Numb Isoforms Deregulation in Medulloblastoma and Role of p66 Isoform in Cancer and Neural Stem Cells

Numb is an intracellular protein with multiple functions. The two prevalent isoforms, Numb p66 and Numb p72, are regulators of differentiation and proliferation in neuronal development. Additionally, Numb functions as cell fate determinant of stem cells and cancer stem cells and its abnormal expression has been described in several types of cancer. Involvement of deregulated Numb expression has been described in the malignant childhood brain tumor medulloblastoma, while Numb isoforms in these tumors and in cancer stem-like cells derived from them, have not been studied to date. Here we show that medulloblastoma stem-like cells and cerebellar neuronal stem cells (NSCs) express Numb p66 where its expression tampers stemness features. Furthermore, medulloblastoma samples evaluated in this study express decreased levels of Numb p66 while overexpressed Numb p72 compared with normal tissues. Our results uncover different roles for the two major Numb isoforms examined in medulloblastoma and a critical role for Numb p66 in regulating stem-like cells and NSCs maintenance

Sex-specific tonic 2-arachidonoylglycerol signaling at inhibitory inputs onto dopamine neurons of Lister Hooded rats

Addiction as a psychiatric disorder involves interaction of inherited predispositions and environmental factors. Similarly to humans, laboratory animals self-administer addictive drugs, whose appetitive properties result from activation and suppression of brain reward and aversive pathways, respectively. The ventral tegmental area (VTA) where dopamine (DA) cells are located is a key component of brain reward circuitry, whereas the rostromedial tegmental nucleus (RMTg) critically regulates aversive behaviors. Reduced responses to either aversive intrinsic components of addictive drugs or to negative consequences of compulsive drug taking might contribute to vulnerability to addiction. In this regard, female Lister Hooded (LH) rats are more vulnerable than male counterparts to cannabinoid self-administration. We, therefore, took advantage of sex differences displayed by LH rats, and studied VTA DA neuronal properties to unveil functional differences. Electrophysiological properties of DA cells were examined performing either single cell extracellular recordings in anesthetized rats or whole-cell patch-clamp recordings in slices. In vivo, DA cell spontaneous activity was similar, though sex differences were observed in RMTg-induced inhibition of DA neurons. In vitro, DA cells showed similar intrinsic and synaptic properties. However, females displayed larger depolarization-induced suppression of inhibition (DSI) than male LH rats. DSI, an endocannabinoid-mediated form of short term plasticity, was mediated by 2-arachidonoylglycerol (2-AG) activating type 1-cannabinoid (CB1) receptors. We found that sex-dependent differences in DSI magnitude were not ascribed to CB1 number and/or function, but rather to a tonic 2-AG signaling. We suggest that sex specific tonic 2-AG signaling might contribute to regulate responses to aversive intrinsic properties to cannabinoids, thus resulting in faster acquisition/initiation of cannabinoid taking and, eventually, in progression to addiction

Digital manufacturing challenges through open innovation perspective

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Comparative histology of the human and teleost fish thymus / Histologia Comparativa de timo de humanos e peixes teleósteos

Thymus is considered a key component of the vertebrates’ immune system. It is an organ that is only found in these animals whose development may be accompanied through the evolutionary scale, being considered as a facilitator and regulator in the interaction of lymphoid cells and lymphoid organs. In this study not only a morphological but also functional homology were demonstrated, in that it affects the immune system, of the humans and teleost fish thymus. The material of study was composed of the thymus tissue samples of humans who were donated by the Department of Pathology of Hospital Parmenio Piñero, Buenos Aires Argentina belonging to two patients with ages between 6 and 8 years, as well as specimens of fish from different origins. The thymic tissue samples were submitted to histological analysis, immunohistochemistry and transmission electron microscopy. Through the data shown here it is possible to consider that, both in fish as in humans, there are two tracks in the modulation of the immune response, an afferent pathway that begins with the presentation of the antigen and an efferent pathway through which  the result of the lymphocytes, antibodies stimulation  or other effector mechanisms are canalized. In these two phases both in humans and in fish, a mixed population of lymphocytes, the differentiation of lymphocytes in the thymus and the T4 lymphocytes production, play a fundamental role in the success of the immune response. Keywords:

Maternal immune activation disrupts dopamine system in the offspring

Background: In utero exposure to maternal viral infections is associated with a higher incidence of psychiatric disorders with a supposed neurodevelopmental origin, including schizophrenia. Hence, immune response factors exert a negative impact on brain maturation that predisposes the offspring to the emergence of pathological phenotypes later in life. Although ventral tegmental area dopamine neurons and their target regions play essential roles in the pathophysiology of psychoses, it remains to be fully elucidated how dopamine activity and functionality are disrupted in maternal immune activation models of schizophrenia. Methods: Here, we used an immune-mediated neurodevelopmental disruption model based on prenatal administration of the polyriboinosinic-polyribocytidilic acid in rats, which mimics a viral infection and recapitulates behavioral abnormalities relevant to psychiatric disorders in the offspring. Extracellular dopamine levels were measured by brain microdialysis in both the nucleus accumbens shell and the medial prefrontal cortex, whereas dopamine neurons in ventral tegmental area were studied by in vivo electrophysiology. Results: Polyriboinosinic-polyribocytidilic acid-treated animals, at adulthood, displayed deficits in sensorimotor gating, memory, and social interaction and increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex. In polyriboinosinic-polyribocytidilic acid rats, dopamine neurons showed reduced spontaneously firing rate and population activity. Conclusions: These results confirm that maternal immune activation severely impairs dopamine system and that the polyriboinosinic-polyribocytidilic acid model can be considered a proper animal model of a psychiatric condition that fulfills a multidimensional set of validity criteria predictive of a human patholog

Vulnerabilities in Mental Health due to Covid-19 Pandemic: The Response of the Italian Physicians

COVID-19 pandemic has exacerbated the pre-existing vulnerabilities and inequalities in societies. In this paper we analyse the categories that have suffered more than others from the pandemic and the restrictions on social life in terms of mental health. We rely on the Serendipity project based on a survey administered between November 2021 and February 2022 to a sample of Italian physicians (n = 1281). The survey aimed to assess the perception of general practitioners, paediatricians, geriatricians, and mental health specialists (psychiatrists, neurologists, child neuropsychiatrists), about changes in the mental health of the population as an effect of the COVID-19 pandemic and the lockdown. The strategies implemented by the doctors interviewed in terms of the intensity of the prevention, emergence, and treatment of mental health interventions, and their association with physicians' characteristics and their opinions on patient vulnerability have been illustrated by means of a multiple correspondence analysis. An overall result of the survey is the consensus of doctors on the worsening of mental health in general population, especially among their patients, due to the pandemic and on the onset of new discomforts. The most exposed individuals to the risk of onset or worsening of mental disorders include women, young people, and patients with psychiatric comorbidity. The paper also illustrates the interventions put in place by the physicians and deemed necessary from a public heath response perspective, that include providing psychoeducation to the general population, improving telehealth services, and increasing financial and human resources for community-based care

L-theanine prevents long-term affective and cognitive side effects of adolescent Δ-9-tetrahydrocannabinol exposure and blocks associated molecular and neuronal abnormalities in the mesocorticolimbic circuitry

Chronic adolescent exposure to Δ-9-tetrahydrocannabinol (THC) is linked to elevated neuropsychiatric risk and induces neuronal, molecular and behavioral abnormalities resembling neuropsychiatric endophenotypes. Previous evidence has revealed that the mesocorticolimbic circuitry, including the prefrontal cortex (PFC) and mesolimbic dopamine (DA) pathway are particularly susceptible to THC-induced pathologic alterations, including dysregulation of DAergic activity states, loss of PFC GABAergic inhibitory control and affective and cognitive abnormalities. There are currently limited pharmacological intervention strategies capable of preventing THC-induced neuropathological adaptations. L-Theanine is an amino acid analog of L-glutamate and L-glutamine derived from various plant sources, including green tea leaves. L-Theanine has previously been shown to modulate levels of GABA, DA, and glutamate in various neural regions and to possess neuroprotective properties. Using a preclinical model of adolescent THC exposure in male rats, we report that L-theanine pretreatment before adolescent THC exposure is capable of preventing long-term, THC-induced dysregulation of both PFC and VTA DAergic activity states, a neuroprotective effect that persists into adulthood. In addition, pretreatment with L-theanine blocked THC-induced downregulation of local GSK-3 (glycogen synthase kinase 3) and Akt signaling pathways directly in the PFC, two biomarkers previously associated with cannabis-related psychiatric risk and subcortical DAergic dysregulation. Finally, L-theanine powerfully blocked the development of both affective and cognitive abnormalities commonly associated with adolescent THC exposure, further demonstrating functional and long-term neuroprotective effects of L-theanine in the mesocorticolimbic system

Breast cancer radiation therapy: A bibliometric analysis of the scientific literature

Background and purpose: Breast cancer is the most common malignancy in women and radiation therapy (RT) is crucial in its multimodality management. Since bibliometrics is a powerful tool to reveal the scientific literature, we decided to perform a bibliometric analysis of the literature on breast cancer radiotherapy. We explored emerging trends and common patterns in research, tracking collaboration and networks, and foreseeing future directions in this clinical setting. Material and methods: The electronic Scopus database was searched using the keywords "breast cancer" and "radiotherapy" to include manuscripts published in English, between 2000 and 2021. Data analysis was performed using R-Studio 0.98.1091 software with a machine-learning bibliometric method, based on the bibliometrix R package. The most relevant authors were quantified per number and fractionalized number of authored documents. Author productivity was analysed through Lotka's law. Bradford's law was applied to identify the nucleus of journals focused on the addressed topic. Mainstream themes area included isolated topics (niche themes), new topics (emerging themes), hot topics (motor themes) and essential topics (basic themes). Results: A total of 27 184 documents was found, mainly original articles (76 %). The annual growth rate was 6.98 %, with an increase in scientific production from 485 to 2000 documents between 2000 and 2021. Overall, 2 544 journals published ≥ 1 documents. The most relevant authors were affiliated in the United States. Surgical procedures, cancer type and treatment strategies represented basic themes, while primary systemic therapy and sentinel lymph node biopsy were emerging themes. Health-related quality of life was a niche theme, while RT techniques had high centrality. Conclusion: The primary interests of breast cancer radiation oncologists have evolved over time, adding safety, health related quality of life, sustainability of treatments and combination to systemic therapies to radiotherapy efficacy and effectiveness and treatment outcomes

Effects Of Circum-nuclear Disk Gas Evolution And The Spin Of Central Black Holes

Mass and spin are the only two parameters needed to completely characterize black holes in General Relativity. However, the interaction between black holes and their environment is where complexity lies, as the relevant physical processes occur over a large range of scales. That is particularly relevant in the case of super-massive black holes (SMBHs), hosted in galaxy centers, and surrounded by swirling gas and various generations of stars. These compete with the SMBH for gas consumption and affect both dynamics and thermodynamics of the gas itself. How the behavior of such fiery environment influence the angular momentum of the gas accreted onto SMBHs, and, hence, black-hole spins is uncertain. We explore the interaction between SMBHs and their environment via first 3D sub-parsec resolution simulations (ranging from 0.1 pc to 1 kpc scales) that study the evolution of the SMBH spin by including the effects of star formation, stellar feedback, radiative transfer, and metal pollution according to the proper stellar yields and lifetimes. This approach is crucial to investigate the impact of star formation processes and feedback effects on the angular momentum of the material that could accrete on the central hole. We find that star formation and feedback mechanisms can locally inject significant amounts of entropy in the surrounding medium, and impact on the inflow inclination angles and Eddington fractions. As a consequence, the resulting trends show upper-intermediate equilibrium values for the spin parameter, a, of about 0.6 - 0.9, corresponding to radiative efficiencies \epsilon = 9% - 15%. These results suggest that star formation feedback taking place in the circum-nuclear disk during the in-fall cannot induce alone very strong chaotic trends in the gas flow, quite independently from the different numerical parameters.Comment: Changes in title and updates in references. Inclusion of additional runs and parameter studies. Conclusions unaffected. Accepte

Repeated exposure to JWH-018 induces adaptive changes in the mesolimbic and mesocortical dopamine pathways, glial cells alteration and behavioural correlates

Spice/K2 herbal mixtures, containing synthetic cannabinoids such as JWH-018, have been marketed as marijuana surrogates since 2004. We demonstrated that JWH-018 has cannabinoid CB1 receptor-dependent reinforcing properties and acutely increases dopamine transmission selectively in the NAc shell. Here we tested the hypothesis that repeated administration of JWH-018 (i) modulates behaviour, (ii) affects dopamine transmission and its responsiveness to motivational stimuli, and (iii) is associated with a neuroinflammatory phenotype