Aberrant APOBEC3B Expression in Breast Cancer Is Linked to Proliferation and Cell Cycle Phase

APOBEC3B (A3B) is aberrantly overexpressed in a subset of breast cancers, where it associates with advanced disease, poor prognosis, and treatment resistance, yet the causes of A3B dysregulation in breast cancer remain unclear. Here, A3B mRNA and protein expression levels were quantified in different cell lines and breast tumors and related to cell cycle markers using RT-qPCR and multiplex immunofluorescence imaging. The inducibility of A3B expression during the cell cycle was additionally addressed after cell cycle synchronization with multiple methods. First, we found that A3B protein levels within cell lines and tumors are heterogeneous and associate strongly with the proliferation marker Cyclin B1 characteristic of the G2/M phase of the cell cycle. Second, in multiple breast cancer cell lines with high A3B, expression levels were observed to oscillate throughout the cell cycle and again associate with Cyclin B1. Third, induction of A3B expression is potently repressed throughout G0/early G1, likely by RB/E2F pathway effector proteins. Fourth, in cells with low A3B, induction of A3B through the PKC/ncNF-κB pathway occurs predominantly in actively proliferating cells and is largely absent in cells arrested in G0. Altogether, these results support a model in which dysregulated A3B overexpression in breast cancer is the cumulative result of proliferation-associated relief from repression with concomitant pathway activation during the G2/M phase of the cell cycle.</p

Methylphenidate Normalizes Fronto-Striatal Underactivation During Interference Inhibition in Medication-Naïve Boys with Attention-Deficit Hyperactivity Disorder

Youth with attention deficit hyperactivity disorder (ADHD) have deficits in interference inhibition, which can be improved with the indirect catecholamine agonist methylphenidate (MPH). Functional magnetic resonance imaging was used to investigate the effects of a single dose of MPH on brain activation during interference inhibition in medication-naïve ADHD boys. Medication-naïve boys with ADHD were scanned twice, in a randomized, double-blind design, under either a single clinical dose of MPH or placebo, while performing a Simon task that measures interference inhibition and controls for the oddball effect of low-frequency appearance of incongruent trials. Brain activation was compared within patients under either drug condition. To test for potential normalization effects of MPH, brain activation in ADHD patients under either drug condition was compared with that of healthy age-matched comparison boys. During incongruent trials compared with congruent–oddball trials, boys with ADHD under placebo relative to controls showed reduced brain activation in typical areas of interference inhibition, including right inferior prefrontal cortex, left striatum and thalamus, mid-cingulate/supplementary motor area, and left superior temporal lobe. MPH relative to placebo upregulated brain activation in right inferior prefrontal and premotor cortices. Under the MPH condition, patients relative to controls no longer showed the reduced activation in right inferior prefrontal and striato-thalamic regions. Effect size comparison, furthermore, showed that these normalization effects were significant. MPH significantly normalized the fronto-striatal underfunctioning in ADHD patients relative to controls during interference inhibition, but did not affect medial frontal or temporal dysfunction. MPH therefore appears to have a region-specific upregulation effect on fronto-striatal activation

A MSFD complementary approach for the assessment of pressures, knowledge and data gaps in Southern European Seas : the PERSEUS experience

PERSEUS project aims to identify the most relevant pressures exerted on the ecosystems of the Southern European Seas (SES), highlighting knowledge and data gaps that endanger the achievement of SES Good Environmental Status (GES) as mandated by the Marine Strategy Framework Directive (MSFD). A complementary approach has been adopted, by a meta-analysis of existing literature on pressure/impact/knowledge gaps summarized in tables related to the MSFD descriptors, discriminating open waters from coastal areas. A comparative assessment of the Initial Assessments (IAs) for five SES countries has been also independently performed. The comparison between meta-analysis results and IAs shows similarities for coastal areas only. Major knowledge gaps have been detected for the biodiversity, marine food web, marine litter and underwater noise descriptors. The meta-analysis also allowed the identification of additional research themes targeting research topics that are requested to the achievement of GES. 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license.peer-reviewe

A novel translational assay of response inhibition and impulsivity: effects of prefrontal cortex lesions, drugs used in ADHD, and serotonin 2C receptor antagonism

Animal models are making an increasing contribution to our understanding of the psychology and brain mechanisms underlying behavioral inhibition and impulsivity. The aim here was to develop, for the first time, a mouse analogue of the stop-signal reaction time task with high translational validity in order to be able to exploit this species in genetic and molecular investigations of impulsive behaviours. Cohorts of mice were trained to nose-poke to presentations of visual stimuli. Control of responding was manipulated by altering the onset of an auditory ‘stop-signal’ during the go response. The anticipated systematic changes in action cancellation were observed as stopping was made more difficult by placing the stop-signal closer to the execution of the action. Excitotoxic lesions of medial prefrontal cortex resulted in impaired stopping, whilst the clinically effective drugs methylphenidate and atomoxetine enhanced stopping abilities. The specific 5-HT2C receptor antagonist SB242084 also led to enhanced response control in this task. We conclude that stop-signal reaction time task performance can be successfully modelled in mice and is sensitive to prefrontal cortex dysfunction and drug treatments in a qualitatively similar manner to humans and previous rat models. Additionally, using the model we show novel and highly discrete effects of 5-HT2C receptor antagonism that suggest manipulation of 5-HT2C receptor function may be of use in correcting maladaptive impulsive behaviors and provide further evidence for dissociable contributions of serotonergic transmission to response control

Apoptosis in The Development and Pathophysiology of The Limbic System

Limbic system is involved in the intangible functions of brain like emotions, inborn and acquired emotional responses, self-awareness, ability to understand intentions of others and and memory. Apoptosis has a critical role in the developing brain and disruption of developmental apoptosis may lead to neurodevelopmental disorders. This review summarizes apoptotic processes in the limbic system during fetal brain development in normal and pathological conditions and focuses on the molecular mechanisms of apoptosis