Factor structure of the Children’s Perception of Interparental Conflict Scale for studies of youths with externalizing behavior problems.

The assessment of children’s perception of marital conflict is an important area of research related to family relations, children’s cognitions about self, and the development of psychopathology. The leading instrument in this domain is the Children’s Perception of Interparental Conflict Scale (CPIC; J. H. Grych, M. Seid, & F. D. Fincham, 1992). It has 48 items organized into 9 conceptual designed subscales, with reports of 3-factor higher order structure to the 9 subscales. However, the 3-factor solution does not capture all 9 subscales well. Further, items have never been subjected to factor analysis to evaluate the best fitting factor structure at the item level. Doing so is particularly important when bringing the scale into new populations such as children with attention-deficit/hyperactivity disorder (ADHD) or disruptive behavior disorders. In the present study, 2 samples of children (total N = 1,190; ages 6–18 years) completed the CPIC. An exploratory factor analysis in Sample 1 (from a clinical study of ADHD and non-ADHD youths) yielded 4 interpretable factors. A confirmatory factor analysis in Sample 2 (a population sample of twins) confirmed the generalizability of the solution with an acceptable fit, although 1 item was dropped. The final solution used 38 of the 48 items. The 4-factor solution captured a Conflict Properties factor, two appraisal factors labeled Threat to Self and Self-Blame, and a Triangulation/Stability factor that included elements of appraisal and content. The authors concluded that the item-based 4-factor solution to the CPIC is preferable to the 9-factor or 3-factor formulation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Longitudinal MRI and cognitive change in healthy elderly.

Cross-sectional studies of normal aging indicate an association between memory and hippocampal volume, and between executive functioning and subcortical-frontal circuits. Much less is known, however, about the relationship between longitudinal MRI changes and cognitive decline. The authors hypothesized that longitudinal change in memory would be best predicted by change in hippocampal volumes, whereas change in executive functioning would be best predicted by cortical atrophy and progression of MRI markers of cerebrovascular disease. For this study, 50 healthy elderly subjects underwent structural MRI and cognitive testing at baseline and again at follow-up, with a mean follow-up interval of 45 months. Volumetric MRI measures were hippocampus, cortical gray matter, white matter signal hyperintensity (WMSH), and lacunae. Neuropsychological measures were psychometrically robust composite scores of episodic memory (MEM) and executive functioning (EXEC). Hierarchical multiple regression indicated that a decrease in hippocampus was associated with a decline in MEM, whereas decreased cortical gray matter and increased WMSH were independently associated with a decline in EXEC. Results suggest that in normal aging, cognitive functioning declines as cortical gray matter and hippocampus decrease, and WMSH increases. The association between WMSH and EXEC further highlights the cognitive sequealae associated with cerebrovascular disease in normal elderly. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Minor Changes for a Major Impact: A Review of Epigenetic Modifications in Cell-Based Therapies for Stroke

Epigenetic changes in stroke may revolutionize cell-based therapies aimed at reducing ischemic stroke risk and damage. Epigenetic changes are a novel therapeutic target due to their specificity and potential for reversal. Possible targets for epigenetic modification include DNA methylation and demethylation, post-translational histone modification, and the actions of non-coding RNAs such as microRNAs. Many of these epigenetic modifications have been reported to modulate atherosclerosis development and progression, ultimately contributing to stroke pathogenesis. Furthermore, epigenetics may play a major role in inflammatory responses following stroke. Stem cells for stroke have demonstrated safety in clinical trials for stroke and show therapeutic benefit in pre-clinical studies. The efficacy of these cell-based interventions may be amplified with adjunctive epigenetic modifications. This review advances the role of epigenetics in atherosclerosis and inflammation in the context of stroke, followed by a discussion on current stem cell studies modulating epigenetics to ameliorate stroke damage.     

Signal Peptide Variants in Inherited Retinal Diseases: A Multi-Institutional Case Series

Signal peptide (SP) mutations are an infrequent cause of inherited retinal diseases (IRDs). We report the genes currently associated with an IRD that possess an SP sequence and assess the prevalence of these variants in a multi-institutional retrospective review of clinical genetic testing records. The online databases, RetNet and UniProt, were used to determine which IRD genes possess a SP. A multicenter retrospective review was performed to retrieve cases of patients with a confirmed diagnosis of an IRD and a concurrent SP variant. In silico evaluations were performed with MutPred, MutationTaster, and the signal peptide prediction tool, SignalP 6.0. SignalP 6.0 was further used to determine the locations of the three SP regions in each gene: the N-terminal region, hydrophobic core, and C-terminal region. Fifty-six (56) genes currently associated with an IRD possess a SP sequence. Based on the records review, a total of 505 variants were present in the 56 SP-possessing genes. Six (1.18%) of these variants were within the SP sequence and likely associated with the patients’ disease based on in silico predictions and clinical correlation. These six SP variants were in the CRB1 (early-onset retinal dystrophy), NDP (familial exudative vitreoretinopathy) (FEVR), FZD4 (FEVR), EYS (retinitis pigmentosa), and RS1 (X-linked juvenile retinoschisis) genes. It is important to be aware of SP mutations as an exceedingly rare cause of IRDs. Future studies will help refine our understanding of their role in each disease process and assess therapeutic approaches.     

The Neonatal Fc Receptor Is Elevated in Monocyte-Derived Immune Cells in Pancreatic Cancer

The neonatal Fc receptor (FcRn) is responsible for recycling of IgG antibodies and albumin throughout the body. This mechanism has been exploited for pharmaceutic delivery across an array of diseases to either enhance or diminish this function. Monoclonal antibodies and albumin-bound nanoparticles are examples of FcRn-dependent anti-cancer therapeutics. Despite its importance in drug delivery, little is known about FcRn expression in circulating immune cells. Through time-of-flight mass cytometry (CyTOF) we were able to characterize FcRn expression in peripheral blood mononuclear cell (PBMC) populations of pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer donors. Furthermore, we were able to replicate these findings in an orthotopic murine model of PDAC. Altogether, we found that in both patients and mice with PDAC, FcRn was elevated in migratory and resident classical dendritic cell type 2 (cDC2) as well as monocytic and granulocytic myeloid-derived suppressor cell (MDSC) populations compared to tumor-free controls. Furthermore, PBMCs from PDAC patients had elevated monocyte, dendritic cells and MDSCs relative to non-cancer donor PBMCs. Future investigations into FcRn activity may further elucidate possible mechanisms of poor efficacy of antibody immunotherapies in patients with PDAC.     

Reward-specific blockade of morphine's effect on brain-stimulation reward by pimozide but not SCH 23390.

To test the hypothesis that dopamine plays an important role in the rewarding effects of abuse opioids, the authors compared the ability of the specific dopamine D? antagonist, SCH 23390, and the D? antagonist, pimozide, to block the threshold-lowering effect of morphine on brain-stimulation reward. Pimozide, at doses that did not alter the threshold, reversed morphine's threshold-lowering effect. Although SCH 23390 also reversed morphine's effect, in contrast to pimozide, it did so only at doses that significantly raised the threshold. Thus to the extent that brain-stimulation reward is a model of drug-induced euphoria, these data suggest that D? receptors are more specifically involved than are D? receptors in mediating the rewarding effects of morphine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Designer Biomaterials to Model Cancer Cell Invasion In Vitro: Predictive Tools or Just Pretty Pictures?

Metastasis is the leading cause of mortality in cancer patients. Underlying this process is the invasion and colonization of cancer cells into healthy tissues. Engineered hydrogel models of tumor microenvironments present an opportunity to understand the microenvironmental determinants of cellular invasion. The biochemical and mechanical cues, presented in the form of adhesion sites, degradable cues, matrix stiffness, and architecture, have significant effects on the extent of cancer cell migration, and the mechanisms employed by these cells to move through their matrix. Coculture with stromal cells such as cancer associated fibroblasts, endothelial cells, and immune cells that are associated with poor prognosis demonstrate that these cells exacerbate cancer cell invasion. With these models, researchers aim not only to recapitulate known cancer cell behaviors in a dish, but also to uncover new insights into mechanisms underlying these phenomena, paving the way for novel treatment strategies. In this perspective, the design of engineered models that are used to study cancer cell invasion and metastasis in vitro is discussed. To this end, the authors seek to understand and put into perspective: do these models reveal relevant mechanisms of cancer cell migration, or are they simply pretty pictures with little biological translatability?     

Design and synthesis of aryl ether inhibitors of the Bacillus anthracis enoyl-ACP reductase

The problem of increasing bacterial resistance to the current generation of antibiotics is well documented. Known resistant pathogens such as methicillin-resistant Staphylococcus aureus are becoming more prevalent, while the potential exists for developing drug-resistant pathogens for use as bioweapons, such as Bacillus anthracis. The biphenyl ether antibacterial agent, triclosan, exhibits broad-spectrum activity by targeting the fatty acid biosynthetic pathway through inhibition of enoyl-acyl carrier protein reductase (ENR) and provides a potential scaffold for the development of new, broad-spectrum antibiotics. We used a structure-based approach to develop novel aryl ether analogues of triclosan that target ENR, the product of the fabI gene, from B. anthracis (BaENR). Structure-based design methods were used for the expansion of the compound series including X-ray crystal structure determination, molecular docking, and QSAR methods. Structural modifications were made to both phenyl rings of the 2-phenoxyphenyl core. A number of compounds exhibited improved potency against BaENR and increased efficacy against both the Sterne strain of B. anthracis and the methicillin-resistant strain of S. aureus. X-ray crystal structures of BaENR in complex with triclosan and two other compounds help explain the improved efficacy of the new compounds and suggest future rounds of optimization that might be used to improve their potency.     

Electron Hopping Across Hemin‐Doped Serum Albumin Mats on Centimeter‐Length Scales

Exploring long‐range electron transport across protein assemblies is a central interest in both the fundamental research of biological processes and the emerging field of bioelectronics. This work examines the use of serum‐albumin‐based freestanding mats as macroscopic electron mediators in bioelectronic devices. In particular, this study focuses on how doping the protein mat with hemin improves charge‐transport. It is demonstrated that doping can increase conductivity 40‐fold via electron hopping between adjacent hemin molecules, resulting in the highest measured conductance for a protein‐based material yet reported, and transport over centimeter length scales. The use of distance‐dependent AC impedance and DC current–voltage measurements allows the contribution from electron hopping between adjacent hemin molecules to be isolated. Because the hemin‐doped serum albumin mats have both biocompatibility and fabrication simplicity, they should be applicable to a range of bioelectronic devices of varying sizes, configurations, and applications.     

Engineering Extracellular Vesicles with the Tools of Enzyme Prodrug Therapy

Extracellular vesicles (EVs) have recently gained significant attention as important mediators of intercellular communication, potential drug carriers, and disease biomarkers. These natural cell‐derived nanoparticles are postulated to be biocompatible, stable under physiological conditions, and to show reduced immunogenicity as compared to other synthetic nanoparticles. Although initial clinical trials are ongoing, the use of EVs for therapeutic applications may be limited due to undesired off‐target activity and potential “dilution effects” upon systemic administration which may affect their ability to reach their target tissues. To fully exploit their therapeutic potential, EVs are embedded into implantable biomaterials designed to achieve local delivery of therapeutics taking advantage of enzyme prodrug therapy (EPT). In this first application of EVs for an EPT approach, EVs are used as smart carriers for stabilizing enzymes in a hydrogel for local controlled conversion of benign prodrugs to active antiinflammatory compounds. It is shown that the natural EVs' antiinflammatory potential is comparable or superior to synthetic carriers, in particular upon repeated long‐term incubations and in different macrophage models of inflammation. Moreover, density‐dependent color scanning electron microscopy imaging of EVs in a hydrogel is presented herein, an impactful tool for further understanding EVs in biological settings.