m(6)A methyltransferase METTL3 relieves cognitive impairment of hyperuricemia mice via inactivating MyD88/NF-κB pathway mediated NLRP3-ASC-Caspase1 inflammasome.

BACKGROUND: Recent studies have uncovered that hyperuricemia (HUA) leads to cognitive deficits, which are accompanied by neuronal damage and neuroinflammation. Here, we aim to explore the role of methyltransferase-like 3 (METTL3) in HUA-mediated neuronal apoptosis and microglial inflammation. METHODS: A HUA mouse model was constructed. The spatial memory ability of the mice was assessed by the Morris water maze experiment (MWM), and neuronal apoptosis was analyzed by the TdT-mediated dUTP nick end labeling (TUNEL) assay. Besides, enzyme-linked immunosorbent assay (ELISA) was utilized to measure the contents of inflammatory factors (IL-1ß, IL-6, and TNF-α) and oxidative stress markers (MDA, SOD, and CAT) in the serum of mice. In vitro, the mouse hippocampal neuron (HT22) and microglia (BV2) were treated with uric acid (UA). Flow cytometry was applied to analyze HT22 and BV2 cell apoptosis, and ELISA was conducted to observe neuroinflammation and oxidative stress. In addition, the expression of MyD88, p-NF-κB, NF-κB, NLRP3, ASC and Caspase1 was determined by Western blot. RESULTS: METTL3 and miR-124-3p were down-regulated, while the MyD88-NF-κB pathway was activated in the HUA mouse model. UA treatment induced neuronal apoptosis in HT22 and stimulated microglial activation in BV2. Overexpressing METTL3 alleviated HT22 neuronal apoptosis and resisted the release of inflammatory cytokines and oxidative stress mediators in BV2 cells. METTL3 repressed MyD88-NF-κB and NLRP3-ASC-Caspase1 inflammasome. In addition, METTL3 overexpression enhanced miR-124-3p expression, while METTL3 knockdown aggravated HT22 cell apoptosis and BV2 cell overactivation. CONCLUSION: METTL3 improves neuronal apoptosis and microglial activation in the HUA model by choking the MyD88/NF-κB pathway and up-regulating miR-124-3p.

E-Health Ultrasonic Diagnostic Monitoring for Analysis of Cardiac Insufficiency and Neuronal Regulation in Patients with Sepsis in Emergency Department under Image Reconstruction Algorithm.

An anisotropic diffusion filtering- (ADF-) ultrasound (ADF-U) for ultrasound reconstruction was constructed based on the ADF to explore the diagnostic application of ultrasound imaging based on electronic health (E-health) for cardiac insufficiency and neuronal regulation in patients with sepsis. The 144 patients with sepsis were divided into an experimental group (78 patients with cardiac insufficiency) and a control group (66 patients with normal cardiac function), and another 58 healthy people were included in a blank control. The ultrasound examination was performed on all patients. In addition, new ultrasound image reconstruction and diagnosis were performed based on ADF and E-health, and its reconstruction effects were compared with those of the Bilateral Filter-ultrasonic (BFU) algorithm and the Wavelet Threshold-ultrasonic (WTU) algorithm. The left and right ventricular parameters and neuropeptide levels were detected and recorded. The results show that the running time, average gradient (AG), and peak signal-to-noise ratio (SNR) (PSNR) of the ADF-U algorithm were greater than those of the Bilateral Filter-ultrasonic (BFU) and Wavelet Threshold-ultrasonic (WTU), but the mean square error (MSE) was opposite (P < 0.05); the left ventricular end-systolic volume (LVESV) and the vertical distance between the mitral valve E-point to septal separation (EPSS) in the experimental group were higher than those in the control and blank group, while the left ventricular ejection fraction (LVEF), stroke volume (SV), cardiac output (CO), and left ventricular fractional shortening (LVFS) were opposite (P < 0.05); the systolic peak velocity of right ventricular free wall tricuspid annulus (Sm) and pulmonary valve blood velocity (PVBV) in the experimental group were lower than those of the control group and blank group (P < 0.05); the messenger ribonucleic acid (mRNA) of Proopiomelanocortin (POMC) and Cocain and amphetamine-regulated transcript (CART) was higher than the mRNA IN control group and blank group (P < 0.05). In short, the ADF-U algorithm proposed in this study improved the resolution, SNR, and reconstruction efficiency of E-health ultrasound images and provided an effective reference value for the diagnosis of cardiac insufficiency and neuronal adjustment analysis in patients with sepsis in the emergency department.

Dor neuropática na prática clínica: ênfase nos instrumentos diagnósticos / Neuropathic pain in clinical practice: emphasis on diagnostic tools

A dor neuropática é causada por uma lesão ou doença do sistema nervoso somatossensitivo. Trata-se de uma manifestação sindrômica que envolve mecanismos inflamatórios e imunes com fisiopatologia ainda pouco esclarecida. O espectro de apresentação da dor neuropática é amplo e, assim, constitui um desafio na prática clínica. Este problema de saúde pública necessita de ampla capacidade técnica dos clínicos generalistas. Torna-se relevante identificar o potencial de cronificação do sintoma e adotar abordagens mitigantes do processo lesivo, estrutural e emocional. Nesse sentido, o diagnóstico adequado da dor neuropática é o primeiro passo na abordagem ao paciente. Diante disso, essa revisão objetiva facilitar a melhor escolha dos métodos diagnósticos no manejo clínico do paciente. Dentre estes, é possível citar a imagem por ressonância magnética funcional, eletroneuromiografia, tomografia por emissão de pósitrons, microneurografia, teste quantitativo sensorial, biópsias de pele, estudos de condução nervosa e de potencial somatossensorial evocado. A dor, por ser um processo sensorial subjetivo, apresenta amplo espectro de manifestações clínicas. Por essa razão, é possível fazer uso de técnicas como métodos de triagem e exames complementares para um diagnóstico mais específico.

Neuropathic pain is caused by an injury or illness of the somatosensory nervous system. It is a syndromic manifestation that involves inflammatory and immune mechanisms, whose pathophysiology is still poorly understood. The spectrum of presentation of neuropathic pain is wide and, therefore, it is a challenge in clinical practice. This public health problem requires the broad technical capacity of general practitioners. It is relevant to identify the potential for chronicity of the symptom and adopt mitigating approaches to the harmful, structural, and emotional process. In this sense, the proper diagnosis of neuropathic pain is the first step in approaching the patient. Therefore, this review aims to facilitate the best choice of diagnostic methods in the clinical management of the patient. Among these, functional magnetic resonance imaging, electroneuromyography, positron emission tomography, microneurography, quantitative sensory testing, skin biopsies, nerve conduction and evoked somatosensory potential studies are possible. Pain, being a subjective sensory process, has a wide spectrum of clinical manifestations. For this reason, it is possible to make use of techniques such as screening methods and complementary exams for a more specific diagnosis.

Identifying knowledge important to teach about the nervous system in the context of secondary biology and science education-A Delphi study.

Teaching about the nervous system has become a challenging task in secondary biology and science education because of the fast development in the field of neuroscience. A major challenge is to determine what content to teach. Curricula goals are often too general to guide instruction, and information about the nervous system has become overwhelming and diverse with ubiquitous relevance in society. In addition, several misconceptions and myths are circulating in educational communities causing world-wide confusion as to what content is correct. To help teachers, textbook authors, and curricula developers in this challenging landscape of knowledge, the aim of the present study is to identify the expert view on what knowledge is important for understanding the nervous system in the context of secondary biology and science education. To accomplish this, we have conducted a thematic content analysis of textbooks followed by a Delphi study of 15 experts in diverse but relevant fields. The results demonstrate six curriculum themes including gross anatomy and function, cell types and functional units, the nerve signal, connections between neurons, when nerve signals travel through networks of neurons, and plasticity in the nervous system, as well as 26 content principles organized in a coherent curriculum progression from general content to more specific content. Whereas some of the principles clarify and elaborate on traditional school biology knowledge, others add new knowledge to the curriculum. Importantly, the new framework for teaching about the nervous system presented here, meets the needs of society, as expressed by recent international policy frameworks of OECD and WHO, and it addresses common misconceptions about the brain. The study suggests an update of the biology and science curriculum.

Effect of Noise on Sleep and Autonomic Activity in Children according to Source.

BACKGROUND: Noise has been a major issue in children due to its effect on emotional symptoms and sleep problems. The present study investigated the effect of noise on sleep and autonomic activity in children according to three variables, namely, road traffic noise, aircraft noise, and noise sensitivity (NS). METHODS: The study is epidemiological in nature. A total of 474 subjects of four elementary schools were evaluated in conjunction with the 2014 noise map data gathered from two metropolitan regions, Seoul and Ulsan, in South Korea. Each subject completed the children's sleep habits questionnaire, and heart rate variability (HRV) was recorded. Analysis of covariance was performed using monthly income as a covariate. RESULTS: Aircraft noise was associated with night waking (P = 0.047), whereas no significant association was observed between sleep and road traffic noise. After stratifying by NS, no significant results were obtained for road traffic noise. However, high levels of aircraft noise in the high-NS group were associated with high degrees of bedtime resistance (P = 0.049). In terms of HRV, no significant difference was observed in the results between groups. CONCLUSION: Road traffic noise did not significantly alter sleep or autonomic activity in children, whereas aircraft noise exerted a negative effect on sleep. The findings suggest that the impact of noise on sleep in children varies depending on noise sources.

Visualizing the organization and differentiation of the male-specific nervous system of C. elegans.

Sex differences in the brain are prevalent throughout the animal kingdom and particularly well appreciated in the nematode Caenorhabditis elegans, where male animals contain a little-studied set of 93 male-specific neurons. To make these neurons amenable for future study, we describe here how a multicolor reporter transgene, NeuroPAL, is capable of visualizing the distinct identities of all male-specific neurons. We used NeuroPAL to visualize and characterize a number of features of the male-specific nervous system. We provide several proofs of concept for using NeuroPAL to identify the sites of expression of gfp-tagged reporter genes and for cellular fate analysis by analyzing the effect of removal of several developmental patterning genes on neuronal identity acquisition. We use NeuroPAL and its intrinsic cohort of more than 40 distinct differentiation markers to show that, even though male-specific neurons are generated throughout all four larval stages, they execute their terminal differentiation program in a coordinated manner in the fourth larval stage. This coordinated wave of differentiation, which we call 'just-in-time' differentiation, couples neuronal maturation programs with the appearance of sexual organs.

Therapeutic Effects of Resveratrol on Ischemia-Reperfusion Injury in the Nervous System.

Resveratrol is a phenol compound produced by some plants in response to pathogens, infection, or physical injury. It is well-known that resveratrol has antioxidant and protective roles in damages potentially caused by cancer or other serious disorders. Thus, it is considered as a candidate agent for the prevention and treatment of human diseases. Evidence has confirmed other bioactive impacts of resveratrol, including cardioprotective, anti-tumorigenic, anti-inflammatory, phytoestrogenic, and neuroprotective effects. Ischemia-reperfusion (IR) can result in various disorders, comprising myocardial infarction, stroke, and peripheral vascular disease, which may continue to induce debilitating conditions and even mortality. In virtue of chronic ischemia or hypoxia, cells switch to anaerobic metabolism, giving rise to some dysfunctions in mitochondria. As the result of lactate accumulation, adenosine triphosphate levels and pH decline in cells. This condition leads cells to apoptosis, necrosis, and autophagy. However, restoring oxygen level upon reperfusion after ischemia by producing reactive oxygen species is an outcome of mitochondrial dysfunction. Considering the neuroprotective effect of resveratrol and neuronal injury that comes from IR, we focused on the mechanism(s) involved in IR injury in the nervous system and also on the functions of resveratrol in the protection, inhibition, and treatment of this injury.

The nervous system of the most complex lophophore provides new insights into the evolution of Brachiopoda.

The lophophore is a tentacle organ unique to the lophophorates. Recent research has revealed that the organization of the nervous and muscular systems of the lophophore is similar in phoronids, brachiopods, and bryozoans. At the same time, the evolution of the lophophore in certain lophophorates is still being debated. Innervation of the adult lophophore has been studied by immunocytochemistry and confocal laser scanning microscopy for only two brachiopod species belonging to two subphyla: Linguliformea and Rhynchonelliformea. Species from both groups have the spirolophe, which is the most common type of the lophophore among brachiopods. In this study, we used transmission electron microscopy, immunocytochemistry, and confocal laser scanning microscopy to describe the innervation of the most complex lophophore (the plectolophe) of the rhynchonelliform species Coptothyris grayi. The C. grayi lophophore (the plectolophe) is innervated by three brachial nerves: the main, second accessory, and lower. Thus, the plectolophe lacks the accessory brachial nerve, which is typically present in other studied brachiopods. All C. grayi brachial nerves contain two types of perikarya. Because the accessory nerve is absent, the cross nerves, which pass into the connective tissue, have a complex morphology: each nerve consists of two ascending and one descending branches. The outer and inner tentacles are innervated by several groups of neurite bundles: one frontal, two lateral, two abfrontal, and two latero-abfrontal (the latter is present in only the outer tentacles). Tentacle nerves originate from the second accessory and lower brachial nerves. The inner and outer tentacles are also innervated by numerous peritoneal neurites, which exhibit acetylated alpha-tubulin-like immunoreactivity. The nervous system of the lophophore of C. grayi manifests several evolutionary trends. On the one hand, it has undergone simplification, i.e., the absence of the accessory brachial nerve, which is apparently correlated with a reduction in the complexity of the lophophore's musculature. On the other hand, C. grayi has a prominent second accessory nerve, which contains large groups of frontal perikarya, and also has additional nerves extending from the both ganglia to the medial arm; these features are consistent with the complex morphology of the C. grayi plectolophe. In brachiopods, the evolution of the lophophore nervous system apparently involved two main modifications. The first modification was the appearance and further strengthening of the second accessory brachial nerve, which apparently arose because of the formation of a double row of tentacles instead of the single row of the brachiopod ancestor. The second modification was the partial or complete reduction of some brachial nerves, which was correlated with the reduced complexity of the lophophore musculature and the appearance of skeletal structures that support the lophophore.

Nerve-associated Schwann cell precursors contribute extracutaneous melanocytes to the heart, inner ear, supraorbital locations and brain meninges.

Melanocytes are pigmented cells residing mostly in the skin and hair follicles of vertebrates, where they contribute to colouration and protection against UV-B radiation. However, the spectrum of their functions reaches far beyond that. For instance, these pigment-producing cells are found inside the inner ear, where they contribute to the hearing function, and in the heart, where they are involved in the electrical conductivity and support the stiffness of cardiac valves. The embryonic origin of such extracutaneous melanocytes is not clear. We took advantage of lineage-tracing experiments combined with 3D visualizations and gene knockout strategies to address this long-standing question. We revealed that Schwann cell precursors are recruited from the local innervation during embryonic development and give rise to extracutaneous melanocytes in the heart, brain meninges, inner ear, and other locations. In embryos with a knockout of the EdnrB receptor, a condition imitating Waardenburg syndrome, we observed only nerve-associated melanoblasts, which failed to detach from the nerves and to enter the inner ear. Finally, we looked into the evolutionary aspects of extracutaneous melanocytes and found that pigment cells are associated mainly with nerves and blood vessels in amphibians and fish. This new knowledge of the nerve-dependent origin of extracutaneous pigment cells might be directly relevant to the formation of extracutaneous melanoma in humans.

Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause chronic and acute disease. Postacute sequelae of SARS-CoV-2 infection (PASC) include injury to the lungs, heart, kidneys, and brain that may produce a variety of symptoms. PASC also includes a post-coronavirus disease 2019 (COVID-19) syndrome ('long COVID') with features that can follow other acute infectious diseases and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Here we summarize what is known about the pathogenesis of ME/CFS and of 'acute' COVID-19, and we speculate that the pathogenesis of post-COVID-19 syndrome in some people may be similar to that of ME/CFS. We propose molecular mechanisms that might explain the fatigue and related symptoms in both illnesses, and we suggest a research agenda for both ME/CFS and post-COVID-19 syndrome.

Parallel Rap1>RalGEF>Ral and Ras signals sculpt the C. elegans nervous system.

Ras is the most commonly mutated oncogene in humans and uses three oncogenic effectors: Raf, PI3K, and RalGEF activation of Ral. Understanding the importance of RalGEF>Ral signaling in cancer is hampered by the paucity of knowledge about their function in animal development, particularly in cell movements. We found that mutations that disrupt function of RalGEF or Ral enhance migration phenotypes of mutants for genes with established roles in cell migration. We used as a model the migration of the canal associated neurons (CANs), and validated our results in HSN cell migration, neurite guidance, and general animal locomotion. These functions of RalGEF and Ral are specific to their control of Ral signaling output rather than other published functions of these proteins. In this capacity Ral functions cell autonomously as a permissive developmental signal. In contrast, we observed Ras, the canonical activator of RalGEF>Ral signaling in cancer, to function as an instructive signal. Furthermore, we unexpectedly identified a function for the close Ras relative, Rap1, consistent with activation of RalGEF>Ral. These studies define functions of RalGEF>Ral, Rap1 and Ras signaling in morphogenetic processes that fashion the nervous system. We have also defined a model for studying how small GTPases partner with downstream effectors. Taken together, this analysis defines novel molecules and relationships in signaling networks that control cell movements during development of the nervous system.

Recurrent Implication of Striatal Cholinergic Interneurons in a Range of Neurodevelopmental, Neurodegenerative, and Neuropsychiatric Disorders.

Cholinergic interneurons are "gatekeepers" for striatal circuitry and play pivotal roles in attention, goal-directed actions, habit formation, and behavioral flexibility. Accordingly, perturbations to striatal cholinergic interneurons have been associated with many neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. The role of acetylcholine in many of these disorders is well known, but the use of drugs targeting cholinergic systems fell out of favor due to adverse side effects and the introduction of other broadly acting compounds. However, in response to recent findings, re-examining the mechanisms of cholinergic interneuron dysfunction may reveal key insights into underlying pathogeneses. Here, we provide an update on striatal cholinergic interneuron function, connectivity, and their putative involvement in several disorders. In doing so, we aim to spotlight recurring physiological themes, circuits, and mechanisms that can be investigated in future studies using new tools and approaches.

Meta-analysis of neural systems underlying placebo analgesia from individual participant fMRI data.

The brain systems underlying placebo analgesia are insufficiently understood. Here we performed a systematic, participant-level meta-analysis of experimental functional neuroimaging studies of evoked pain under stimulus-intensity-matched placebo and control conditions, encompassing 603 healthy participants from 20 (out of 28 eligible) studies. We find that placebo vs. control treatments induce small, widespread reductions in pain-related activity, particularly in regions belonging to ventral attention (including mid-insula) and somatomotor networks (including posterior insula). Behavioral placebo analgesia correlates with reduced pain-related activity in these networks and the thalamus, habenula, mid-cingulate, and supplementary motor area. Placebo-associated activity increases occur mainly in frontoparietal regions, with high between-study heterogeneity. We conclude that placebo treatments affect pain-related activity in multiple brain areas, which may reflect changes in nociception and/or other affective and decision-making processes surrounding pain. Between-study heterogeneity suggests that placebo analgesia is a multi-faceted phenomenon involving multiple cerebral mechanisms that differ across studies.

Ten-year follow-up of cardiac function and neural regulation in a group of amateur half-marathon runners.

OBJECTIVE: In the last years, a debate exists about type, intensity and frequency of physical exercise that is really indicated to protect healthy subjects from cardiovascular disease. Regular physical training has been associated with an improved cardiovascular risk profile, but it has also been demonstrated that strenuous and uncontrolled physical exercise could be dangerous, in terms of increased cardiovascular morbidity and mortality. In the present study, we evaluated a group of 35 amateur half-marathon runners, who were likewise studied 10 years before (B). The results of B suggested that an increased cardiac sympathetic modulation could potentially represent a negative prognostic factor. The aim of this follow-up was to assess the medium-long-term effects of moderate to vigorous physical training on the cardiovascular neural control, cardiac function and occurrence of cardiovascular diseases. METHODS: Each enrolled subject underwent: (1) an interview and physical examination to ascertain the presence of cardiovascular disease; (2) standing test to evaluate the cardiovascular neural control by means of heart rate variability (HRV), arterial blood pressure (AP) variability and baroreflex sensitivity (BRS); (3) transthoracic echocardiography to evaluate cardiac function. RESULTS: At 10-year follow-up (FU), in this group of middle-aged athletes the occurrence of cardiovascular diseases was low, not unlike that of the overall population. The results of HRV analysis showed a decreased sympathetic and increased vagal modulation directed to the heart, compared with B. In addition, HRV, AP variability and BRS indices showed a physiological response to active standing. Finally, athletes had normal echocardiographic measures. CONCLUSION: We conclude that in our group of athletes a regular moderate-vigorous physical training through the 10 years was quite beneficial as the prevalence of sympathetic cardiac modulation observed at B was not accompanied by increased cardiovascular risk, on the contrary a slight prevalence of vagal indices was observed at FU.