Locomotion and morphological adaptations in the glass lizard Ophiodes cf. fragilis (Raddi, 1820) (Squamata: Anguidae).

There are few studies related to the biological and ecological aspects of the glass snake, a limbless lizard and with a wide geographic distribution. The aim of this study was to analyze the locomotion mode of specimens of Ophiodes cf. fragilis in different substrates and to investigate the morphological adaptations associated with this type of behavior. We observed that the analyzed specimens presented slide-push locomotion modes and lateral undulation in different substrates, using their hind limbs to aid locomotion in three of the four substrates analyzed. The bones of the hind limbs (proximal - femur - and distal - tibia and fibula) were present and highly reduced and the femur is connected to a thin pelvic girdle. Our data support that hind limbs observed in species of this genus are reduced rather than vestigial. The costocutaneous musculature was macroscopically absent. This is the first study of locomotor behavior and morphology associated with locomotion in Ophiodes, providing important information for studies on morphological evolution in the genus.

EFFECTS OF THE USE OF BETA-BLOCKERS ON CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ASSOCIATED WITH CARDIOVASCULAR COMORBITIES: SYSTEMATIC REVIEW AND META-ANALYSIS.

Introduction: Cardiovascular comorbidity is common in individuals with Chronic obstructive pulmonary disease (COPD). These factor interferes in pharmacological treatment. The use of beta-blockers has been proposed for their known cardioprotective effects. However, there is a reluctance to use them due to adverse reactions and the risk of causing bronchospasm. Objective: To summarize existing evidences on the effects of beta-blocker use in COPD associated with cardiovascular comorbidities in relation to disease severity, exacerbation and mortality outcomes. Material and Methods: EMBASE, Medline, Lilacs, Cochrane Library and Science Direct databases were used. Study selection and data extraction, observational studies were included that evaluated the effects of beta-blockers in individuals with COPD and cardiovascular comorbidities, and related disease severity, exacerbations, or mortality to outcomes. Studies that did not present important information about the sample and pharmacological treatment were excluded. Twenty studies were included. Results: Relevance to patient care and clinical practice: The use of beta-blockers in individuals with COPD and cardiovascular disease caused positive effects on mortality and exacerbations outcomes compared with the results of individuals who did not use them. The severity of the disease caused a slight change in FEV1. The OR for mortality was 0.50 (95 % CI: 0.39-0.63; p-value <0.00001) and for exacerbations 0.76 (95 % CI: 0.62-0.92; p -value = 0.005), being favorable to the group that used beta-blockers. Conclusion: Further studies are needed to study the effect of using a specific beta-blocker in COPD associated with a specific cardiovascular comorbidity.

Somatostatin and the pathophysiology of Alzheimer's disease.

Among the central features of Alzheimer's disease (AD) progression are altered levels of the neuropeptide somatostatin (SST), and the colocalisation of SST-positive interneurons (SST-INs) with amyloid-ß plaques, leading to cell death. In this theoretical review, I propose a molecular model for the pathogenesis of AD based on SST-IN hypofunction and hyperactivity. Namely, hypofunctional and hyperactive SST-INs struggle to control hyperactivity in medial regions in early stages, leading to axonal Aß production through excessive presynaptic GABAB inhibition, GABAB1a/APP complex downregulation and internalisation. Concomitantly, excessive SST-14 release accumulates near SST-INs in the form of amyloids, which bind to Aß to form toxic mixed oligomers. This leads to differential SST-IN death through excitotoxicity, further disinhibition, SST deficits, and increased Aß release, fibrillation and plaque formation. Aß plaques, hyperactive networks and SST-IN distributions thereby tightly overlap in the brain. Conversely, chronic stimulation of postsynaptic SST2/4 on gulutamatergic neurons by hyperactive SST-INs promotes intense Mitogen-Activated Protein Kinase (MAPK) p38 activity, leading to somatodendritic p-tau staining and apoptosis/neurodegeneration - in agreement with a near complete overlap between p38 and neurofibrillary tangles. This model is suitable to explain some of the principal risk factors and markers of AD progression, including mitochondrial dysfunction, APOE4 genotype, sex-dependent vulnerability, overactive glial cells, dystrophic neurites, synaptic/spine losses, inter alia. Finally, the model can also shed light on qualitative aspects of AD neuropsychology, especially within the domains of spatial and declarative (episodic, semantic) memory, under an overlying pattern of contextual indiscrimination, ensemble instability, interference and generalisation.

Global IL4Rα blockade exacerbates heart failure after an ischemic event in mice and humans.

Ischemic heart failure continues to be a highly prevalent disease among westernized countries and there is great interest in understanding the mechanisms preventing or exacerbating disease progression. The literature suggests an important role for the activation of interleukin-13 or interleukin-4 signaling in improving ischemic heart failure outcomes after myocardial infarction in mice. Dupilumab, a neutralizing antibody that inhibits the shared IL13/IL4 receptor subunit IL4Rα, is widely used for conditions such as ectopic dermatitis in humans. If global depletion of IL4Rα influences ischemic heart failure, either in mice or in humans taking dupilumab, is unknown. Here, we investigated the pathophysiological effects of global IL4Rα genetic deletion in adult mice after surgically induced myocardial infarction (MI). We also determined heart failure risk in patients with ischemic heart disease and concomitant usage of dupilumab using the collaborative patient data network TriNetX. Global deletion of IL4Rα results in exacerbated cardiac dysfunction associated with reduced capillary size after myocardial infarction in mice. In agreement with our findings in mice, dupilumab treatment significantly increased the risk of heart failure development in patients with preexisting diagnosis of ischemic heart disease. Our results indicate that systemic IL4Rα signaling is protective against heart failure development in adult mice and human patients specifically following an ischemic event. Thus, the compelling evidence presented hereby advocates for the development of a randomized clinical trial specifically investigating heart failure development after myocardial ischemia in patients taking dupilumab for another underlying condition.NEW & NOTEWORTHY A body of literature suggests a protective role for IL4Rα signaling postmyocardial infarction in mice. Here, our observational study demonstrates that humans taking the IL4Rα neutralizing antibody, dupilumab, have increased incidence of heart failure following an ischemic event. Similarly, global IL4Rα deletion in mice exacerbates heart failure postinfarct. To our knowledge, this is the first study reporting an adverse association in humans of dupilumab use with heart failure following a cardiac ischemic event.

IL-13 promotes functional recovery after myocardial infarction via direct signaling to macrophages.

There is great interest in identifying signaling pathways that promote cardiac repair after myocardial infarction (MI). Prior studies suggest a beneficial role for IL-13 signaling in neonatal heart regeneration; however, the cell types mediating cardiac regeneration and the extent of IL-13 signaling in the adult heart after injury are unknown. We identified an abundant source of IL-13 and the related cytokine, IL-4, in neonatal cardiac type 2 innate lymphoid cells, but this phenomenon declined precipitously in adult hearts. Moreover, IL-13 receptor deletion in macrophages impaired cardiac function and resulted in larger scars early after neonatal MI. By using a combination of recombinant IL-13 administration and cell-specific IL-13 receptor genetic deletion models, we found that IL-13 signaling specifically to macrophages mediated cardiac functional recovery after MI in adult mice. Single transcriptomics revealed a subpopulation of cardiac macrophages in response to IL-13 administration. These IL-13-induced macrophages were highly efferocytotic and were identified by high IL-1R2 expression. Collectively, we elucidated a strongly proreparative role for IL-13 signaling directly to macrophages following cardiac injury. While this pathway is active in proregenerative neonatal stages, reactivation of macrophage IL-13 signaling is required to promote cardiac functional recovery in adults.

The utilisation of primary health care system concepts positively impacts the assistance of patients with rare diseases despite limited knowledge and experience by health care professionals: A qualitative synopsis of the evidence including approximately 78 000 individuals.

Background: Individuals with rare diseases (RD) have been historically understudied. Previous publications reported that existing primary health care (PHC) workforces and associated infrastructure had been shown to improve their access and health-related outcomes in low- and middle-income countries (LMICs). As current evidence about the impact of PHC on patients diagnosed with RD is yet highly dispersed, this scoping review aimed to collate available evidence of the impact of PHC on patients with RD and summarize published information from multiple stakeholders about the perceived usefulness and barriers to effective use of the PHC system. Methods: We searched Embase, Health System Evidence, PubMed, LILACS / BVS, and The Cochrane Library, from inception to September 1, 2022, for publications providing clear expert- or experience-based insights or data from patients living with RD at the PHC level of care. We included publications highlighting barriers to integrated care of patients with RD, reported by multiple social actors involved in caring for patients with RD. Two investigators screened publications, extracted data, and clustered information among records deemed eligible for inclusion. Data synthesis was performed using narrative and thematic-based analysis. Major findings identified and coded through a semantic-driven analysis were processed in vosViewer software and reported using descriptive statistics. Findings: Eighty publications were included in this review. Quali-quantitative analyses evidenced that the PHC level is essential for approaching patients with RD, mainly due to its longitudinal, multidisciplinary, and coordinated care delivery. In addition, several publications highlighted that the medical curriculum is inappropriate for preparing health care providers to deal with patients presenting unusual signs and symptoms and being diagnosed with RD. PHC teams are essential in orienting patients and families on emergency events. Technology-related concepts were reported in 19 publications, emphasizing their effectiveness on early diagnosis, optimal treatment definition, improvement of quality of life, and long-lasting follow-up. Conclusions: We provided valuable information on the effectiveness of the PHC in fostering a creative, integrative, and supportive environment for patients living with RD. Our results can be helpful to several stakeholders in deciding what actions are still pending to achieve a solid and positive experience for patients with RD in the PHC. Registration: PROSPERO (CRD42022332347).

Bipedicled and structured mammoplasty "in three pillars" / Mamoplastia bipediculada e estruturada "em três pilares"

Introduction: Reduction mammoplasty has a long and established history. Since the end of the 19th century, numerous techniques for reducing and elevating breast tissue have been described, seeking the best aesthetic result and greater safety in relation to areolar vascularization and innervation. The purpose of the present study is to describe a new bipedicled and structured mammoplasty technique: safe, reproducible, with a fast-learning curve and predictable esthetic results. Methods: From January 2015 to August 2021, 86 patients underwent surgical treatment of mammoplasty using the technique in question. The analysis of the cases was carried out retrospectively through the evaluation of medical records and review of pre and postoperative photographs. Results: The support and projection achieved were lasting results. There were no hematomas or necrosis of the nipple-areola complex or other areas. Conclusion: The technique has high reproducibility, easy execution, high applicability and versatility, extremely satisfactory aesthetic and functional results for surgeon and patient, and above all, a high degree of safety.

Introdução: A mamoplastia redutora tem uma história longa e estabelecida. Desde o final do século XIX, foram descritas inúmeras técnicas para redução e elevação do tecido mamário, buscando não apenas o melhor resultado estético, como também maior segurança em relação a vascularização e inervação areolar. O presente estudo tem como propósito a descrição de uma nova técnica de mamoplastia bipediculada e estruturada: segura, reprodutível, de baixa curva de aprendizado e com resultados estéticos previsíveis. Método: De janeiro de 2015 a agosto de 2021, 86 pacientes foram submetidas ao tratamento cirúrgico de mamoplastia com a utilização da técnica em questão. A análise dos casos foi realizada de forma retrospectiva, através de avaliação de prontuários e revisão de fotografias de pré e pós-operatório. Resultados: A sustentação e projeção atingidas foram duradouras. Não houve ocorrência de hematomas ou necrose do complexo areolomamilar ou de quaisquer outras áreas. Conclusão: Tratase de uma técnica de alta reprodutibilidade, fácil execução, alta aplicabilidade e versatilidade, resultados estéticos e funcionais extremamente satisfatórios para cirurgião e paciente, além de, principalmente, um alto grau de segurança.

Myofibroblast Ccn3 is regulated by Yap and Wwtr1 and contributes to adverse cardiac outcomes.

Introduction: While Yap and Wwtr1 regulate resident cardiac fibroblast to myofibroblast differentiation following cardiac injury, their role specifically in activated myofibroblasts remains unexplored. Methods: We assessed the pathophysiological and cellular consequence of genetic depletion of Yap alone (Yap fl/fl ;Postn MCM ) or Yap and Wwtr1 (Yap fl/fl ;Wwtr1 fl/+ ;Postn MCM ) in adult mouse myofibroblasts following myocardial infarction and identify and validate novel downstream factors specifically in cardiac myofibroblasts that mediate pathological remodeling. Results: Following myocardial infarction, depletion of Yap in myofibroblasts had minimal effect on heart function while depletion of Yap/Wwtr1 resulted in smaller scars, reduced interstitial fibrosis, and improved ejection fraction and fractional shortening. Single cell RNA sequencing of interstitial cardiac cells 7 days post infarction showed suppression of pro-fibrotic genes in fibroblasts derived from Yap fl/fl ,Wwtr1 fl/+ ;Postn MCM hearts. In vivo myofibroblast depletion of Yap/Wwtr1 as well in vitro knockdown of Yap/Wwtr1 dramatically decreased RNA and protein expression of the matricellular factor Ccn3. Administration of recombinant CCN3 to adult mice following myocardial infarction remarkably aggravated cardiac function and scarring. CCN3 administration drove myocardial gene expression of pro-fibrotic genes in infarcted left ventricles implicating CCN3 as a novel driver of cardiac fibrotic processes following myocardial infarction. Discussion: Yap/Wwtr1 depletion in myofibroblasts attenuates fibrosis and significantly improves cardiac outcomes after myocardial infarction and we identify Ccn3 as a factor downstream of Yap/Wwtr1 that contributes to adverse cardiac remodeling post MI. Myofibroblast expression of Yap, Wwtr1, and Ccn3 could be further explored as potential therapeutic targets for modulating adverse cardiac remodeling post injury.

Esquecidos após a exclusão escolar: uma meta-análise do estudo da deriva educacional / Forgotten after school exclusion: an educational drift study meta-analysis / Olvidados tras la exclusión escolar: un metanálisis del estudio de la deriva educativa

Este artigo tem como objetivo analisar os desafios e possibilidades encontradas no estudo da deriva educacional, condição em que os sujeitos já estiveram na escola, mas foram dela excluídos antes de concluir a educação básica, sendo responsabilizados pelo retorno aos estudos. Trata-se de um ensaio teórico-metodológico que foca no pensamento categorial, sobretudo a categoria da dimensão subjetiva como recurso para apreensão da concreticidade do fenômeno social estudado. A deriva educacional é um fenômeno social pouco estudado no campo da Psicologia da Educação e a possibilidade de explicá-lo é desafiadora, tendo em vista as armadilhas presentes nos discursos carregados da intenção de ocultar o modo como se trata de uma condição social e historicamente determinada no modo de produção capitalista. Diante dessa dificuldade, ter como base teórico-etodológica o Materialismo Histórico-dialético (MHD) e a Psicologia Sócio-histórica (PSH) foi fundamental. O pensamento categorial possibilitou, partindo das significações dos participantes da pesquisa, superar as múltiplas camadas de aparência para compreender a deriva educacional em sua complexidade. A categoria da dimensão subjetiva e o processo de análise por meio dos núcleos de significação possibilitaram chegar a uma síntese das múltiplas determinações da deriva educacional que permitiu explicá-la de forma contra-hegemônica, apontando para os movimentos já existentes ou ainda necessários para a transformação, sem recorrer à justificativas individualizantes, psicologizantes ou sociologizantes. (AU)

This article aims to analyze the challenges and possibilities experienced in the educational drift study, condition in which the subjects had already been to school, but were excluded from it before completing basic education, being held responsible for returning to their studies. This is a theoretical-methodological essay that focuses on categorical thinking, especially the subjective dimension category as a resource for apprehending the social phenomenon concreteness. Educational drift is a social phenomenon on which there are few studies in the field of Educational Psychology. The possibility of explaining this issue is a challenge, since the pitfalls present in the discourses intended to hide the way in which it is a social and historically determined condition in the capitalist mode of production. Faced with this difficulty, it was fundamental to have Historical-Dialectical Materialism (MHD) and Socio-Historical Psychology (PSH) as a theoreticalmethodological basis. The categorical thinking enabled us, starting from the research participants significations, to overcome the appearance of multiple layers and to understand the educational drift in its complexity. The subjective dimension category and the analysis processes through the signification nuclei made it possible to reach an educational drift multiple determinations synthesis that allowed us to explain the issue in a counter-hegemonic way, pointing to the already existing or still necessary movements to transformation, without resorting to individualizing, psychologizing or sociologizing justifications. (AU)

Este artículo tiene como objetivo analizar los desafíos y las posibilidades encontradas en el estudio de la deriva educativa, condición en la que los sujetos ya habían ido a la escuela, pero fueron excluidos de ella antes de completar la educación básica, siendo responsables de regresar a sus estudios. Este es un ensayo teórico-metodológico que se centra en el pensamiento categorial, en especial la categoría de la dimensión subjetiva como recurso para aprehender la concreción del fenómeno social estudiado. Este es un fenómeno social poco estudiado en el campo de la Psicología Educativa, y la posibilidad de explicarlo es desafiante, dadas las trampas presentes en los discursos cargados con la intención de ocultar la forma en que es una condición social e históricamente determinada en la forma de producción capitalista. Ante esta dificultad, tener como base teórico-metodológica el Materialismo Histórico-Dialéctico (MHD) y la Psicología Socio-Histórica (PSH) fue fundamental. El pensamiento categórico nos permitió, a partir de los significados de los participantes de la investigación, superar las múltiples capas de apariencia para comprender la deriva educativa en su complejidad. La categoría de la dimensión subjetiva y los procesos de análisis a través de los núcleos de significación permitieron llegar a una síntesis de múltiples determinaciones de la deriva educativa que permitieron explicarla de manera contrahegemónico, apuntando a los movimientos ya existentes o aún necesarios a la transformación, sin recurrir a justificaciones individualizantes, psicologizantes o sociologizantes.(AU)

Semantic processing and neurobiology in Alzheimer's disease and Mild Cognitive Impairment.

In the present theoretical review we will perform a critical surveillance of linguistic and semantic processing in Mild Cognitive Impairment and Alzheimer's disease, explicitly favouring a neurobiological prism. We conjecture that most linguistic alterations arise from semantic indiscrimination through inhibitory hypofunction. Specifically, a conjoint cluster of cholinergic dysfunction, Aß load and somatostatin-positive cell loss renders the semantic network disinhibited and overly noisy: fine discriminatory processes in temporal and medial-frontal regions cannot differentiate semantic representations from baseline unconscious activity, which leads to failures in faithful retrieval (preferentially idiosyncratic lexical-semantic links, e.g., proper names), verbal fluency anomalies, semantic interference, dampened N400 effects, and various semiological deviances.

Prevalence and Impact of Comorbidities in Individuals with Chronic Obstructive Pulmonary Disease: A Systematic Review.

This study aimed to describe the prevalence of comorbidities associated with chronic obstructive pulmonary disease (COPD) and their relation with relevant outcomes. A systematic review based on the PRISMA methodology was performed from January 2020 until July 2021. The MEDLINE, Lilacs, and Scielo databases were searched to identify studies related to COPD and its comorbidities. Observational studies on the prevalence of comorbidities in COPD patients and costs with health estimates, reduced quality of life, and mortality were included. Studies that were restricted to one or more COPD pain assessments and only specific comorbidities such as osteoporosis, bronchitis, and asthma were excluded. The initial search identified 1,409 studies and after applying the inclusion and exclusion criteria, 20 studies were finally selected for analysis (comprising data from 447,459 COPD subjects). The most frequent COPD comorbidities were: hypertension (range, 17%-64.7%), coronary artery disease (19.9%-47.8%), diabetes (10.2%-45%), osteoarthritis (18%-43.8%), psychiatric conditions (12.1%-33%), and asthma (14.7%-32.5%). Several comorbidities had an impact on the frequency and severity of COPD exacerbations, quality of life, and mortality risk, in particular malignancies, coronary artery disease, chronic heart failure, and cardiac arrhythmias. Comorbidities, especially cardiovascular diseases and diabetes, are frequent in COPD patients, and some of them are associated with higher mortality.

The neural hierarchy of consciousness: A theoretical model and review on neurophysiology and NCCs.

The chief undertaking in the studies of consciousness is that of unravelling the neural correlates of consciousness. To this day, this crusade remains at an impasse, with a clash of two main theoretical stances: the Global Neuronal Workspace and the Recurrent Processing. Yet, cellular and neurophysiological studies of consciousness have been mostly dissociated from the two. Herein, a theoretical review will be put forth with the aim to change that. In its first half, I will cover the hard available evidence on the neurophysiology of consciousness, and in its second half, I will weave a theoretical model that reconciles the all-or-none cortical ignition (P3b) and graded recurrent processing (VAN) theories on the basis of neurophysiological evidence. As should be made clear, this Neural Hierarchy model substantiates and expands on a novel take on conscious awareness: the levels of processing approach, partitioning the conscious architecture into lower- and higher-order, graded and nonlinear.

Knockdown of the inducible nitric oxide synthase (NOS2) splicing variant S3 promotes autophagic cell death from nitrosative stress in SW480 human colon cancer cells.

Low levels of nitric oxide (NO) produced by constitutively expressed inducible NO synthase (NOS2) in tumor cells may be an important factor in their development. NOS2 expression is associated with high mortality rates for various cancers. Alternative splicing of NOS2 down-regulates its enzymatic activity, resulting in decreased intracellular NO concentrations. Specific probes to detect alternative splicing of NOS2 were used in two isogenic human colon cancer cell lines derived either from the primary tumor (SW480) or from a lymph node metastasis (SW620). Splicing variant of NOS2 S3, lacking exons 9, 10, and 11, was overexpressed in SW480 cells. NOS2 S3 was silenced in SW480 cells. Flow-cytometry analysis was used to estimate the intracellular NO levels and to analyze the cell cycle of the studied cell lines. Western blot analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were used to determine apoptosis and autophagy markers. SW480 and SW620 cells expressed NOS2 S3. Overexpression of the NOS2 S3 in SW480 cells downregulated intracellular NO levels. SW480 cells with knocked down NOS2 S3 (referred to as S3C9 cells) had higher intracellular levels of NO compared to the wild-type SW480 cells under serum restriction. Higher NO levels resulted in the loss of viability of S3C9 cells, which was associated with autophagy. Induction of autophagy by elevated intracellular NO levels in S3C9 cells under serum restriction, suggests that autophagy operates as a cytotoxic response to nitrosative stress. The expression of NOS2 S3 plays an important role in regulating intracellular NO production and maintaining viability in SW480 cells under serum restriction. These findings may prove significant in the design of NOS2/NO-based therapies for colon cancer.

Subcortical Aphasia.

PURPOSE OF REVIEW: Subcortical structures have long been thought to play a role in language processing. Increasingly spirited debates on language studies, arising from as early as the nineteenth century, grew remarkably sophisticated as the years pass. In the context of non-thalamic aphasia, a few theoretical frameworks have been laid out. The disconnection hypothesis postulates that basal ganglia insults result in aphasia due to a rupture of connectivity between Broca and Wernicke's areas. A second viewpoint conjectures that the basal ganglia would more directly partake in language processing, and a third stream proclaims that aphasia would stem from cortical deafferentation. On the other hand, thalamic aphasia is more predominantly deemed as a resultant of diaschisis. This article reviews the above topics with recent findings on deep brain stimulation, neurophysiology, and aphasiology. RECENT FINDINGS: The more recent approach conceptualizes non-thalamic aphasias as the offspring of unpredictable cortical hypoperfusion. Regarding the thalamus, there is mounting evidence now pointing to leading contributions of the pulvinar/lateral posterior nucleus and the anterior/ventral anterior thalamus to language disturbances. While the former appears to relate to lexical-semantic indiscrimination, the latter seems to bring about a severe breakdown in word selection and/or spontaneous top-down lexical-semantic operations. The characterization of subcortical aphasias and the role of the basal ganglia and thalamus in language processing continues to pose a challenge. Neuroimaging studies have pointed a path forward, and we believe that more recent methods such as tractography and connectivity studies will significantly expand our knowledge in this particular area of aphasiology.

Semantic priming and neurobiology in schizophrenia: A theoretical review.

In this theoretical review we bridge the cognitive and neurobiological sciences to shed light on the neurocognitive foundations of the semantic priming effect in schizophrenia. We review and theoretically evaluate the neurotransmitter systems (dopaminergic, GABAergic and glutamatergic) and neurobiological underpinnings of behavioural and electrophysiological (N400) semantic priming in the pathology, and the main hypotheses on their geneses: a disinhibition of the semantic spread of activation, a disorganised semantic storage or noisy lexical-semantic associations, a psychomotor artefact, an artefact of relatedness proportions, or an inability to mobilise contextual information. We further assess the literature on the endophenotype of Formal Thought Disorder from multiple standpoints, ranging from neurophysiology to cognition: considerations are weaved on neuronal (PV basket cell, SST, VIP) and receptor deficits (DRD1, NMDA), neurotransmitter imbalances (dopamine), cortical and dopaminergic lateralisation, inter alia. In conclusion, we put forth novel postulates on the underlying causes of controlled hypopriming, automatic hyperpriming, N400 reversals (larger amplitudes for close associations), indirect versus direct hyperpriming, and the endophenotype of lexical-semantic disturbances in schizophrenia.

IL4Rα signaling promotes neonatal cardiac regeneration and cardiomyocyte cell cycle activity.

Neonatal heart regeneration depends on proliferation of pre-existing cardiomyocytes, yet the mechanisms driving regeneration and cardiomyocyte proliferation are not comprehensively understood. We recently reported that the anti-inflammatory cytokine, interleukin 13 (IL13), promotes neonatal cardiac regeneration; however, the signaling pathway and cell types mediating this regenerative response remain unknown. Here, we hypothesized that expression of the type II heterodimer receptor for IL13, comprised of IL4Rα and IL13Rα1, expressed directly on cardiomyocytes mediates cardiomyocyte cell cycle and heart regeneration in neonatal mice. Our data demonstrate that indeed global deletion of one critical subunit of the type II receptor, IL4Rα (IL4Rα-/-), decreases cardiomyocyte proliferation during early postnatal development and significantly impairs cardiac regeneration following injury in neonatal mice. While multiple myocardial cell types express IL4Rα, we demonstrate that IL4Rα deletion specifically in cardiomyocytes mediates cell cycle activity and neonatal cardiac regeneration. This demonstrates for the first time a functional role for IL4Rα signaling directly on cardiomyocytes in vivo. Reciprocally, we examined the therapeutic benefit of activating the IL4Rα receptor in non-regenerative hearts via IL13 administration. Following myocardial infarction, administration of IL13 reduced scar size and promoted cardiomyocyte DNA synthesis and karyokinesis, but not complete cytokinesis, in 6-day old non-regenerative mice. Our data demonstrate a novel role for IL4Rα signaling directly on cardiomyocytes during heart regeneration and suggest the potential for type II receptor activation as one potential therapeutic target for promoting myocardial repair.

Neurophysiological basis of the N400 deflection, from Mismatch Negativity to Semantic Prediction Potentials and late positive components.

The first theoretical model on the neurophysiological basis of the N400: the deflection reflects layer I dendritic plateaus on a preparatory state of synaptic integration that precedes layer V somatic burst firing for conscious identification of the higher-order features of the stimulus (a late positive shift). Plateaus ensue from apical disinhibition by vasoactive intestinal polypeptide-positive interneurons (VIPs) through suppression of Martinotti cells, opening the gates for glutamatergic feedback to trigger dendritic regenerative potentials. Cholinergic transients contribute to these dynamics directly, holding a central role in the N400 deflection. The stereotypical timing of the (frontal) glutamatergic feedback and the accompanying cholinergic transients account for the enigmatic "invariability" of the peak latency in the face of a gamut of different stimuli and paradigms. The theoretical postulations presented here may bring about unprecedented level of detail for the N400 deflection to be used in the study of schizophrenia, Alzheimer's disease and other higher-order pathologies. The substrates of a late positive component, the Mismatch Negativity and the Semantic Prediction Potentials are also surveyed.