EBF factors drive expression of multiple classes of target genes governing neuronal development

<p>Abstract</p> <p>Background</p> <p>Early B cell factor (EBF) family members are transcription factors known to have important roles in several aspects of vertebrate neurogenesis, including commitment, migration and differentiation. Knowledge of how EBF family members contribute to neurogenesis is limited by a lack of detailed understanding of genes that are transcriptionally regulated by these factors.</p> <p>Results</p> <p>We performed a microarray screen in <it>Xenopus </it>animal caps to search for targets of EBF transcriptional activity, and identified candidate targets with multiple roles, including transcription factors of several classes. We determined that, among the most upregulated candidate genes with expected neuronal functions, most require EBF activity for some or all of their expression, and most have overlapping expression with <it>ebf </it>genes. We also found that the candidate target genes that had the most strongly overlapping expression patterns with <it>ebf </it>genes were predicted to be direct transcriptional targets of EBF transcriptional activity.</p> <p>Conclusions</p> <p>The identification of candidate targets that are transcription factor genes, including <it>nscl-1</it>, <it>emx1 </it>and <it>aml1</it>, improves our understanding of how EBF proteins participate in the hierarchy of transcription control during neuronal development, and suggests novel mechanisms by which EBF activity promotes migration and differentiation. Other candidate targets, including <it>pcdh8 </it>and <it>kcnk5</it>, expand our knowledge of the types of terminal differentiated neuronal functions that EBF proteins regulate.</p

Complement Targets Newborn Retinal Ganglion Cells for Phagocytic Elimination by Microglia

Microglia play important roles in shaping the developing CNS, and at early stages they have been proposed to regulate progenitor proliferation, differentiation, and neuronal survival. However, these studies reveal contradictory outcomes, highlighting the complexity of these cell-cell interactions. Here, we investigate microglia function during embryonic mouse retina development, where only microglia, progenitors, and neurons are present. In both sexes, we determine that microglia primarily interact with retinal neurons and find that depletion of microglia via conditional KO of the Csf1 receptor results in increased density of retinal ganglion cells (RGCs). Pharmacological inhibition of microglia also results in an increase in RGCs, with no effect on retinal progenitor proliferation, RGC genesis, or apoptosis. We show that microglia in the embryonic retina are enriched for phagocytic markers and observe engulfment of nonapoptotic Brn3-labeled RGCs. We investigate the molecular pathways that can mediate cell engulfment by microglia and find selective downregulation of complement pathway components with microglia inhibition, and further show that C1q protein marks a subset of RGCs in the embryonic retina. KO of complement receptor 3 (CR3; Itgam), which is only expressed by microglia, results in increased RGC density, similar to what we observed after depletion or inhibition of microglia. Thus, our data suggest that microglia regulate neuron elimination in the embryonic mouse retina by complement-mediated phagocytosis of non-apoptotic newborn RGCs. SIGNIFICANCE STATEMENT Microglia are emerging as active and important participants in regulating neuron number in development, during adult neurogenesis, and following stem cell therapies. However, their role in these contexts and the mechanisms involved are not fully defined. Using a well-characterized in vivo system, we provide evidence that microglia regulate neuronal elimination by complement-mediated engulfment of nonapoptotic neurons. This work provides a significant advancement of the field by defining in vivo molecular mechanisms for microglia-mediated cell elimination. Our data add to a growing body of evidence that microglia are essential for proper nervous system development. In addition, we elucidate microglia function in the developing retina, which may shed light on microglia involvement in the context of retinal injury and disease

The eyeless mouse mutation (ey1) removes an alternative start codon from the Rx/rax homeobox gene

Summary: The eyeless inbred mouse strain ZRDCT has long served as a spontaneous model for human anophthalmia and the evolutionary reduction of eyes that has occurred in some naturally blind mammals. ZRDCT mice have orbits but lack eyes and optic tracts and have hypothalamic abnormalities. Segregation data suggest that a small number of interacting genes are responsible, including at least one major recessive locus, ey1 . Although predicted since the 1940s, these loci were never identified. We mapped ey1 to chromosome 18 using an F2 genome scan and there found a Met10→Leu mutation in Rx/rax , a homeobox gene that is expressed in the anterior headfold, developing retina, pineal, and hypothalamus and is translated via a leaky scanning mechanism. The mutation affects a conserved AUG codon that functions as an alternative translation initiation site and consequently reduces the abundance of Rx protein. In contrast to a targeted Rx null allele, which causes anophthalmia, central nervous system defects, and neonatal death, the hypomorphic M10L allele is fully viable. genesis 31:43–53, 2001. © 2001 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35266/1/10003_ftp.pd

Tracking a Medically Important Spider: Climate Change, Ecological Niche Modeling, and the Brown Recluse (Loxosceles reclusa)

Most spiders use venom to paralyze their prey and are commonly feared for their potential to cause injury to humans. In North America, one species in particular, Loxosceles reclusa (brown recluse spider, Sicariidae), causes the majority of necrotic wounds induced by the Araneae. However, its distributional limitations are poorly understood and, as a result, medical professionals routinely misdiagnose brown recluse bites outside endemic areas, confusing putative spider bites for other serious conditions. To address the issue of brown recluse distribution, we employ ecological niche modeling to investigate the present and future distributional potential of this species. We delineate range boundaries and demonstrate that under future climate change scenarios, the spider's distribution may expand northward, invading previously unaffected regions of the USA. At present, the spider's range is centered in the USA, from Kansas east to Kentucky and from southern Iowa south to Louisiana. Newly influenced areas may include parts of Nebraska, Minnesota, Wisconsin, Michigan, South Dakota, Ohio, and Pennsylvania. These results illustrate a potential negative consequence of climate change on humans and will aid medical professionals in proper bite identification/treatment, potentially reducing bite misdiagnoses

Recognition of Depression in Older Medical Inpatients

BACKGROUND: Studies of recognition of depression in older (aged 65 or more) medical inpatients show low rates of recognition of depression by attending physicians. However, few studies have compared different measures of recognition of depression. OBJECTIVES: (1) To compare the validity of four indicators of recognition of depression and a global measure of recognition against a diagnosis of depression and (2) to explore the effect of patient characteristics on recognition of depression. METHODS: In a cohort of 264 medical inpatients 65 years and older (115 with major or minor depression, 78 with no depression), sensitivities, specificities, and diagnostic odds ratios (DOR) of 4 indicators of recognition (symptoms, diagnosis, treatment, and referral) and a global measure of recognition (any of the 4 indicators) were calculated. The associations between patient characteristics (age, sex, history of depression, antidepressant use before admission, severity of depression, comorbidity, duration of hospitalization, disability, and hospital of admission) and recognition were explored using multiple logistic regression. RESULTS: Less than half of the depressed patients were recognized. The indicator with the highest sensitivity was treatment (27.8%, 95% confidence interval [CI] 20.0–37.0), whereas the indicator with the best specificity was diagnosis (96.6%, 95% CI 91.9–98.7). The unadjusted DOR of global recognition was 2.6 (95% CI 1.5, 4.4). Less comorbidity, more severe depression symptoms, a history of depression, longer hospital stay, and antidepressant use before admission were significantly associated with better global recognition. CONCLUSION: Recognition of depression in elderly medical inpatients depends upon the indicator of recognition used

Simple mindreading abilities predict complex theory of mind: developmental delay in autism spectrum disorders

Theory of Mind (ToM) is impaired in individuals with Autism Spectrum Disorders (ASD). The aims of this study were to: i) examine the developmental trajectories of ToM abilities in two different mentalizing tasks in children with ASD compared to TD children; and ii) to assess if a ToM simple test known as Eyes-test could predict performance on the more advanced ToM task, i.e. Comic Strip test. Based on a sample of 37 children with ASD and 55 TD children, our results revealed slower development at varying rates in all ToM measures in children with ASD, with delayed onset compared to TD children. These results could stimulate new treatments for social abilities, which would lessen the social deficit in ASD

Resilience, hope and flourishing are inversely associated with burnout among members of the Society for Gynecologic Oncology

Purpose: In this study we sought to: 1) determine rates of burnout and other associated indices of psychosocial distress such as alcohol and substance abuse, 2) establish the baseline performance of gynecologic oncologists on several positive psychology metrics, 3) determine if increased hope, resilience, and flourishing are associated with decreased burnout. Methods: A survey of members of the Society of Gynecologic Oncology (SGO) was conducted in spring of 2017. Participants were sent an electronic questionnaire consisting of 82 items measuring burnout, depression, substance abuse, flourishing, resilience, hope, and psychological wellbeing. Results: A total of 1745 members were invited and 374 (21.4%) responded. Overall, 23.0% of respondents scores above clinical cutoffs indicating burnout. Almost 50.0% of participants screened positive for depression, 17.0% screened positive for alcohol abuse and 12.0% screened positive for substance abuse. Respondents meeting criteria for burnout were more likely to screen positive for depression (p < .001) and substance abuse (p < .001). Participants not meeting criteria for burnout had higher resilience, flourishing, hope, and wellbeing scores (p < .001). Male respondents had higher levels of hope, resilience, and wellbeing while married participants had higher flourishing and wellbeing scores than their unmarried counterparts. Parents had higher levels of resilience and wellbeing compared to non-parents. Conclusion(s): Burnout and associated indices of physiological distress continue to affect a large segment of SGO membership. Participants not meeting the criteria for burnout had higher scores on resilience, flourishing, hope, and wellbeing metrics. This suggests new targets for evidence-based interventions to mitigate burnout among members of SGO. Keywords: Burnout, Resilience, Flourishing, Wellbein