Molecular Characterization of the Mouse Superior Lateral Parabrachial Nucleus through Expression of the Transcription Factor Runx1

The ability to precisely identify separate neuronal populations is essential to the understanding of the development and function of different brain structures. This necessity is particularly evident in regions such as the brainstem, where the anatomy is quite complex and little is known about the identity, origin, and function of a number of distinct nuclei due to the lack of specific cellular markers. In this regard, the gene encoding the transcription factor Runx1 has emerged as a specific marker of restricted neuronal populations in the murine central and peripheral nervous systems. The aim of this study was to precisely characterize the expression of Runx1 in the developing and postnatal mouse brainstem.Anatomical and immunohistochemical studies were used to characterize mouse Runx1 expression in the brainstem. It is shown here that Runx1 is expressed in a restricted population of neurons located in the dorsolateral rostral hindbrain. These neurons define a structure that is ventromedial to the dorsal nucleus of the lateral lemniscus, dorsocaudal to the medial paralemniscal nucleus and rostral to the cerebellum. Runx1 expression in these cells is first observed at approximately gestational day 12.5, persists into the adult brain, and is lost in knockout mice lacking the transcription factor Atoh1, an important regulator of the development of neuronal lineages of the rhombic lip. Runx1-expressing neurons in the rostral hindbrain produce cholecystokinin and also co-express members of the Groucho/Transducin-like Enhancer of split protein family.Based on the anatomical and molecular characteristics of the Runx1-expressing cells in the rostral hindbrain, we propose that Runx1 expression in this region of the mouse brain defines the superior lateral parabrachial nucleus

Establishment of Motor Neuron-V3 Interneuron Progenitor Domain Boundary in Ventral Spinal Cord Requires Groucho-Mediated Transcriptional Corepression

Background: Dorsoventral patterning of the developing spinal cord is important for the correct generation of spinal neuronal types. This process relies in part on cross-repressive interactions between specific transcription factors whose expression is regulated by Sonic hedgehog. Groucho/transducin-like Enhancer of split (TLE) proteins are transcriptional corepressors suggested to be recruited by at least certain Sonic hedgehog-controlled transcription factors to mediate the formation of spatially distinct progenitor domains within the ventral spinal cord. The aim of this study was to characterize the involvement of TLE in mechanisms regulating the establishment of the boundary between the most ventral spinal cord progenitor domains, termed pMN and p3. Because the pMN domain gives rise to somatic motor neurons while the p3 domain generates V3 interneurons, we also examined the involvement of TLE in the acquisition of these neuronal fates. Methodology and Principal Findings: A combination of in vivo loss- and gain-of-function studies in the developing chick spinal cord was performed to characterize the role of TLE in ventral progenitor domain formation. It is shown here that TLE overexpression causes increased numbers of p3 progenitors and promotes the V3 interneuron fate while suppressing the motor neuron fate. Conversely, dominant-inhibition of TLE increases the numbers of pMN progenitors and postmitotic motor neurons. Conclusion: Based on these results, we propose that TLE is important to promote the formation of the p3 domain an

Rhetoric and reality: Critical perspective on education in a 3D virtual world

The emergence of any new educational technology is often accompanied by inflated expectations about its potential for transforming pedagogical practice and improving student learning outcomes. A critique of the rhetoric accompanying the evolution of 3D virtual world education reveals a similar pattern, with the initial hype based more on rhetoric than research demonstrating the extent to which rhetoric matches reality. Addressed are the perceived gaps in the literature through a critique of the rhetoric evident throughout the evolution of the application of virtual worlds in education and the reality based on the reported experiences of experts in the field of educational technology, who are all members of the Australian and New Zealand Virtual Worlds Working Group. The experiences reported highlight a range of effective virtual world collaborative and communicative teaching experiences conducted in members’ institutions. Perspectives vary from those whose reality is the actuation of the initial rhetoric in the early years of virtual world education, to those whose reality is fraught with challenges that belie the rhetoric. Although there are concerns over institutional resistance, restrictions, and outdated processes on the one-hand, and excitement over the rapid emergence of innovation on the other, the prevailing reality seems to be that virtual world education is both persistent and sustainable. Explored are critical perspectives on the rhetoric and reality on the educational uptake and use of virtual worlds in higher education, providing an overview of the current and future directions for learning in virtual worlds

Rhetoric and reality: Critical perspective on education in a 3D virtual world

The emergence of any new educational technology is often accompanied by inflated expectations about its potential for transforming pedagogical practice and improving student learning outcomes. A critique of the rhetoric accompanying the evolution of 3D virtual world education reveals a similar pattern, with the initial hype based more on rhetoric than research demonstrating the extent to which rhetoric matches reality. Addressed are the perceived gaps in the literature through a critique of the rhetoric evident throughout the evolution of the application of virtual worlds in education and the reality based on the reported experiences of experts in the field of educational technology, who are all members of the Australian and New Zealand Virtual Worlds Working Group. The experiences reported highlight a range of effective virtual world collaborative and communicative teaching experiences conducted in members’ institutions. Perspectives vary from those whose reality is the actuation of the initial rhetoric in the early years of virtual world education, to those whose reality is fraught with challenges that belie the rhetoric. Although there are concerns over institutional resistance, restrictions, and outdated processes on the one-hand, and excitement over the rapid emergence of innovation on the other, the prevailing reality seems to be that virtual world education is both persistent and sustainable. Explored are critical perspectives on the rhetoric and reality on the educational uptake and use of virtual worlds in higher education, providing an overview of the current and future directions for learning in virtual worlds

The prevalence of triggers in paediatric migraine: a questionnaire study in 102 children and adolescents

The prevalence and characterization of migraine triggers have not been rigorously studied in children and adolescents. Using a questionnaire, we retrospectively studied the prevalence of 15 predefined trigger factors in a clinic-based population. In 102 children and adolescents fulfilling the Second Edition of The International Headache Classification criteria for paediatric migraine, at least one migraine trigger was reported by the patient and/or was the parents’ interpretation in 100% of patients. The mean number of migraine triggers reported per subject was 7. Mean time elapsed between exposure to a trigger factor and attack onset was comprised between 0 and 3 h in 88 patients (86%). The most common individual trigger was stress (75.5% of patients), followed by lack of sleep (69.6%), warm climate (68.6%) and video games (64.7%). Stress was also the most frequently reported migraine trigger always associated with attacks (24.5%). In conclusion, trigger factors were frequently reported by children and adolescents with migraine and stress was the most frequent

Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion

PURPOSE: We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune response and immune evasion in patients with NSCLC. EXPERIMENTAL DESIGN: We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti–PD-1/anti–PD-L1 drugs. RESULTS: As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell–excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti–PD-1/PD-L1 drugs. CONCLUSIONS: We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men. TRANSLATIONAL RELEVANCE: It is well known that sex (i.e., the biological differences between men and women) and gender (i.e., behavioral differences associated with being male or female) are variables that affect immune responses to both foreign and selfantigens. Such sex- and gender-based dimorphism of immune system function, in turn reflects complex interactions between genes, hormones, the environment, and commensal microbiome composition. In our previous works, we showed that patients' sex is significantly associated with effectiveness of immune checkpoint inhibitors (ICIs) in patients with several solid tumors, including NSCLC. Here, we identified meaningful differences in molecular mechanisms that drive anticancer immune response as well as in immune evasion mechanisms exploited by NSCLCs arising in men and women. Importantly, we showed that all the findings reported, were not related to other variables potentially associated with sex such as patients' age, stage of disease, tumor histotype, and smoking status. The findings reported in this our work explain our previous clinical observations and can open this area to different immunotherapy strategies in males and females with NSCLC to further improve prognosis of both

Virtual worlds in Australian and New Zealand higher education: remembering the past, understanding the present and imagining the future

3D virtual reality, including the current generation of multi-user virtual worlds, has had a long history of use in education and training, and it experienced a surge of renewed interest with the advent of Second Life in 2003. What followed shortly after were several years marked by considerable hype around the use of virtual worlds for teaching, learning and research in higher education. For the moment, uptake of the technology seems to have plateaued, with academics either maintaining the status quo and continuing to use virtual worlds as they have previously done or choosing to opt out altogether. This paper presents a brief review of the use of virtual worlds in the Australian and New Zealand higher education sector in the past and reports on its use in the sector at the present time, based on input from members of the Australian and New Zealand Virtual Worlds Working Group. It then adopts a forward-looking perspective amid the current climate of uncertainty, musing on future directions and offering suggestions for potential new applications in light of recent technological developments and innovations in the area

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Abstract Background: Elevated total homocysteine (tHcy) levels are associated with an increased risk of cerebrovascular disease. It is uncertain whether tHcy is also an independent risk factor for cognitive impairment. Methods: We examined 95 stroke subjects 3 months after their strokes, and 55 healthy comparison subjects, with a detailed neuropsychological assessment, and MRI brain scans in a proportion (n = 97). Baseline measurements of tHcy, serum folate and B 12 , creatinine and plasma fibrinogen levels were obtained. Results: tHcy levels were higher in the stroke subjects by a mean 34%. These levels were significantly correlated with the first factor of a principal component analysis of the neuropsychological data, after controlling for age, folate, B 12 and creatinine levels. The correlation of Hcy levels was particularly significant with frontal-executive functioning and attention. tHcy levels were significantly correlated with number of infarcts and total stroke volume in the stroke group, but not with T 2 -weighted deep white matter hyperintensity scores, after correction for age. In the control group, tHcy levels were significantly correlated with ventricle-tobrain ratios as measures of brain atrophy. Conclusion: This study provides evidence that high tHcy levels are associated with cognitive impairment, in particular that of frontal-executive function. The major component of this association is accounted for by small and large strokes, but non-vascular neurotoxic effects of tHcy also appear to play a role. tHcy must receive greater attention as a risk factor for cognitive impairment. Copyright © 2003 S. Karger AG, Basel Homocysteine (Hcy) is a sulfur-containing amino acid formed during the metabolism of the essential amino acid methionine. Elevated plasma homocysteine levels were first linked with vascular disease by McCully A high level of Hcy is both proatherogenic and prothrombotic If Hcy promotes cognitive impairment and is a risk factor for AD, it has important epidemiological implications. In this study, we examined plasma Hcy levels in a stroke sample to determine if there was an association between Hcy levels and cognition, and if this could be accounted for by infarct size or small vessel disease as detected by MRI. Methods Sample Subjects (n = 95) were consecutive patients admitted to two large teaching hospitals affiliated with the University of New South Wales who had recently suffered an ischemic stroke as diagnosed by two neurologists, and who met the diagnostic criteria for cerebral infarction Assessment Stroke subjects had a baseline assessment within 1 week of admission which included a detailed medical history and examination, history of risk factors for cerebrovascular disease and dementia, a functional assessment and the Mini-Mental State Examination Homocysteine Measurement Fasting blood was collected and centrifuged within 6 h, and the plasma stored at -20°C for later analysis. Total Hcy was measured using a fluorescence-based immunochemical technique with demonstrated high repeatability Neuropsychological Assessment Premorbid ability was estimated on the basis of performance on the National Adult Reading Test MRI Brain Scans MRI was performed on a proportion of subjects (n = 55 stroke; n = 42 controls) using a 1.5-T Signa GE magnet and the following protocol: a scout mid-sagittal cut (2D, TR 300 ms, TE 14 ms; 5 mm thick, number of excitations 1.5); 1.5-mm-thick T 1 -weighted contiguous coronal sections through whole brain using a FSPGR sequence and 3D acquisition (TR 14.3 ms, TE 5.4 ms); 4-mm-thick T 2 -weighted FLAIR coronal slices through whole brain (TR 8900, TE 145, TI 2200, FOV 25, 256 ! 192). Fifty-three subjects did not receive MRI scans because of claustrophobia or unwillingness to undergo the test. Analysis of Data Neuropsychological Tests. Raw scores were converted to agescaled scores using published norms [24-26, 28, 36, 38-41]. Composite z-scores were obtained for each domain. The raw scores from individual tests were also used in the exploratory analyses. MRI Scans. These were rated by a trained rater with good interrater (Î scores from 0.7 to 0.9 on various measures) and intra-rater (Î 0.8 to 0.9) reliability determined on five scans each. All ratings were carried out on a computer console using ANALYZE (Mayo Foundation) software. Brain infarctions were identified on T 1 -Homocysteine and Cognitive Impairment Dement Geriatr Cogn Disord 2003;15:155-162 15

Effect of sampling effort and sampling frequency on the composition of the planktonic crustacean assemblage: a case study of the river Danube

Although numerous studies have focused on the seasonal dynamics of riverine zooplankton, little is known about its short-term variation. In order to examine the effects of sampling frequency and sampling effort, microcrustacean samples were collected at daily intervals between 13 June and 21 July of 2007 in a parapotamal side arm of the river Danube, Hungary. Samples were also taken at biweekly intervals from November 2006 to May 2008. After presenting the community dynamics, the effect of sampling effort was evaluated with two different methods; the minimal sample size was also estimated. We introduced a single index (potential dynamic information loss; to determine the potential loss of information when sampling frequency is reduced. The formula was calculated for the total abundance, densities of the dominant taxa, adult/larva ratios of copepods and for two different diversity measures. Results suggest that abundances may experience notable fluctuations even within 1 week, as do diversities and adult/larva ratios