Search

BackgroundPrenatal vitamin D deficiency is a common health concern among immigrants. No previous studies have examined the associations between prenatal vitamin D levels and developmental disorders of language, scholastic skills, and coordination in an immigrant sample.MethodsThe sample included 542 immigrant mothers of cases with language, scholastic, coordination or mixed developmental disorders, 443 immigrant mothers of controls without these disorders and 542 Finnish mothers of controls. Maternal vitamin D was measured in serum samples collected during early pregnancy and stored in a national biobank.ResultsThe mean vitamin D levels during pregnancy were 25.0 (SD 14.4) nmol/L for immigrant mothers of cases, 25.4 (SD 15.5) for immigrant mothers of controls and 42.3 (SD 19.1) for Finnish mothers of controls. Low maternal vitamin D levels during pregnancy were not associated with the selected developmental disorders in offspring when immigrant mothers of cases were compared to immigrant mothers of controls (adjusted OR for continuous log-transformed vitamin D: 1.01, 95% CI 0.75-1.36, p = 0.96). When immigrant mothers of cases were compared to Finnish mothers of controls, the adjusted OR for continuous vitamin D was 18.94 (95% CI 11.47-31.25), p ConclusionsPrenatal vitamin D levels were low, and similar, among immigrant mothers of cases with selected developmental disorders and unaffected controls. This indicates that vitamin D unlikely mediates previously observed associations between maternal immigrant status and the selected developmental disorders in offspring. The proportion of immigrant mothers with severe vitamin D deficiency was very high, which underlines the importance of prenatal counselling and overall public health efforts to improve immigrant health.

Abstract Background The CyberKnife Xsight lung-tracking system (XLTS) provides an alternative to fiducial-based target-tracking systems (FTTS) for non-small-cell lung cancer (NSCLC) patients without invasive fiducial insertion procedures. This study provides a method for 3D independent dosimetric verification of the accuracy of the FTTS compared to the XLTS without relying on log-files generated by the CyberKnife system. Methods A respiratory motion trace was taken from a 4D-CT of a real lung cancer patient and applied to a modified QUASAR™ respiratory motion phantom. A novel approach to 3D dosimetry was developed using Gafchromic EBT3 film, allowing the 3D dose distribution delivered to the moving phantom to be reconstructed. Treatments were planned using the recommended margins for one and three fiducial markers and XLTS 2-view, 1-view and 0-view target-tracking modalities. The dose delivery accuracy was analysed by comparing the reconstructed dose distributions to the planned dose distributions using gamma index analysis. Results For the 3%/2 mm gamma criterion, gamma passing rates up to 99.37% were observed for the static deliveries. The 3-fiducial and 1-fiducial-based deliveries exhibited passing rates of 93.74% and 97.82%, respectively, in the absence of target rotation. When target rotation was considered, the passing rate for 1-fiducial tracking degraded to 91.24%. The passing rates observed for XLTS 2-view, 1-view and 0-view target-tracking were 92.78%, 96.22% and 76.08%, respectively. Conclusions Except for the XLTS 0-view, the dosimetric accuracy of the XLTS was comparable to the FTTS under equivalent treatment conditions. This study gives us further confidence in the CyberKnife XLTS and FTTS systems.

Rapid and accurate mRNA translation requires efficient codon-dependent delivery of the correct aminoacyl-tRNA (aa-tRNA) to the ribosomal A site. In mammals, this fidelity-determining reaction is facilitated by the GTPase elongation factor-1 alpha (eEF1A), which escorts aa-tRNA as an eEF1A(GTP)-aa-tRNA ternary complex into the ribosome. The structurally unrelated cyclic peptides didemnin B and ternatin-4 bind to the eEF1A(GTP)-aa-tRNA ternary complex and inhibit translation but have different effects on protein synthesis in vitro and in vivo. Here, we employ single-molecule fluorescence imaging and cryogenic electron microscopy to determine how these natural products inhibit translational elongation on mammalian ribosomes. By binding to a common site on eEF1A, didemnin B and ternatin-4 trap eEF1A in an intermediate state of aa-tRNA selection, preventing eEF1A release and aa-tRNA accommodation on the ribosome. We also show that didemnin B and ternatin-4 exhibit distinct effects on the dynamics of aa-tRNA selection that inform on observed disparities in their inhibition efficacies and physiological impacts. These integrated findings underscore the value of dynamics measurements in assessing the mechanism of small-molecule inhibition and highlight potential of single-molecule methods to reveal how distinct natural products differentially impact the human translation mechanism.

Cortical microtubules (MTs) in Apicomplexa are specialized MTs involved in maintaining the parasite’s shape and are, as such, unusually stable. Here, cryo-EM analysis of cortical MTs from Toxoplasma gondii offers insight into the mechanism of their stabilization by three bona fide microtubule inner proteins.

Axonemal dyneins are tethered to doublet microtubules inside cilia to drive ciliary beating but the mechanisms regulating their localization and function are poorly understood. Here authors report a cryo-EM reconstruction of a three-headed axonemal dynein natively bound to doublet microtubules isolated from cilia which provides a framework to understand the roles of individual subunits.

Variability is inherent to cyber systems. Here, we introduce ideas from stochastic population biology to describe the properties of two broad kinds of cyber systems. First, we assume that each of N0 components can be in only one of two states: functional or nonfunctional. We model this situation as a Markov process that describes the transitions between functional and nonfunctional states. We derive an equation for the probability that an individual cyber component is functional and use stochastic simulation to develop intuition about the dynamics of individual cyber components. We introduce a metric of performance of the system of N0 components that depends on the numbers of functional and nonfunctional components. We numerically solve the forward Kolmogorov (or Fokker-Planck) equation for the number of functional components at time t, given the initial number of functional components. We derive a Gaussian approximation for the solution of the forward equation so that the properties of the system with many components can be determined from the transition probabilities of an individual component, allowing scaling to very large systems. Second, we consider the situation in which the operating system (OS) of cyber components is updated in time. We motivate the question of OS in use as a function of the most recent OS release with data from a network of desktop computers. We begin the analysis by specifying a temporal schedule of OS updates and the probability of transitioning from the current OS to a more recent one. We use a stochastic simulation to capture the pattern of the motivating data, and derive the forward equation for the OS of an individual computer at any time. We then include compromise of OSs to compute that a cyber component has an unexploited OS at any time. We conclude that an interdisciplinary approach to the variability of cyber systems can shed new light on the properties of those systems and offers new and exciting ways to understand them.

This paper considers intersectional social identities of race, class, and gender through an examination of women in baseball from the late 1800s to today. At its core, the article revolves around a fictional character named Lizzie Bright Griffin from Gary Schmidt’s (2004) adolescent novel Lizzie Bright and the Buckminster Boy while interweaving dynamic historic and contemporary baseball figures, including Mamie “Peanut” Johnson and Mo’ne Davis, ultimately inviting readers to consider what it would mean for a new generation of young women to overcome racial prejudice, class differences, and gender discrimination to find opportunity and success in the game of baseball.

Bardet-Biedl syndrome (BBS) is a currently incurable ciliopathy caused by the failure to correctly establish or maintain cilia-dependent signaling pathways. Eight proteins associated with BBS assemble into the BBSome, a key regulator of the ciliary membrane proteome. We report the electron cryomicroscopy (cryo-EM) structures of the native bovine BBSome in inactive and active states at 3.1 and 3.5 Å resolution, respectively. In the active state, the BBSome is bound to an Arf-family GTPase (ARL6/BBS3) that recruits the BBSome to ciliary membranes. ARL6 recognizes a composite binding site formed by BBS1 and BBS7 that is occluded in the inactive state. Activation requires an unexpected swiveling of the β-propeller domain of BBS1, the subunit most frequently implicated in substrate recognition, which widens a central cavity of the BBSome. Structural mapping of disease-causing mutations suggests that pathogenesis results from folding defects and the disruption of autoinhibition and activation.

Solution of near-field underwater explosion (UNDEX) problems frequently require the modeling of two-way coupled fluid-structure interaction (FSI). This paper describes the addition of an embedded boundary method to an UNDEX modeling framework for multiphase, compressible and inviscid fluid using the combined algorithms of Runge-Kutta, discontinuous-Galerkin, level-set and direct ghost-fluid methods. A computational fluid dynamics (CFD) solver based on these algorithms has been developed as described in previous work. A fluid-structure coupling approach was required to perform FSI simulation interfacing with an external structural mechanics solver. Large structural deformation and possible rupture and cracking characterize the FSI phenomenon in an UNDEX, so the embedded boundary method (EBM) is more appealing for this application in comparison to dynamic mesh methods such as the arbitrary Lagrangian-Eulerian (ALE) method to enable the fluid-structure coupling algorithm in the fluid. Its limitation requiring a closed interface that is fully submerged in the fluid domain is relaxed by an adjustment described in this paper so that its applicability is extended. Two methods of implementing the fluid-structure wall boundary condition are also compared. The first solves a local 1D fluid-structure Riemann problem at each intersecting point between the wetted elements and fluid mesh. In this method, iterations are required when the Tait equation of state is utilized. A second method that does not require the Riemann solution and iterations is also implemented and the results are compared.

This work describes the development of a hybrid framework of Runge–Kutta (RK), discontinuous Galerkin (DG), level set (LS) and direct ghost fluid (DGFM) methods for the simulation of near-field and early-time underwater explosions (UNDEX) in early-stage ship design. UNDEX problems provide a series of challenging issues to be solved. The multi-dimensional, multi-phase, compressible and inviscid fluid-governing equations must be solved numerically. The shock front in the solution field must be captured accurately while maintaining the total variation diminishing (TVD) properties. The interface between the explosive gas and water must be tracked without letting the numerical diffusion across the material interface lead to spurious pressure oscillations and thus the failure of the simulation. The non-reflecting boundary condition (NRBC) must effectively absorb the wave and prevent it from reflecting back into the fluid. Furthermore, the CFD solver must have the capability of dealing with fluid–structure interactions (FSI) where both the fluid and structural domains respond with significant deformation. These issues necessitate a hybrid model. In-house CFD solvers (UNDEXVT) are developed to test the applicability of this framework. In this development, code verification and validation are performed. Different methods of implementing non-reflecting boundary conditions (NRBCs) are compared. The simulation results of single and multi-dimensional cases that possess near-field and early-time UNDEX features—such as shock and rarefaction waves in the fluid, the explosion bubble, and the variation of its radius over time—are presented. Continuing research on two-way coupled FSI with large deformation is introduced, and together with a more complete description of the direct ghost fluid method (DGFM) in this framework will be described in subsequent papers.

The prediction of surface ship response to a far-field underwater explosion (UNDEX) requires the simulation of shock wave propagation in the fluid, cavitation, fluid-structure interaction, and structural response. Effective approaches to model the fluid include cavitating acoustic finite element (CAFE) and cavitating acoustic spectral element (CASE) methods. Although the spectral element method offers the potential for greater accuracy at lower computational cost, it also generates more spurious oscillations around discontinuities which are difficult to avoid in shock-related problems. Thus, the advantage of CASE remains unproven. In this paper, we present a 3D-partitioned FSI framework and investigate the application of CAFE and CASE to a surface ship early-time far-field UNDEX problem to determine which method has the best computational efficiency for this problem. We also associate the accuracy of the structural response with the modeling of cavitation distribution. A further contribution of this work is the examination of different nonmatching mesh information exchange schemes to demonstrate how they affect the structural response and improve the CAFE/CASE methodologies.

The cellular levels and activities of ribosomes directly regulate gene expression during numerous physiological processes. The mechanisms that globally repress translation are incompletely understood. Here, we use electron cryomicroscopy to analyze inactive ribosomes isolated from mammalian reticulocytes, the penultimate stage of red blood cell differentiation. We identify two types of ribosomes that are translationally repressed by protein interactions. The first comprises ribosomes sequestered with elongation factor 2 (eEF2) by SERPINE mRNA binding protein 1 (SERBP1) occupying the ribosomal mRNA entrance channel. The second type are translationally repressed by a novel ribosome-binding protein, interferon-related developmental regulator 2 (IFRD2), which spans the P and E sites and inserts a C-terminal helix into the mRNA exit channel to preclude translation. IFRD2 binds ribosomes with a tRNA occupying a noncanonical binding site, the ‘Z site’, on the ribosome. These structures provide functional insights into how ribosomal interactions may suppress translation to regulate gene expression.

Background. The extent of coronary artery calcium (CAC) improves cardiovascular disease (CVD) risk prediction. The association between common dyslipidemias (combined hyperlipidemia, simple hypercholesterolemia, metabolic Syndrome (MetS), isolated low high-density lipoprotein cholesterol, and isolated hypertriglyceridemia) compared with normolipidemia and the risk of multivessel CAC is underinvestigated. Objectives. To determine whether there is an association between common dyslipidemias compared with normolipidemia, and the extent of coronary artery involvement among MESA participants who were free of clinical cardiovascular disease at baseline. Methods. In a cross-sectional analysis, 4,917 MESA participants were classified into six groups defined by specific LDL-c, HDL-c, or triglyceride cutoff points. Multivessel CAC was defined as involvement of at least 2 coronary arteries. Multivariate Poisson regression analysis evaluated the association of each group with multivessel CAC after adjusting for CVD risk factors. Results. Unadjusted analysis showed that all groups except hypertriglyceridemia had statistically significant prevalence ratios of having multivessel CAC as compared to the normolipidemia group. The same groups maintained statistical significance prevalence ratios with multivariate analysis adjusting for other risk factors including Agatston CAC score [combined hyperlipidemia 1.41 (1.06–1.87), hypercholesterolemia 1.55 (1.26–1.92), MetS 1.28 (1.09–1.51), and low HDL-c 1.20 (1.02–1.40)]. Conclusion. Combined hyperlipidemia, simple hypercholesterolemia, MetS, and low HDL-c were associated with multivessel coronary artery disease independent of CVD risk factors and CAC score. These findings may lay the groundwork for further analysis of the underlying mechanisms in the observed relationship, as well as for the development of clinical strategies for primary prevention.

Cooperative binding pervades Nature. This review discusses the use of isothermal titration calorimetry (ITC) in the identification and characterisation of cooperativity in biological interactions. ITC has broad scope in the analysis of cooperativity as it determines binding stiochiometries, affinities and thermodynamic parameters, including enthalpy and entropy in a single experiment. Examples from the literature are used to demonstrate the applicability of ITC in the characterisation of cooperative systems.

Malaria inflicts an enormous burden on global human health. The emergence of parasite resistance to front-line drugs has prompted a renewed focus on the repositioning of clinically approved drugs as potential anti-malarial therapies. Antibiotics that inhibit protein translation are promising candidates for repositioning. We have solved the cryo-EM structure of the cytoplasmic ribosome from the human malaria parasite, Plasmodium falciparum, in complex with emetine at 3.2 Å resolution. Emetine is an anti-protozoan drug used in the treatment of ameobiasis that also displays potent anti-malarial activity. Emetine interacts with the E-site of the ribosomal small subunit and shares a similar binding site with the antibiotic pactamycin, thereby delivering its therapeutic effect by blocking mRNA/tRNA translocation. As the first cryo-EM structure that visualizes an antibiotic bound to any ribosome at atomic resolution, this establishes cryo-EM as a powerful tool for screening and guiding the design of drugs that target parasite translation machinery.