Movement-related increases in subthalamic activity optimize locomotion.

The subthalamic nucleus (STN) is traditionally thought to restrict movement. Lesion or prolonged STN inhibition increases movement vigor and propensity, while optogenetic excitation has opposing effects. However, STN neurons often exhibit movement-related increases in firing. To address this paradox, STN activity was recorded and manipulated in head-fixed mice at rest and during self-initiated and self-paced treadmill locomotion. We found that (1) most STN neurons (type 1) exhibit locomotion-dependent increases in activity, with half firing preferentially during the propulsive phase of the contralateral locomotor cycle; (2) a minority of STN neurons exhibit dips in activity or are uncorrelated with movement; (3) brief optogenetic inhibition of the lateral STN (where type 1 neurons are concentrated) slows and prematurely terminates locomotion; and (4) in Q175 Huntington's disease mice, abnormally brief, low-velocity locomotion is associated with type 1 hypoactivity. Together, these data argue that movement-related increases in STN activity contribute to optimal locomotor performance.

DNA G-quadruplexes in the genome of Trypanosoma cruzi as potential therapeutic targets for Chagas disease: Dithienylethene ligands as effective antiparasitic agents.

Chagas disease is caused by the parasite Trypanosoma cruzi and affects over 7 million people worldwide. The two actual treatments, Benznidazole (Bzn) and Nifurtimox, cause serious side effects due to their high toxicity leading to treatment abandonment by the patients. In this work, we propose DNA G-quadruplexes (G4) as potential therapeutic targets for this infectious disease. We have found 174 PQS per 100,000 nucleotides in the genome of T. cruzi and confirmed G4 formation of three frequent motifs. We synthesized a family of 14 quadruplex ligands based in the dithienylethene (DTE) scaffold and demonstrated their binding to these identified G4 sequences. Several DTE derivatives exhibited micromolar activity against epimastigotes of four different strains of T. cruzi, in the same concentration range as Bzn. Compounds L3 and L4 presented remarkable activity against trypomastigotes, the active form in blood, of T. cruzi SOL strain (IC50 = 1.5-3.3 µM, SI = 25-40.9), being around 40 times more active than Bzn and displaying much better selectivity indexes.

Structure-Activity Study on Substituted, Core-Extended, and Dyad Naphthalene Diimide G-Quadruplex Ligands Leading to Potent Antitrypanosomal Agents.

Several G-quadruplex nucleic acid (G4s) ligands have been developed seeking target selectivity in the past decade. Naphthalene diimide (NDI)-based compounds are particularly promising due to their biological activity and red-fluorescence emission. Previously, we demonstrated the existence of G4s in the promoter region of parasite genomes, assessing the effectiveness of NDI-derivatives against them. Here, we explored the biological activity of a small library of G4-DNA ligands, exploiting the NDI pharmacophore, against both Trypanosoma brucei and Leishmania major parasites. Biophysical and biological assays were conducted. Among the various families analyzed, core-extended NDIs exhibited the most promising results concerning the selectivity and antiparasitic effects. NDI 16 emerged as the most potent, with an IC50 of 0.011 nM against T. brucei and remarkable selectivity vs MRC-5 cells (3454-fold). Fascinating, 16 is 480-fold more potent than the standard drug pentamidine (IC50 = 5.3 nM). Cellular uptake and parasite localization were verified by exploiting core-extended NDI red-fluorescent emission.

Cortistatin as a Novel Multimodal Therapy for the Treatment of Parkinson's Disease.

Parkinson's disease (PD) is a complex disorder characterized by the impairment of the dopaminergic nigrostriatal system. PD has duplicated its global burden in the last few years, becoming the leading neurological disability worldwide. Therefore, there is an urgent need to develop innovative approaches that target multifactorial underlying causes to potentially prevent or limit disease progression. Accumulating evidence suggests that neuroinflammatory responses may play a pivotal role in the neurodegenerative processes that occur during the development of PD. Cortistatin is a neuropeptide that has shown potent anti-inflammatory and immunoregulatory effects in preclinical models of autoimmune and neuroinflammatory disorders. The goal of this study was to explore the therapeutic potential of cortistatin in a well-established preclinical mouse model of PD induced by acute exposure to the neurotoxin 1-methil-4-phenyl1-1,2,3,6-tetrahydropyridine (MPTP). We observed that treatment with cortistatin mitigated the MPTP-induced loss of dopaminergic neurons in the substantia nigra and their connections to the striatum. Consequently, cortistatin administration improved the locomotor activity of animals intoxicated with MPTP. In addition, cortistatin diminished the presence and activation of glial cells in the affected brain regions of MPTP-treated mice, reduced the production of immune mediators, and promoted the expression of neurotrophic factors in the striatum. In an in vitro model of PD, treatment with cortistatin also demonstrated a reduction in the cell death of dopaminergic neurons that were exposed to the neurotoxin. Taken together, these findings suggest that cortistatin could emerge as a promising new therapeutic agent that combines anti-inflammatory and neuroprotective properties to regulate the progression of PD at multiple levels.

Movement-related increases in subthalamic activity optimize locomotion.

The subthalamic nucleus (STN) is traditionally thought to restrict movement. Lesion or prolonged STN inhibition increases movement vigor and propensity, while ontogenetic excitation typically has opposing effects. Subthalamic and motor activity are also inversely correlated in movement disorders. However, most STN neurons exhibit movement-related increases in firing. To address this paradox, STN activity was recorded and manipulated in head-fixed mice at rest and during self-initiated treadmill locomotion. The majority of STN neurons (type 1) exhibited locomotion-dependent increases in activity, with half encoding the locomotor cycle. A minority of neurons exhibited dips in activity or were uncorrelated with movement. Brief optogenetic inhibition of the dorsolateral STN (where type 1 neurons are concentrated) slowed and prematurely terminated locomotion. In Q175 Huntington's disease mice abnormally brief, low-velocity locomotion was specifically associated with type 1 hyperactivity. Together these data argue that movement-related increases in STN activity contribute to optimal locomotor performance.

¿Agua para todos? La intermitencia en el suministro de agua en los hogares en México.

OBJETIVO: Medir el acceso a través de la intermitencia en el suministro de agua potable en hogares mexicanos. Material y métodos. A través de la Encuesta Nacional de Salud y Nutrición 2022 (Ensanut 2022), se recolectó información sobre intermitencia en días por semana y horas por día durante las últimas cuatro semanas y el suministro de agua durante el año para la temporada de mayor escasez. RESULTADOS: 31.5% de los hogares recibieron agua los siete días de la semana, las 24 horas del día. De estos, 17.4% no tuvo escasez en los últimos 12 meses. La intermitencia es más común entre hogares de las regiones en el sur del país y entre los más pobres. El 81% de las familias almacena agua y 16% almacena en contenedores portátiles como cubetas. Conclusión. En este artículo se presentan por primera vez patrones de intermitencia en el suministro de agua a nivel nacional en México. La gran mayoría de las familias no reciben agua de forma continua y tienen que almacenar agua. El almacenamiento podría disminuir la calidad del agua y la falta de confianza para su consumo con consecuencias para la salud. La conexión al sistema potable no refleja el acceso real de las familias al agua.

Lysophosphatidic acid receptor LPA1 trafficking and interaction with Rab proteins, as evidenced by Förster resonance energy transfer.

LPA1 internalization to endosomes was studied employing Förster Resonance Energy Transfer (FRET) in cells coexpressing the mCherry-lysophosphatidic acid LPA1 receptors and distinct eGFP-tagged Rab proteins. Lysophosphatidic acid (LPA)-induced internalization was rapid and decreased afterward: phorbol myristate acetate (PMA) action was slower and sustained. LPA stimulated LPA1-Rab5 interaction rapidly but transiently, whereas PMA action was rapid but sustained. Expression of a Rab5 dominant-negative mutant blocked LPA1-Rab5 interaction and receptor internalization. LPA-induced LPA1-Rab9 interaction was only observed at 60 min, and LPA1-Rab7 interaction after 5 min with LPA and after 60 min with PMA. LPA triggered immediate but transient rapid recycling (i.e., LPA1-Rab4 interaction), whereas PMA action was slower but sustained. Agonist-induced slow recycling (LPA1-Rab11 interaction) increased at 15 min and remained at this level, whereas PMA action showed early and late peaks. Our results indicate that LPA1 receptor internalization varies with the stimuli.

Non-canonical Wnt/Ca2+ signaling is essential to promote self-renewal and proliferation in colon cancer stem cells.

Introduction: Cancer Stem Cells (CSC) are responsible for maintaining tumor growth, chemoresistance, and metastasis. Therefore, understanding their characteristics is critical to progress in cancer therapy. While the contribution of the canonical Wnt/b-catenin signaling in both normal and CSCs had been well established, the function of non-canonical Wnt signaling cascades in stem cells is unclear. Recently, we reported that Wnt ligands trigger complex signaling in which the canonical and non-canonical responses can be simultaneously activated by one ligand in colon cancer cells, suggesting, therefore, that noncanonical Wnt pathways may also be important in CSCs. Methods: The present work aimed to know the role of the Wnt/Ca2+ pathway in colon CSCs. We used tumorspheres as a model of CSCs enrichment of CRC cell lines with different Wnt/b-catenin contexts. Results: Using Wnt3a and Wnt5a as prototype ligands to activate the canonical or the non-canonical pathways, respectively, we found that both Wnt3a and Wnt5a promote sphere-formation capacity and proliferation without stimulating b-catenin-dependent transcription. Upregulation of sphere formation by Wnt5a or Wnt3a requires the downstream activation of Phospholipase C and transcriptional factor NFAT. Moreover, the single specific inhibition of PLC or NFAT, using U73122 and 11R-VIVIT, respectively, leads to impaired sphere formation. Discussion: Our results indicate that both types of ligands activate the Wnt/Ca2+ signaling axis to induce/maintain the self-renewal efficiency of CSCs, demonstrating to be essential for the functions of CSC in colon cancer.

Synthesis and antimicrobial activity of aminoalkyl resveratrol derivatives inspired by cationic peptides.

Antimicrobial resistance is a global concern, far from being resolved. The need of new drugs against new targets is imminent. In this work, we present a family of aminoalkyl resveratrol derivatives with antibacterial activity inspired by the properties of cationic amphipathic antimicrobial peptides. Surprisingly, the newly designed molecules display modest activity against aerobically growing bacteria but show surprisingly good antimicrobial activity against anaerobic bacteria (Gram-negative and Gram-positive) suggesting specificity towards this bacterial group. Preliminary studies into the action mechanism suggest that activity takes place at the membrane level, while no cross-resistance with traditional antibiotics is observed. Actually, some good synergistic relations with existing antibiotics were found against Gram-negative pathogens. However, some cytotoxicity was observed, despite their low haemolytic activity. Our results show the importance of the balance between positively charged moieties and hydrophobicity to improve antimicrobial activity, setting the stage for the design of new drugs based on these molecules.

Cell Trafficking and Function of G Protein-coupled Receptors.

The G protein-coupled receptors (GPCRs) are plasma membrane proteins that function as sensors of changes in the internal and external milieux and play essential roles in health and disease. They are targets of hormones, neurotransmitters, local hormones (autacoids), and a large proportion of the drugs currently used as therapeutics and for "recreational" purposes. Understanding how these receptors signal and are regulated is fundamental for progress in areas such as physiology and pharmacology. This review will focus on what is currently known about their structure, the molecular events that trigger their signaling, and their trafficking to endosomal compartments. GPCR phosphorylation and its role in desensitization (signaling switching) are also discussed. It should be mentioned that the volume of information available is enormous given the large number and variety of GPCRs. However, knowledge is fragmentary even for the most studied receptors, such as the adrenergic receptors. Therefore, we attempt to present a panoramic view of the field, conscious of the risks and limitations (such as oversimplifications and incorrect generalizations). We hope this will provoke further research in the area. It is currently accepted that GPCR internalization plays a role signaling events. Therefore, the processes that allow them to internalize and recycle back to the plasma membrane are briefly reviewed. The functions of cytoskeletal elements (mainly actin filaments and microtubules), the molecular motors implicated in receptor trafficking (myosin, kinesin, and dynein), and the GTPases involved in GPCR internalization (dynamin) and endosomal sorting (Rab proteins), are discussed. The critical role phosphoinositide metabolism plays in regulating these events is also depicted.

Índices de oxigenación, índice de choque diastólico y tiempo en presión soporte como predictores de éxito en el retiro de la ventilación mecánica invasiva en paciente críticamente enfermo con COVID-19 / Oxygenation indices, diastolic shock index, and time in support pressure as predictors of success in the removal of invasive mechanical ventilation in critically ill patients with COVID-19 / Índices de oxigenação, índice de choque diastólico e tempo em pressão de suporte como preditores de sucesso na retirada de ventilação mecânica invasiva em pacientes em estado crítico com COVID-19

Resumen Introducción: El porcentaje de pacientes gravemente enfermos por COVID-19 que toleran el retiro de la ventilación mecánica es mínimo, por lo cual es fundamental determinar cuáles son los predictores de éxito en el retiro de la ventilación mecánica. Objetivos: Determinar si los índices de oxigenación, tiempo en presión soporte e índice de choque diastólico son predictores de éxito en el retiro de la ventilación mecánica en pacientes críticamente enfermos por COVID-19. Material y métodos: Estudio de cohorte prospectivo en pacientes con COVID-19 que ingresaron a la Unidad de Cuidados Intensivos y fueron sometidos a pruebas de ventilación espontánea, siendo posteriormente liberados del ventilador mecánico. Se recolectaron datos demográficos, resultados de laboratorio y parámetros ventilatorios con la finalidad de analizar y determinar predictores de éxito en el retiro de la ventilación mecánica. Resultados: Se observó una diferencia significativa entre los pacientes que toleraron y los que no toleraron el retiro de la ventilación mecánica en las siguientes variables: índice de respiración rápida superficial 47 ± 17.9 vs 90 ± 20.2 (p = 0.08), días de ventilación mecánica 5.8 vs 9.3 (p = 0.03), sesiones de prono 1.36 vs 2.33 (p = 0.058) y presión arterial diastólica 57 ± 3.6 (p = 0.027). Conclusión: En los pacientes críticamente enfermos por COVID-19 que son candidatos a retiro de la ventilación mecánica sugerimos usar como predictores de éxito: el índice de respiraciones rápidas superficiales < 64, días de ventilación mecánica < 8, presión arterial diastólica > 57 mmHg y haber tenido máximo dos sesiones de prono como predictores de éxito en el retiro de la ventilación mecánica.

Abstract Introduction: The percentage of critically ill patients due to COVID-19 who tolerate the withdrawal of mechanical ventilation is minimal. It is essential to determine which are the predictors of success in weaning. Objectives: To determine if the oxygenation indices, time in pressure support, and diastolic shock index are predictors of success in the withdrawal of mechanical ventilation in critically ill patients due to COVID-19. Material and methods: Prospective cohort study in patients with COVID-19 who were admitted to the ICU and underwent tests of spontaneous ventilation, being later released from the mechanical ventilator. Demographic data, laboratory results, ventilatory parameters were collected in order to analyze and determine predictors of success in weaning. Results: A significant difference was found between those who tolerated and those who did not tolerate the withdrawal of mechanical ventilation in the following variables: rapid shallow breathing index 47 ± 17.9 vs 90 ± 20.2 (p = 0.08), days of mechanical ventilation 5.8 vs 9.3 (p = 0.03), prone sessions 1.36 vs 2.33 (p = 0.058), diastolic blood pressure 57 ± 3.6 (p = 0.027). Conclusion: In critically ill patients due to COVID-19 who are candidates for withdrawal from mechanical ventilation, we suggest using as predictors of success: Index of rapid shallow breaths < 64, days of mechanical ventilation < 8, diastolic blood pressure > 57 mmHg and having had a maximum two prone sessions as predictors of success in the withdrawal of mechanical ventilation.

Resumo Introdução: A porcentagem de pacientes graves com COVID-19 que toleram a retirada da ventilação mecânica é mínima, por isso é essencial determinar os preditores de sucesso na retirada da ventilação mecânica. Objetivos: Determinar se os índices de oxigenação, tempo em pressão suporte, índice de choque diastólico são preditores de sucesso no desmame da ventilação mecânica em pacientes críticos com COVID-19. Material e métodos: Estudo de coorte prospectivo em pacientes com COVID-19 admitidos na unidade de terapia intensiva e submetidos a testes de ventilação espontânea e posteriormente liberados do ventilador mecânico. Foram coletados dados demográficos, resultados laboratoriais e parâmetros ventilatórios para analisar e determinar os preditores de sucesso no desmame da ventilação mecânica. Resultados: Observou-se uma diferença significativa entre os pacientes que toleraram e os que não toleraram a retirada da ventilação mecânica nas seguintes variáveis: índice de respiração rápida e superficial 47 ±17.9 vs 90 ± 20.2 (p = 0.08), dias de ventilação mecânica 5.8 vs 9.3 (p = 0.03), sessões de prona 1.36 vs 2.33 (p = 0.058) e pressão arterial diastólica 57 ± 3.6 (p = 0.027). Conclusão: Em pacientes em estado crítico com COVID-19 candidatos à retirada da ventilação mecânica, sugerimos usar como preditores de sucesso: índice de respirações rápidas e superficiais < 64, dias de ventilação mecânica < 8, pressão arterial diastólica > 57 mmHg e ter realizado no máximo 2 sessões em decúbito ventral como preditores de sucesso no desmame da ventilação mecânica.

Chemically Tuning Resveratrol for the Effective Killing of Gram-Positive Pathogens.

In the era of antimicrobial resistance, the identification of new compounds with strong antimicrobial activity and the development of alternative therapies to fight drug-resistant bacteria are urgently needed. Here, we have used resveratrol, a safe and well-known plant-derived stilbene with poor antimicrobial properties, as a scaffold to design several new families of antimicrobials by adding different chemical entities at specific positions. We have characterized the mode of action of the most active compounds prepared and have examined their synergistic antibacterial activity in combination with traditional antibiotics. Some alkyl- and silyl-resveratrol derivatives show bactericidal activity against Gram-positive bacteria in the same low micromolar range of traditional antibiotics, with an original mechanism of action that combines membrane permeability activity with ionophore-related activities. No cross-resistance or antagonistic effect was observed with traditional antibiotics. Synergism was observed for some specific general-use antibiotics, such as aminoglycosides and cationic antimicrobial peptide antibiotics. No hemolytic activity was observed at the active concentrations or above, although some low toxicity against an MRC-5 cell line was noted.

Machine-Learning-Based Late Fusion on Multi-Omics and Multi-Scale Data for Non-Small-Cell Lung Cancer Diagnosis.

Differentiation between the various non-small-cell lung cancer subtypes is crucial for providing an effective treatment to the patient. For this purpose, machine learning techniques have been used in recent years over the available biological data from patients. However, in most cases this problem has been treated using a single-modality approach, not exploring the potential of the multi-scale and multi-omic nature of cancer data for the classification. In this work, we study the fusion of five multi-scale and multi-omic modalities (RNA-Seq, miRNA-Seq, whole-slide imaging, copy number variation, and DNA methylation) by using a late fusion strategy and machine learning techniques. We train an independent machine learning model for each modality and we explore the interactions and gains that can be obtained by fusing their outputs in an increasing manner, by using a novel optimization approach to compute the parameters of the late fusion. The final classification model, using all modalities, obtains an F1 score of 96.81±1.07, an AUC of 0.993±0.004, and an AUPRC of 0.980±0.016, improving those results that each independent model obtains and those presented in the literature for this problem. These obtained results show that leveraging the multi-scale and multi-omic nature of cancer data can enhance the performance of single-modality clinical decision support systems in personalized medicine, consequently improving the diagnosis of the patient.

Thiosugar naphthalene diimide conjugates: G-quadruplex ligands with antiparasitic and anticancer activity.

Glycosyl conjugation to drugs is a strategy being used to take advantage of glucose transporters (GLUT) overexpression in cancer cells in comparison with non-cancerous cells. Its extension to the conjugation of drugs to thiosugars tries to exploit their higher biostability when compared to O-glycosides. Here, we have synthesized a series of thiosugar naphthalene diimide conjugates as G-quadruplex ligands and have explored modifications of the amino sidechain comparing dimethyl amino and morpholino groups. Then, we studied their antiproliferative activity in colon cancer cells, and their antiparasitic activity in T. brucei and L. major parasites, together with their ability to bind quadruplexes and their cellular uptake and location. We observed higher toxicity for the sugar-NDI-NMe2 derivatives than for the sugar-NDI-morph compounds, both in mammalian cells and in parasites. Our experiments indicate that a less efficient binding to quadruplexes and a worse cellular uptake of the carb-NDI-morph derivatives could be the reasons for these differences. We found small variations in cytotoxicity between O-carb-NDIs and S-carb-NDIs, except against non-cancerous human fibroblasts MRC-5, where thiosugar-NDIs tend to be less toxic. This leads to a notable selectivity for ß-thiomaltosyl-NDI-NMe212 (9.8 fold), with an IC50 of 0.3 µM against HT-29 cells. Finally, the antiparasitic activity observed for the carb-NDI-NMe2 derivatives against T. brucei was in the nanomolar range with a good selectivity index in the range of 30- to 69- fold.

Mutation of putative phosphorylation sites in the free fatty acid receptor 1: Effects on signaling, receptor phosphorylation, and internalization.

Free fatty acid receptor 1 phosphorylation sites were studied using mutants, including a) a mutant with T215V in the third intracellular loop (3IL), b) another with changes in the carboxyl terminus (C-term): T287V, T293V, S298A, and c) a mutant with all of these changes (3IL/C-term). Agonist-induced increases in intracellular calcium were similar between cells expressing wild-type or mutant receptors. In contrast, agonist-induced FFA1 receptor phosphorylation was reduced in mutants compared to wild type. Phorbol ester-induced FFA1 receptor phosphorylation was rapid and robust in cells expressing the wild-type receptor and essentially abolished in the mutants. Agonist-induced ERK 1/2 phosphorylation and receptor internalization were decreased in cells expressing the mutant receptors compared to those expressing the wild-type receptor. Our data suggest that the identified sites might participate in receptor phosphorylation, signaling, and internalization.

G-Quadruplex DNA as a Target in Pathogenic Bacteria: Efficacy of an Extended Naphthalene Diimide Ligand and Its Mode of Action.

Guanidine DNA quadruplex (G4-DNA) structures convey a distinctive layer of epigenetic information that is critical for regulating key biological activities and processes as transcription, replication, and repair in living cells. The information regarding their role and use as therapeutic drug targets in bacteria is still scarce. Here, we tested the biological activity of a G4-DNA ligand library, based on the naphthalene diimide (NDI) pharmacophore, against both Gram-positive and Gram-negative bacteria. For the best compound identified, NDI-10, a different action mechanism was described for Gram-positive or negative bacteria. This asymmetric activity profile could be related to the different prevalence of putative G4-DNA structures in each group, the influence that they can exert on gene expression, and the different roles of the G4 structures in these bacteria, which seem to promote transcription in Gram-positive bacteria and repress transcription in Gram-negatives.

Applications of artificial intelligence in dentistry: A comprehensive review.

OBJECTIVE: To perform a comprehensive review of the use of artificial intelligence (AI) and machine learning (ML) in dentistry, providing the community with a broad insight on the different advances that these technologies and tools have produced, paying special attention to the area of esthetic dentistry and color research. MATERIALS AND METHODS: The comprehensive review was conducted in MEDLINE/PubMed, Web of Science, and Scopus databases, for papers published in English language in the last 20 years. RESULTS: Out of 3871 eligible papers, 120 were included for final appraisal. Study methodologies included deep learning (DL; n = 76), fuzzy logic (FL; n = 12), and other ML techniques (n = 32), which were mainly applied to disease identification, image segmentation, image correction, and biomimetic color analysis and modeling. CONCLUSIONS: The insight provided by the present work has reported outstanding results in the design of high-performance decision support systems for the aforementioned areas. The future of digital dentistry goes through the design of integrated approaches providing personalized treatments to patients. In addition, esthetic dentistry can benefit from those advances by developing models allowing a complete characterization of tooth color, enhancing the accuracy of dental restorations. CLINICAL SIGNIFICANCE: The use of AI and ML has an increasing impact on the dental profession and is complementing the development of digital technologies and tools, with a wide application in treatment planning and esthetic dentistry procedures.

Roles of Receptor Phosphorylation and Rab Proteins in G Protein-Coupled Receptor Function and Trafficking.

The G protein-coupled receptors form the most abundant family of membrane proteins and are crucial physiologic players in the homeostatic equilibrium, which we define as health. They also participate in the pathogenesis of many diseases and are frequent targets of therapeutic intervention. Considering their importance, it is not surprising that different mechanisms regulate their function, including desensitization, resensitization, internalization, recycling to the plasma membrane, and degradation. These processes are modulated in a highly coordinated and specific way by protein kinases and phosphatases, ubiquitin ligases, protein adaptors, interaction with multifunctional complexes, molecular motors, phospholipid metabolism, and membrane distribution. This review describes significant advances in the study of the regulation of these receptors by phosphorylation and endosomal traffic (where signaling can take place); we revisited the bar code hypothesis and include two additional observations: 1) that different phosphorylation patterns seem to be associated with internalization and endosome sorting for recycling or degradation, and 2) that, surprisingly, phosphorylation of some G protein-coupled receptors appears to be required for proper receptor insertion into the plasma membrane. SIGNIFICANCE STATEMENT: G protein-coupled receptor phosphorylation is an early event in desensitization/signaling switching, endosomal traffic, and internalization. These events seem crucial for receptor responsiveness, cellular localization, and fate (recycling/degradation) with important pharmacological/therapeutic implications. Phosphorylation sites vary depending on the cells in which they are expressed and on the stimulus that leads to such covalent modification. Surprisingly, evidence suggests that phosphorylation also seems to be required for proper insertion into the plasma membrane for some receptors.

Pedagogical intervention in team sports: a systematic review / Intervenção pedagógica nos esportivos coletivos: uma revisão sistemática

ABSTRACT The production of literature with intervention programs was analyzed, applied to team sports. The databases consulted on the subject, in the last 20 years, were the Web of Science, Scielo and PubMed. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines were used with the keywords: team sports and team sports games, associated with the terms: teaching models, sports teaching, teaching-learning-training, pedagogical intervention, tactical-technical performance and cognitive processes, in Portuguese, English and Spanish. After screening with defined criteria, 39 manuscripts were selected to compose the sample. The descriptive analysis showed that the years 2016 and 2018 presented a higher number of publications (17.95% each year); the English language most used in publications (69.24%); football and basketball have comprised the highest number of studies (25.64% and 17.95%, respectively); the teaching programs spanned between 5 and 54 class sessions; the sample of studies with schoolchildren was the most chosen (64.1%); most teaching programs focused on tactics; and the main variables analyzed were tactical knowledge, tactical-technical performance and specific skills. In the production of literature analyzed, there was a tendency in the last 10 years to apply sports teaching programs with tactical approaches and also change and/or add content to these programs, in order to enhance the development of students/athletes. These changes leave open reflections on possible changes in teacher guidance in the praxis in teaching-learning of team sports.

RESUMO Analisou-se a produção da literatura com programas de intervenção, aplicados aos esportes coletivos. As bases de dados consultadas quanto ao tema, nos últimos 20 anos, foram o Web of Science, Scielo e PubMed. Utilizou-se as diretrizes PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) com as palavras-chave: jogo coletivo e jogos esportivos coletivos, associados aos termos: modelos de ensino, ensino do esporte, ensino-aprendizagem-treinamento, intervenção pedagógica, desempenho tático-técnico e processos cognitivos, nos idiomas português, inglês e espanhol. Após triagem com critérios definidos, 39 manuscritos foram selecionados para compor a amostra. A análise descritiva apontou que os anos de 2016 e 2018 apresentou maior quantitativo de publicações (17,95% cada ano); a língua inglesa a mais utilizada nas publicações (69,24%); as modalidades futebol e basquetebol compreenderam o maior número de trabalhos (25,64% e 17,95%, respectivamente); os programas de ensino abrangeram entre 5 e 54 sessões de aula; a amostra dos estudos com escolares foi a mais eleita (64,1%); a maioria dos programas de ensino centrou-se na tática; e as principais variáveis analisadas foram conhecimentos táticos, desempenho tático-técnico e habilidades específicas. Na produção de literatura analisada observou-se uma tendência nos últimos 10 anos à aplicação de programas de ensino dos esportes com abordagens táticas e ainda alterar e/ou agregar conteúdos a esses modelos, com o intuito de potencializar o desenvolvimento de alunos/atletas. Essas mudanças deixam abertas as reflexões sobre possíveis alterações de orientação docente na práxis no ensino-aprendizagem dos esportes coletivos.