retrospective review on the health records of 106 patients admitted to the University of Alberta Hospital Neurosciences ICU, Edmonton AB, Canada, with SAH from June 2013 to December 2015 was conducted. Serum sodium changes in patients receiving vasoactive drugs were compared. In addition, independent predictors for hyponatremia (Na < 135 mmol/L) were determined using a multivariate logistic regression model.Results: Patients treated with vasopressin in addition to other vasoactive drugs had significantly higher sodium changes compared to those treated with other vasoactive drugs (-4.7 ± 6 vs -0.1 ± 2.4 mmol/L, respectively, p value 0.001). Hyponatremia occurred in 14 patients (70 %) treated with vasopressin, 10 patients (44 %) treated with vasoactive drugs other than vasopressin (p value 0.081), and 24 patients (38 %) who did not receive any vasoactive drug (p value 0.013). In multivariate logistic regression analysis, when adjusting for disease severity, age, sex, aneurysm location, and treatment, vasopressin was associated with hyponatremia (OR 3.58, 95 % CI, 1.02-12.5, p value 0.046).Conclusions: The results of the present study suggest that hyponatremia may be more common in SAH patients treated with exogenous vasopressin compared to those who did not receive it. Serum sodium should be monitored closely when vasopressin is being used in the SAH population. Further studies are needed to confirm the effect of exogenous vasopressin on serum sodium levels in SAH populations. [ABSTRACT FROM AUTHOR]

Motivation: High throughput screening by fluorescence activated cell sorting (FACS) is a common task in protein engineering and directed evolution. It can also be a rate-limiting step if high false positive or negative rates necessitate multiple rounds of enrichment. Current FACS software requires the user to define sorting gates by intuition and is practically limited to two dimensions. In cases when multiple rounds of enrichment are required, the software cannot forecast the enrichment effort required. Results: We have developed CellSort, a support vector machine (SVM) algorithm that identifies optimal sorting gates based on machine learning using positive and negative control populations. CellSort can take advantage of more than two dimensions to enhance the ability to distinguish between populations. We also present a Bayesian approach to predict the number of sorting rounds required to enrich a population from a given library size. This Bayesian approach allowed us to determine strategies for biasing the sorting gates in order to reduce the required number of enrichment rounds. This algorithm should be generally useful for improve sorting outcomes and reducing effort when using FACS. [ABSTRACT FROM AUTHOR]

Objective The current study examines changes in coping among 165 adults meeting DSM-IV criteria for co-morbid posttraumatic stress disorder (PTSD) and alcohol dependence (AD). Method Participants were randomized to receive naltrexone or placebo, with or without prolonged exposure (PE). All participants received supportive counseling focused on alcohol use (BRENDA). Assessments of coping, PTSD, and AD were conducted at pre-treatment, mid-treatment, post-treatment, 3-month follow-up, and 6-month follow-up. Results Participants exhibited significant decreases in both avoidant coping and adaptive coping from pre-treatment to 6-month follow-up across all groups. Participants who received PE showed faster decreases in avoidant coping during this period than participants who did not receive PE. PTSD symptom reduction was associated with changes in both avoidant and adaptive coping across groups. Improvement in PTSD symptoms was related to a faster rate of reduction in avoidant coping in the PE groups compared to those receiving BRENDA alone. Conclusions The current results suggest that concurrent treatment for co-morbid PTSD-AD decreases avoidant and adaptive coping, and participants who show greater reductions in PTSD symptoms also show greater changes in coping style. Consistent with theorized mechanisms of change in PE, the addition of PE to supportive counseling for AD was associated with a greater reduction of avoidant coping than supportive counseling alone. [ABSTRACT FROM AUTHOR]

The need for the research reported in this paper was driven by the Crossrail project in London for which new tunnels were constructed close to numerous existing operational tunnels of the London Underground (LU) network. This research is based on experimental work conducted on half-scale grey cast iron (GCI) tunnel lining segments with chemical composition similar to the Victorian age GCI segments in the LU network. This paper discusses the deformation behaviour of the bolted segmental lining under the influence of factors such as overburden pressure, bolt preload and presence of grommets at small distortions. The measured behaviour of the segmental lining is compared against the calculated response of a continuous lining based on the assumption of elasticity. The industry practice for tunnel lining assessment is to calculate the induced bending moment in the tunnel lining using an elastic continuum model, while adopting a reduced lining stiffness to take into account the presence of the joints. Case studies have recorded that both loosening and tightening of lining bolts have been used as mitigation measures to reduce the impact of new tunnel excavations on existing GCI tunnels. The experimental work on the half-scale GCI lining has shown that a bolted segmental lining behaves as a continuous ring under small distortions imposed when subjected to hoop forces relevant to the depth of burial of LU tunnels. In the presence of hoop force, joint opening was minimal and the magnitude of preload in the bolts had little impact on the behaviour of the lining. It is therefore concluded that disturbance of the bolts in existing tunnels is not recommended as a mitigation measure as in addition to being ineffective it is both time consuming and introduces the risk of damaging the tunnel lining flanges. [ABSTRACT FROM AUTHOR]