Asymmetric localisation of Miranda and its cargo proteins during neuroblast division requires the anaphase-promoting complex/cyclosome

Asymmetric cell divisions generate cell fate diversity during both invertebrate and vertebrate development. Drosophila neural progenitors or neuroblasts (NBs) each divide asymmetrically to produce a larger neuroblast and a smaller ganglion mother cell (GMC). The asymmetric localisation of neural cell fate determinants and their adapter proteins to the neuroblast cortex during mitosis facilitates their preferential segregation to the GMC upon cytokinesis. In this study we report a novel role for the anaphase-promoting complex/cyclosome (APC/C) during this process. Attenuation of APC/C activity disrupts the asymmetric localisation of the adapter protein Miranda and its associated cargo proteins Staufen, Prospero and Brat, but not other components of the asymmetric division machinery. We demonstrate that Miranda is ubiquitylated via its C-terminal domain; removal of this domain disrupts Miranda localisation and replacement of this domain with a ubiquitin moiety restores normal asymmetric Miranda localisation. Our results demonstrate that APC/C activity and ubiquitylation of Miranda are required for the asymmetric localisation of Miranda and its cargo proteins to the NB cortex

A mosaic genetic screen for novel mutations affecting Drosophila neuroblast divisions

BACKGROUND: The asymmetric segregation of determinants during cell division is a fundamental mechanism for generating cell fate diversity during development. In Drosophila, neural precursors (neuroblasts) divide in a stem cell-like manner generating a larger apical neuroblast and a smaller basal ganglion mother cell. The cell fate determinant Prospero and its adapter protein Miranda are asymmetrically localized to the basal cortex of the dividing neuroblast and segregated into the GMC upon cytokinesis. Previous screens to identify components of the asymmetric division machinery have concentrated on embryonic phenotypes. However, such screens are reaching saturation and are limited in that the maternal contribution of many genes can mask the effects of zygotic loss of function, and other approaches will be necessary to identify further genes involved in neuroblast asymmetric division. RESULTS: We have performed a genetic screen in the third instar larval brain using the basal localization of Miranda as a marker for neuroblast asymmetry. In addition to the examination of pupal lethal mutations, we have employed the MARCM (Mosaic Analysis with a Repressible Cell Marker) system to generate postembryonic clones of mutations with an early lethal phase. We have screened a total of 2,300 mutagenized chromosomes and isolated alleles affecting cell fate, the localization of basal determinants or the orientation of the mitotic spindle. We have also identified a number of complementation groups exhibiting defects in cell cycle progression and cytokinesis, including both novel genes and new alleles of known components of these processes. CONCLUSION: We have identified four mutations which affect the process of neuroblast asymmetric division. One of these, mapping to the imaginal discs arrested locus, suggests a novel role for the anaphase promoting complex/cyclosome (APC/C) in the targeting of determinants to the basal cortex. The identification and analysis of the remaining mutations will further advance our understanding of the process of asymmetric cell division. We have also isolated a number of mutations affecting cell division which will complement the functional genomics approaches to this process being employed by other laboratories. Taken together, these results demonstrate the value of mosaic screens in the identification of genes involved in neuroblast division

The effects of tryptophan loading on Attention Deficit Hyperactivity in adults:A remote double blind randomised controlled trial

BackgroundDespite the impact and prevalence of Attention Deficit Hyperactivity Disorder (ADHD), current treatment options remain limited and there is a drive for alternative approaches, including those building on evidence of a role for tryptophan (TRP) and serotonin (5-HT). This study aimed to evaluate the effect of acute TRP loading on attention and impulsivity in adults with ADHD.Trial design and methods We conducted a remote double blind randomised controlled trial (RCT) using TRP loading to examine the effects of a balanced amino acid load in comparison to low and high TRP loading in individuals with ADHD (medicated, N = 48, and unmedicated, N = 46) and controls (N = 50). Participants were randomised into one of three TRP treatment groups using stratified randomisation considering participant group and gender using a 1:1:1 ratio. Baseline testing of attention and impulsivity using the Test of Variables of Attention Task, Delay Discounting Task, and Iowa Gambling Task was followed by consumption of a protein drink (BAL, LOW, or HIGH TRP) before repeated testing. Results and ConclusionsNo effects of TRP were observed for any of the measures. In the present study, TRP loading did not impact on any measure of attention or impulsivity in those with ADHD or Controls. The findings need to be confirmed in another trial with a larger number of patients that also considers additional measures of dietary protein, plasma TRP and aggression. (Registration ID ISRCTN15119603)<br/

Co-occurrence of ASD and ADHD traits in an adult population

Objective: ADHD and autism spectrum disorder (ASD) can be viewed as the extreme end of traits found in the general population. Clinical and genetic studies suggest that ADHD and ASD often co-occur and share genetic susceptibility. The aim of this study was to examine co-occurrence of ADHD and ASD traits in the general population. Method: In total, 334 participants were recruited from a population-based sample. Four questionnaires assessing current and retrospective ADHD and ASD traits were administered online: the Adult ADHD Self-Report Scale (ASRS) Symptom Checklist, the Wender Utah Rating Scale (WURS-25), the Broad Autism Phenotype Questionnaire (BAPQ), and the Autism Spectrum Quotient (AQ). Results: A significant correlation was found between ADHD and autistic traits. In particular, higher inattention and overall ADHD scores were associated with self-reported deficits in communication and social skills. Conclusion: Our findings are similar to results from studies on clinical populations, suggesting that ADHD and ASD might share common etiology

Interactions between the Midbrain Superior Colliculus and the Basal Ganglia

An important component of the architecture of cortico-basal ganglia connections is the parallel, re-entrant looped projections that originate and return to specific regions of the cerebral cortex. However, such loops are unlikely to have been the first evolutionary example of a closed-loop architecture involving the basal ganglia. A phylogenetically older, series of subcortical loops can be shown to link the basal ganglia with many brainstem sensorimotor structures. While the characteristics of individual components of potential subcortical re-entrant loops have been documented, the full extent to which they represent functionally segregated parallel projecting channels remains to be determined. However, for one midbrain structure, the superior colliculus (SC), anatomical evidence for closed-loop connectivity with the basal ganglia is robust, and can serve as an example against which the loop hypothesis can be evaluated for other subcortical structures. Examination of ascending projections from the SC to the thalamus suggests there may be multiple functionally segregated systems. The SC also provides afferent signals to the other principal input nuclei of the basal ganglia, the dopaminergic neurones in substantia nigra and to the subthalamic nucleus. Recent electrophysiological investigations show that the afferent signals originating in the SC carry important information concerning the onset of biologically significant events to each of the basal ganglia input nuclei. Such signals are widely regarded as crucial for the proposed functions of selection and reinforcement learning with which the basal ganglia have so often been associated

Nicotine enhances an auditory Event-Related Potential component which is inversely related to habituation

Nicotine is a psychoactive substance that is commonly consumed in the context of music. However, the reason why music and nicotine are coconsumed is uncertain. One possibility is that nicotine affects cognitive processes relevant to aspects of music appreciation in a beneficial way. Here we investigated this possibility using Event-Related Potentials (ERPs). Participants underwent a simple decision-making task (to maintain attentional focus), responses to which were signaled by auditory stimuli. Unlike most previous research looking at the effects of nicotine on auditory processing, we used tones of different pitch, a fundamental element of music. In addition, unlike most other studies, we tested non-smoking subjects to avoid withdrawal-related complications. We found that nicotine (4.0 mg, administered as gum) increased P2 amplitude in the frontal region. Since a decrease in P2 amplitude and latency is related to habituation processes, and an enhanced ability to disengage from irrelevant stimuli, our findings suggest that nicotine may cause a reduction in habituation, resulting in non-smokers being less able to adapt to repeated stimuli. A corollary of that decrease in adaptation may be that nicotine extends the temporal window during which a listener is able and willing to engage with a piece of music

A comprehensive collection of chicken cDNAs

AbstractBirds have played a central role in many biological disciplines, particularly ecology, evolution, and behavior. The chicken, as a model vertebrate, also represents an important experimental system for developmental biologists, immunologists, cell biologists, and geneticists. However, genomic resources for the chicken have lagged behind those for other model organisms, with only 1845 nonredundant full-length chicken cDNA sequences currently deposited in the EMBL databank. We describe a large-scale expressed-sequence-tag (EST) project aimed at gene discovery in chickens (http://www.chick.umist.ac.uk). In total, 339,314 ESTs have been sequenced from 64 cDNA libraries generated from 21 different embryonic and adult tissues. These were clustered and assembled into 85,486 contiguous sequences (contigs). We find that a minimum of 38% of the contigs have orthologs in other organisms and define an upper limit of 13,000 new chicken genes. The remaining contigs may include novel avian specific or rapidly evolving genes. Comparison of the contigs with known chicken genes and orthologs indicates that 30% include cDNAs that contain the start codon and 20% of the contigs represent full-length cDNA sequences. Using this dataset, we estimate that chickens have approximately 35,000 genes in total, suggesting that this number may be a characteristic feature of vertebrates

Differential disgust responding in people with cancer and implications for psychological wellbeing

Objectives: Evidence suggests that disgust responses, known to negatively affect psychological wellbeing, may differ in people with cancer. We performed the first quantitative investigation of three discrete types of disgust trait - disgust propensity, sensitivity, and self-directed disgust - in people diagnosed with a broad range of cancers (versus cancer-free controls), and explored their associations with psychological wellbeing. Design: In a cross-sectional survey design, 107 participants with heterogeneous cancer diagnoses, recruited from cancer charities and support groups, were matched with cancer-free controls by age and gender. Outcome measures: Measures of the three disgust traits were taken alongside measures of anxiety and depression. Results: Disgust sensitivity and physical self-disgust were significantly higher in the cancer than control sample, while disgust propensity and behavioural self-disgust were lower. The disgust traits had a different pattern of associations to psychological wellbeing across the two groups, with disgust sensitivity predicting depressive symptoms to a significantly greater extent in the cancer than control group. Conclusions: People with cancer differ from matched controls in their disgust responses and these responses have significant predictive relationships with aspects of their psychological wellbeing. The results suggest that emotion-based interventions may be useful for improving psychological wellbeing in people with cancer

A genetic variation map for chicken with 2.8 million single-nucleotide polymorphisms

We describe a genetic variation map for the chicken genome containing 2.8 million single-nucleotide polymorphisms ( SNPs). This map is based on a comparison of the sequences of three domestic chicken breeds ( a broiler, a layer and a Chinese silkie) with that of their wild ancestor, red jungle fowl. Subsequent experiments indicate that at least 90% of the variant sites are true SNPs, and at least 70% are common SNPs that segregate in many domestic breeds. Mean nucleotide diversity is about five SNPs per kilobase for almost every possible comparison between red jungle fowl and domestic lines, between two different domestic lines, and within domestic lines - in contrast to the notion that domestic animals are highly inbred relative to their wild ancestors. In fact, most of the SNPs originated before domestication, and there is little evidence of selective sweeps for adaptive alleles on length scales greater than 100 kilobases