Mother and Adolescent Reports of Associations Between Child Behavior Problems and Mother-Child Relationship Qualities: Separating Shared Variance from Individual Variance

This study contrasts results from different correlational methods for examining links between mother and child (N = 72 dyads) reports of early adolescent (M = 11.5 years) behavior problems and relationship negativity and support. Simple (Pearson) correlations revealed a consistent pattern of statistically significant associations, regardless of whether scores came from the same reporter or from different reporters. When correlations between behavior problems and relationship quality differed, within-reporter correlations were always greater in magnitude than between-reporter correlations. Dyadic (common fate) analyses designed for interdependent data decomposed within-reporter correlations into variance shared across reporters (dyadic correlations) and variance unique to specific reporters (individual correlations). Dyadic correlations were responsible for most associations between adolescent behavior problems and relationship negativity; after partitioning variance shared across reporters, no individual correlations emerged as statistically significant. In contrast, adolescent behavior problems were linked to relationship support via both shared variance and variance unique to maternal perceptions. Dyadic analyses provide a parsimonious alternative to multiple contrasts in instances when identical measures have been collected from multiple reporters. Findings from these analyses indicate that same-reporter variance bias should not be assumed in the absence of dyadic statistical analyses

Potentiation of thrombus instability: a contributory mechanism to the effectiveness of antithrombotic medications

© The Author(s) 2018The stability of an arterial thrombus, determined by its structure and ability to resist endogenous fibrinolysis, is a major determinant of the extent of infarction that results from coronary or cerebrovascular thrombosis. There is ample evidence from both laboratory and clinical studies to suggest that in addition to inhibiting platelet aggregation, antithrombotic medications have shear-dependent effects, potentiating thrombus fragility and/or enhancing endogenous fibrinolysis. Such shear-dependent effects, potentiating the fragility of the growing thrombus and/or enhancing endogenous thrombolytic activity, likely contribute to the clinical effectiveness of such medications. It is not clear how much these effects relate to the measured inhibition of platelet aggregation in response to specific agonists. These effects are observable only with techniques that subject the growing thrombus to arterial flow and shear conditions. The effects of antithrombotic medications on thrombus stability and ways of assessing this are reviewed herein, and it is proposed that thrombus stability could become a new target for pharmacological intervention.Peer reviewedFinal Published versio

Astrocytic Ion Dynamics: Implications for Potassium Buffering and Liquid Flow

We review modeling of astrocyte ion dynamics with a specific focus on the implications of so-called spatial potassium buffering, where excess potassium in the extracellular space (ECS) is transported away to prevent pathological neural spiking. The recently introduced Kirchoff-Nernst-Planck (KNP) scheme for modeling ion dynamics in astrocytes (and brain tissue in general) is outlined and used to study such spatial buffering. We next describe how the ion dynamics of astrocytes may regulate microscopic liquid flow by osmotic effects and how such microscopic flow can be linked to whole-brain macroscopic flow. We thus include the key elements in a putative multiscale theory with astrocytes linking neural activity on a microscopic scale to macroscopic fluid flow.Comment: 27 pages, 7 figure

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

The attachments of the anteromedial and posterolateral fibre bundles of the anterior cruciate ligament. Part 2: femoral attachment.

Accepted versio

Effect of health information technology interventions on lipid management in clinical practice: A systematic review of randomized controlled trials

BACKGROUND: Large gaps in lipid treatment and medication adherence persist in high-risk outpatients in the United States. Health information technology (HIT) is being applied to close quality gaps in chronic illness care, but its utility for lipid management has not been widely studied. OBJECTIVE: To perform a qualitative review of the impact of HIT interventions on lipid management processes of care (screening or testing; drug initiation, titration or adherence; or referrals) or clinical outcomes (percent at low density lipoprotein cholesterol goal; absolute lipid levels; absolute risk scores; or cardiac hospitalizations) in outpatients with coronary heart disease or at increased risk. METHODS: PubMed and Google Scholar databases were searched using Medical Subject Headings related to clinical informatics and cholesterol or lipid management. English language articles that described a randomized controlled design, tested at least one HIT tool in high risk outpatients, and reported at least 1 lipid management process measure or clinical outcome, were included. RESULTS: Thirty-four studies that enrolled 87,874 persons were identified. Study ratings, outcomes, and magnitude of effects varied widely. Twenty-three trials reported a significant positive effect from a HIT tool on lipid management, but only 14 showed evidence that HIT interventions improve clinical outcomes. There was mixed evidence that provider-level computerized decision support improves outcomes. There was more evidence in support of patient-level tools that provide connectivity to the healthcare system, as well as system-level interventions that involve database monitoring and outreach by centralized care teams. CONCLUSION: Randomized controlled trials show wide variability in the effects of HIT on lipid management outcomes. Evidence suggests that multilevel HIT approaches that target not only providers but include patients and systems approaches will be needed to improve lipid treatment, adherence and quality

PepDist: A New Framework for Protein-Peptide Binding Prediction based on Learning Peptide Distance Functions

BACKGROUND: Many different aspects of cellular signalling, trafficking and targeting mechanisms are mediated by interactions between proteins and peptides. Representative examples are MHC-peptide complexes in the immune system. Developing computational methods for protein-peptide binding prediction is therefore an important task with applications to vaccine and drug design. METHODS: Previous learning approaches address the binding prediction problem using traditional margin based binary classifiers. In this paper we propose PepDist: a novel approach for predicting binding affinity. Our approach is based on learning peptide-peptide distance functions. Moreover, we suggest to learn a single peptide-peptide distance function over an entire family of proteins (e.g. MHC class I). This distance function can be used to compute the affinity of a novel peptide to any of the proteins in the given family. In order to learn these peptide-peptide distance functions, we formalize the problem as a semi-supervised learning problem with partial information in the form of equivalence constraints. Specifically, we propose to use DistBoost [1,2], which is a semi-supervised distance learning algorithm. RESULTS: We compare our method to various state-of-the-art binding prediction algorithms on MHC class I and MHC class II datasets. In almost all cases, our method outperforms all of its competitors. One of the major advantages of our novel approach is that it can also learn an affinity function over proteins for which only small amounts of labeled peptides exist. In these cases, our method's performance gain, when compared to other computational methods, is even more pronounced. We have recently uploaded the PepDist webserver which provides binding prediction of peptides to 35 different MHC class I alleles. The webserver which can be found at is powered by a prediction engine which was trained using the framework presented in this paper. CONCLUSION: The results obtained suggest that learning a single distance function over an entire family of proteins achieves higher prediction accuracy than learning a set of binary classifiers for each of the proteins separately. We also show the importance of obtaining information on experimentally determined non-binders. Learning with real non-binders generalizes better than learning with randomly generated peptides that are assumed to be non-binders. This suggests that information about non-binding peptides should also be published and made publicly available

Conformational Dynamics of Single pre-mRNA Molecules During \u3cem\u3eIn Vitro\u3c/em\u3e Splicing

The spliceosome is a complex small nuclear RNA (snRNA)-protein machine that removes introns from pre-mRNAs via two successive phosphoryl transfer reactions. The chemical steps are isoenergetic, yet splicing requires at least eight RNA-dependent ATPases responsible for substantial conformational rearrangements. To comprehensively monitor pre-mRNA conformational dynamics, we developed a strategy for single-molecule FRET (smFRET) that uses a small, efficiently spliced yeast pre-mRNA, Ubc4, in which donor and acceptor fluorophores are placed in the exons adjacent to the 5′ and 3′ splice sites. During splicing in vitro, we observed a multitude of generally reversible time-and ATP-dependent conformational transitions of individual pre-mRNAs. The conformational dynamics of branchpoint and 3′-splice site mutants differ from one another and from wild type. Because all transitions are reversible, spliceosome assembly appears to be occurring close to thermal equilibrium

Vasodilator Phosphostimulated Protein (VASP) Protects Endothelial Barrier Function During Hypoxia

The endothelial barrier controls the passage of solutes from the vascular space. This is achieved through active reorganization of the actin cytoskeleton. A central cytoskeletal protein involved into this is vasodilator-stimulated phosphoprotein (VASP). However, the functional role of endothelial VASP during hypoxia has not been thoroughly elucidated. We determined endothelial VASP expression through real-time PCR (Rt-PCR), immunhistochemistry, and Western blot analysis during hypoxia. VASP promoter studies were performed using a PGL3 firefly luciferase containing plasmid. Following approval by the local authorities, VASP−/− mice and littermate controls were subjected to normobaric hypoxia (8% O2, 92% N2) after intravenous injection of Evans blue dye. In in vitro studies, we found significant VASP repression in human microvascular and human umbilical vein endothelial cells through Rt-PCR, immunhistochemistry, and Western blot analysis. The VASP promoter construct demonstrated significant repression in response to hypoxia, which was abolished when the binding of hypoxia-inducible factor 1 alpha was excluded. Exposure of wild-type (WT) and VASP−/− animals to normobaric hypoxia for 4 h resulted in an increase in Evans blue tissue extravasation that was significantly increased in VASP−/− animals compared to WT controls. In summary, we demonstrate here that endothelial VASP holds significant importance for endothelial barrier properties during hypoxia

Derivation of Chondrogenically-Committed Cells from Human Embryonic Cells for Cartilage Tissue Regeneration

Background: Heterogeneous and uncontrolled differentiation of human embryonic stem cells (hESCs) in embryoid bodies (EBs) limits the potential use of hESCs for cell-based therapies. More efficient strategies are needed for the commitment and differentiation of hESCs to produce a homogeneous population of specific cell types for tissue regeneration applications. Methodology/Principal Findings: We report here that significant chondrocytic commitment of feeder-free cultured human embryonic stem cells (FF-hESCs), as determined by gene expression and immunostaining analysis, was induced by coculture with primary chondrocytes. Furthermore, a dynamic expression profile of chondrocyte-specific genes was observed during monolayer expansion of the chondrogenically-committed cells. Chondrogenically-committed cells synergistically responded to transforming growth factor-b1 (TGF-b1) and b1-integrin activating antibody by increasing tissue mass in pellet culture. In addition, when encapsulated in hydrogels, these cells formed cartilage tissue both in vitro and in vivo. In contrast, the absence of chondrocyte co-culture did not result in an expandable cell population from FF-hESCs. Conclusions/Significance: The direct chondrocytic commitment of FF-hESCs can be induced by morphogenetic factor