Effects of Inhibiting CoQ10 Biosynthesis with 4-nitrobenzoate in Human Fibroblasts

Coenzyme Q10 (CoQ10) is a potent lipophilic antioxidant in cell membranes and a carrier of electrons in the mitochondrial respiratory chain. We previously characterized the effects of varying severities of CoQ10 deficiency on ROS production and mitochondrial bioenergetics in cells harboring genetic defects of CoQ10 biosynthesis. We observed a unimodal distribution of ROS production with CoQ10 deficiency: cells with <20% of CoQ10 and 50–70% of CoQ10 did not generate excess ROS while cells with 30–45% of CoQ10 showed increased ROS production and lipid peroxidation. Because our previous studies were limited to a small number of mutant cell lines with heterogeneous molecular defects, here, we treated 5 control and 2 mildly CoQ10 deficient fibroblasts with varying doses of 4-nitrobenzoate (4-NB), an analog of 4-hydroxybenzoate (4-HB) and inhibitor of 4-para-hydroxybenzoate:polyprenyl transferase (COQ2) to induce a range of CoQ10 deficiencies. Our results support the concept that the degree of CoQ10 deficiency in cells dictates the extent of ATP synthesis defects and ROS production and that 40–50% residual CoQ10 produces maximal oxidative stress and cell death

Group membership and racial bias modulate the temporal estimation of in-group/out-group body movements

Social group categorization has been mainly studied in relation to ownership manipulations involving highly-salient multisensory cues. Here, we propose a novel paradigm that can implicitly activate the embodiment process in the presence of group affiliation information, whilst participants complete a task irrelevant to social categorization. Ethnically White participants watched videos of White- and Black-skinned models writing a proverb. The writing was interrupted 7, 4 or 1 s before completion. Participants were tasked with estimating the residual duration following interruption. A video showing only hand kinematic traces acted as a control condition. Residual duration estimates for out-group and control videos were significantly lower than those for in-group videos only for the longest duration. Moreover, stronger implicit racial bias was negatively correlated to estimates of residual duration for out-group videos. The underestimation bias for the out-group condition might be mediated by implicit embodiment, affective and attentional processes, and finalized to a rapid out-group categorization

Case Management as a Significant Component of Usual Care Psychotherapy for Youth with Disruptive Behavior Problems

Youth with disruptive behavior problems (DBPs) represent the majority of youth served in usual care (UC) psychotherapy, and are at high risk for maladaptive outcomes. Little is known about UC psychotherapeutic strategies utilized with this population. Researchers and clinicians suggest that case management (CM) is a major activity occurring in usual care. CM includes coordinating care with service providers and individuals, including schools, psychiatrists, and community-based services. This study assesses the prevalence and predictors of clinician use of CM in usual care. Results from this study suggest that CM is frequently used in UC psychotherapy with youth with DBPs. The extent of use of CM in UC may have implications for implementation of evidence-based practices in usual care psychotherapy

Post mortem magnetic resonance imaging in the fetus, infant and child: A comparative study with conventional autopsy (MaRIAS Protocol)

<p>Abstract</p> <p>Background</p> <p>Minimally invasive autopsy by post mortem magnetic resonance (MR) imaging has been suggested as an alternative for conventional autopsy in view of the declining consented autopsy rates. However, large prospective studies rigorously evaluating the accuracy of such an approach are lacking. We intend to compare the accuracy of a minimally invasive autopsy approach using post mortem MR imaging with that of conventional autopsy in fetuses, newborns and children for detection of the major pathological abnormalities and/or determination of the cause of death.</p> <p>Methods/Design</p> <p>We recruited 400 consecutive fetuses, newborns and children referred for conventional autopsy to one of the two participating hospitals over a three-year period. We acquired whole body post mortem MR imaging using a 1.5 T MR scanner (Avanto, Siemens Medical Solutions, Enlargen, Germany) prior to autopsy. The total scan time varied between 90 to 120 minutes. Each MR image was reported by a team of four specialist radiologists (paediatric neuroradiology, paediatric cardiology, paediatric chest & abdominal imaging and musculoskeletal imaging), blinded to the autopsy data. Conventional autopsy was performed according to the guidelines set down by the Royal College of Pathologists (UK) by experienced paediatric or perinatal pathologists, blinded to the MR data. The MR and autopsy data were recorded using predefined categorical variables by an independent person.</p> <p>Discussion</p> <p>Using conventional post mortem as the gold standard comparator, the MR images will be assessed for accuracy of the anatomical morphology, associated lesions, clinical usefulness of information and determination of the cause of death. The sensitivities, specificities and predictive values of post mortem MR alone and MR imaging along with other minimally invasive post mortem investigations will be presented for the final diagnosis, broad diagnostic categories and for specific diagnosis of each system.</p> <p>Clinical Trial Registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01417962">NCT01417962</a></p> <p><b>NIHR Portfolio Number: </b>6794</p

Intra- and Inter-Individual Differences in Adolescent Depressive Mood: the Role of Relationships with Parents and Friends

Abstract: Utilizing four waves of data from 1126 secondary school Dutch adolescents (Mage = 13.95 at the first wave; 53% boys), the current study examined the interplay between parent-adolescent and friend-adolescent relationship quality (satisfaction and conflict) in relation to adolescents’ depressive mood. Using multilevel analyses, the interacting effects of parent/friend relationship quality on depressive mood were tested at both the intra- and inter-individual level. Analyses at the intra-individual level investigated whether individual depressive mood fluctuated along with changes in their social relationships regardless of one’s general level of depressive mood; and analyses at the inter-individual level examined whether the average differences in depressive mood between adolescents were associated with different qualities of social relationships. We interpreted the patterns of interactions between parent and friend relationships using four theoretical models: the reinforcement, toxic friends, compensation, and additive model. The results demonstrate the covariation of parent- and friend- relationship quality with adolescents’ depressive mood, and highlight that parent and peer effects are not independent from each other—affirming the compensation and additive models at the intra-individual and the reinforcement and additive models at the inter-individual level. The findings highlight the robustness of the protective effects of parent and peer support and the deleterious effects of conflictual relationships for adolescent mental health. The results have implications for both the theoretical and practical design of (preventive) interventions aimed at decreasing adolescents’ depressive mood

Community Violence and Youth: Affect, Behavior, Substance Use, and Academics

Community violence is recognized as a major public health problem (WHO, World Report on Violence and Health,2002) that Americans increasingly understand has adverse implications beyond inner-cities. However, the majority of research on chronic community violence exposure focuses on ethnic minority, impoverished, and/or crime-ridden communities while treatment and prevention focuses on the perpetrators of the violence, not on the youth who are its direct or indirect victims. School-based treatment and preventive interventions are needed for children at elevated risk for exposure to community violence. In preparation, a longitudinal, community epidemiological study, The Multiple Opportunities to Reach Excellence (MORE) Project, is being fielded to address some of the methodological weaknesses presented in previous studies. This study was designed to better understand the impact of children’s chronic exposure to community violence on their emotional, behavioral, substance use, and academic functioning with an overarching goal to identify malleable risk and protective factors which can be targeted in preventive and intervention programs. This paper describes the MORE Project, its conceptual underpinnings, goals, and methodology, as well as implications for treatment and preventive interventions and future research

System-based proteomic and metabonomic analysis of the Df(16)A(+/-) mouse identifies potential miR-185 targets and molecular pathway alterations

Deletions on chromosome 22q11.2 are a strong genetic risk factor for development of schizophrenia and cognitive dysfunction. We employed shotgun liquid chromatography-mass spectrometry (LC-MS) proteomic and metabonomic profiling approaches on prefrontal cortex (PFC) and hippocampal (HPC) tissue from Df(16)A(+/-) mice, a model of the 22q11.2 deletion syndrome. Proteomic results were compared with previous transcriptomic profiling studies of the same brain regions. The aim was to investigate how the combined effect of the 22q11.2 deletion and the corresponding miRNA dysregulation affects the cell biology at the systems level. The proteomic brain profiling analysis revealed PFC and HPC changes in various molecular pathways associated with chromatin remodelling and RNA transcription, indicative of an epigenetic component of the 22q11.2DS. Further, alterations in glycolysis/gluconeogenesis, mitochondrial function and lipid biosynthesis were identified. Metabonomic profiling substantiated the proteomic findings by identifying changes in 22q11.2 deletion syndrome (22q11.2DS)-related pathways, such as changes in ceramide phosphoethanolamines, sphingomyelin, carnitines, tyrosine derivates and panthothenic acid. The proteomic findings were confirmed using selected reaction monitoring mass spectrometry, validating decreased levels of several proteins encoded on 22q11.2, increased levels of the computationally predicted putative miR-185 targets UDP-N-acetylglucosamine-peptide N-acetylglucosaminyltransferase 110 kDa subunit (OGT1) and kinesin heavy chain isoform 5A and alterations in the non-miR-185 targets serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform, neurofilament light chain and vesicular glutamate transporter 1. Furthermore, alterations in the proteins associated with mammalian target of rapamycin signalling were detected in the PFC and with glutamatergic signalling in the hippocampus. Based on the proteomic and metabonomic findings, we were able to develop a schematic model summarizing the most prominent molecular network findings in the Df(16)A(+/-) mouse. Interestingly, the implicated pathways can be linked to one of the most consistent and strongest proteomic candidates, (OGT1), which is a predicted miR-185 target. Our results provide novel insights into system-biological mechanisms associated with the 22q11DS, which may be linked to cognitive dysfunction and an increased risk to develop schizophrenia. Further investigation of these pathways could help to identify novel drug targets for the treatment of schizophrenia.Molecular Psychiatry advance online publication, 22 March 2016; doi:10.1038/mp.2016.27