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1.
Mol Psychiatry ; 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38503929

RESUMO

The precise function of specialized GABAergic interneuron subtypes is required to provide appropriate synaptic inhibition for regulating principal neuron excitability and synchronization within brain circuits. Of these, parvalbumin-type (PV neuron) dysfunction is a feature of several sex-biased psychiatric and brain disorders, although, the underlying developmental mechanisms are unclear. While the transcriptional action of sex hormones generates sexual dimorphism during brain development, whether kinase signaling contributes to sex differences in PV neuron function remains unexplored. In the hippocampus, we report that gephyrin, the main inhibitory post-synaptic scaffolding protein, is phosphorylated at serine S268 and S270 in a developmentally-dependent manner in both males and females. When examining GphnS268A/S270A mice in which site-specific phosphorylation is constitutively blocked, we found that sex differences in PV neuron density in the hippocampal CA1 present in WT mice were abolished, coincident with a female-specific increase in PV neuron-derived terminals and increased inhibitory input onto principal cells. Electrophysiological analysis of CA1 PV neurons indicated that gephyrin phosphorylation is required for sexually dimorphic function. Moreover, while male and female WT mice showed no difference in hippocampus-dependent memory tasks, GphnS268A/S270A mice exhibited sex- and task-specific deficits, indicating that gephyrin phosphorylation is differentially required by males and females for convergent cognitive function. In fate mapping experiments, we uncovered that gephyrin phosphorylation at S268 and S270 establishes sex differences in putative PV neuron density during early postnatal development. Furthermore, patch-sequencing of putative PV neurons at postnatal day 4 revealed that gephyrin phosphorylation contributes to sex differences in the transcriptomic profile of developing interneurons. Therefore, these early shifts in male-female interneuron development may drive adult sex differences in PV neuron function and connectivity. Our results identify gephyrin phosphorylation as a new substrate organizing PV neuron development at the anatomical, functional, and transcriptional levels in a sex-dependent manner, thus implicating kinase signaling disruption as a new mechanism contributing to the sex-dependent etiology of brain disorders.

2.
Eur J Neurosci ; 57(12): 1966-1979, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37165567

RESUMO

Anxiety disorders are the most prevalent co-morbidity factor associated with the core domains of autism spectrum disorders (ASD). Investigations on potential common neuronal mechanisms that may explain the co-occurrence of ASD and anxiety disorders are still poorly explored. One of the key questions that remained unsolved is the role of Shank3 protein in anxiety behaviours. Firstly, we characterize the developmental trajectories of locomotor, social behaviour and anxiety traits in a mouse model of ASD. We highlight that the anxiety phenotype is a late-onset emerging phenotype in mice with a Shank3Δe4-22 mutation. Consequently, we used an shRNA strategy to model Shank3 insufficiency in the bed nucleus of the stria terminalis (BNST), a brain region exerting a powerful control on anxiety level. We found that Shank3 downregulation in the anteromedial BNST (amBNST) induced anxiogenic effects and enhanced social avoidance after aversive social defeat. Associated with these behavioural defects, we showed alteration of glutamatergic synaptic functions in the amBNST induced by Shank3 insufficiency during adolescence. Our data strongly support the role of Shank3 in the maturation of amBNST, and its key role in anxiety control. Our results may further help to pave the road on a better understanding of the neuronal mechanisms underlying anxiety disorders implicated in ASDs.


Assuntos
Núcleos Septais , Camundongos , Animais , Núcleos Septais/metabolismo , Comportamento Social , Ansiedade/metabolismo , Transtornos de Ansiedade/metabolismo , Fenótipo , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo
3.
Glob Chang Biol ; 29(12): 3318-3330, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37020174

RESUMO

Scientists and managers rely on indicator taxa such as coral and macroalgal cover to evaluate the effects of human disturbance on coral reefs, often assuming a universally positive relationship between local human disturbance and macroalgae. Despite evidence that macroalgae respond to local stressors in diverse ways, there have been few efforts to evaluate relationships between specific macroalgae taxa and local human-driven disturbance. Using genus-level monitoring data from 1205 sites in the Indian and Pacific Oceans, we assess whether macroalgae percent cover correlates with local human disturbance while accounting for factors that could obscure or confound relationships. Assessing macroalgae at genus level revealed that no genera were positively correlated with all human disturbance metrics. Instead, we found relationships between the division or genera of algae and specific human disturbances that were not detectable when pooling taxa into a single functional category, which is common to many analyses. The convention to use percent cover of macroalgae as an indication of local human disturbance therefore likely obscures signatures of local anthropogenic threats to reefs. Our limited understanding of relationships between human disturbance, macroalgae taxa, and their responses to human disturbances impedes the ability to diagnose and respond appropriately to these threats.


Assuntos
Antozoários , Alga Marinha , Animais , Humanos , Recifes de Corais , Ecossistema , Alga Marinha/fisiologia , Antozoários/fisiologia , Oceano Pacífico
4.
Artigo em Inglês | MEDLINE | ID: mdl-36917386

RESUMO

The continuous endemic of the new SARS-CoV-2 virus brought a halt to the world's activities from February 2020. Our study intends to gauge public perceptions on the consequences of post-pandemic changes on the marine environment, particularly as they are related to tourist beach amenities. Totally, 16 nations' knowledge and views on various environmental viewpoints over the effects of epidemic were gathered through public polls live on social media during social confinement in 2020. The results indicate that around 85% of respondents were most concerned about the alarming sights of widespread plastic trash and the increase of dangerous biomedical wastes through wastewater in the marine ecosystem. The outcomes of this study will undoubtedly aid in the establishment of a management strategy and for future studies on the consequences of any epidemic on the beaches.

5.
Trends Ecol Evol ; 37(12): 1032-1035, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36244864

RESUMO

Defining the context dependence of ecological states or processes is a fundamental goal of ecology. Stressor-response functions are the quantitative representation of context dependence, where the context (environmental contingency) is defined by location on the stressor (x) axis, and represents a unifying concept in biological science.

6.
Neuron ; 110(15): 2359-2361, 2022 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-35926450

RESUMO

In this issue of Neuron, Bossi, Dhanasobhon, and colleagues uncover the functional relevance of GluN1/GluN3A excitatory glycine receptors (eGlyRs) in the neocortex and amygdala. This study provides exciting new insights into the role of unconventional eGlyRs in brain function.


Assuntos
Fenômenos Fisiológicos do Sistema Nervoso , Receptores de Glicina , Glicina , Neurônios , Receptores de N-Metil-D-Aspartato/fisiologia
7.
Int J Mol Sci ; 23(12)2022 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-35743018

RESUMO

Early life exposure to sex hormones affects several brain areas involved in regulating locomotor and motivation behaviors. Our group has shown that neonatal exposure to testosterone propionate (TP) or estradiol valerate (EV) affected the brain dopamine (DA) system in adulthood. Here, we studied the long-lasting effects of neonatal exposure to sex hormones on behavioral and neurochemical responses to amphetamine (AMPH) and methylphenidate (MPD). Our results show that AMPH-induced locomotor activity was higher in female than male control rats. The conditioned place preference (CPP) to AMPH was only observed in EV male rats. In EV female rats, AMPH did not increase locomotor activity, but MPD-induced CPP was observed in control, EV and TP female rats. Using in vivo brain microdialysis, we observed that AMPH-induced extracellular DA levels were lower in nucleus accumbens (NAcc) of EV and TP female rats than control rats. In addition, MPD did not increase NAcc extracellular DA levels in EV rats. Using in vivo fast-scan cyclic voltammetry in striatum, MPD-induced DA reuptake was higher in EV than control rats. In summary, our results show that early life exposure to sex hormones modulates mesolimbic and nigrostriatal DA neurons producing opposite neurochemical effects induced by psychostimulant drugs in NAcc or striatum.


Assuntos
Estimulantes do Sistema Nervoso Central , Metilfenidato , Transtornos Relacionados ao Uso de Substâncias , Propionato de Testosterona , Anfetamina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Dopamina/farmacologia , Estradiol/farmacologia , Feminino , Masculino , Metilfenidato/farmacologia , Atividade Motora , Núcleo Accumbens , Ratos
8.
Fish Fish (Oxf) ; 23(4): 963-976, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35603326

RESUMO

The COVID-19 pandemic has spread around the world, disrupting economies, societies and daily life. Early research anticipated significant negative impacts for the globalized seafood supply network. Here, we explore the impact of the COVID-19 pandemic on wholesale prices from five major seafood markets around the world. An anomalies analysis was used to establish a 5-year baseline price for each commodity. Daily price data from 2020 were compared to the baseline to identify collapses (>1.96 SE from baseline) and analyse collapse characteristics (timing, duration and magnitude). Non-uniform price collapses were observed across, and within, the markets analysed. Toyosu (Tokyo) Market experienced price collapses to 51% of commodities, Rungis (Paris) 36%, Mercamadrid (Madrid) 19%, Mercado La Nueva Viga (Mexico City) 35% and the Portland Fish Exchange (Portland, Maine) 32%. Collapse magnitude varied from 11% to 79% of the 5-year average price. Average collapse duration ranged from 13 to 24 weeks with some commodities (4%-22%) remaining collapsed at the end of 2020. For markets where volume data were available, collapses were also noted (59% of commodities in Toyosu, 10% in Mercamadrid and 19% in Portland Fish Exchange); in these cases, the volume collapse was more severe than the related price collapse. To better detect, anticipate and respond to future shocks, we recommend that relevant government agencies conduct comprehensive economic reviews of the COVID-19 pandemic throughout the seafood supply chain, including the outcomes of emergency measures, short- and long-term implications of market volatility and identify areas of supply and labour vulnerabilities.

9.
Environ Sci Pollut Res Int ; 29(41): 61698-61710, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35347601

RESUMO

The vertical distribution pattern and concentrations of elements (Fe, Al, Ca, Mg, Mn, Cr, Cu, Ni, Co, Pb, Zn, and As) in the estuarine and lagoon region of Marquelia coast, Guerrero, Mexico, were studied to comprehend the origin and pollutant phases of geochemical elements. Henceforth, two sediment core samples [C1 (127 cm) and C2 (110 cm)] were collected to assess the pollution status using geochemical indices, namely anthropogenic factor (AF), enrichment factor (EF), and geoaccumulation index (Igeo). Additionally, the elemental concentrations were compared with the sediment quality guidelines (SQGs) to examine the potential risks to biota. Among the two depositional environments, the sediments of lagoon Apozahualco exhibited higher concentrations of elements. The granulometry characteristics of sediment grains also attested that the concentration and mobilization of metals are largely governed by the fine-grained fractions. Major elemental concentration and grain size changes were identified at several depths (30-40, 60-70, and 90-100 cm) revealing the internal hydrodynamic condition. The overall assessment of geochemical indices revealed that the sediments were unpolluted to moderately polluted. The anthropogenic factor indicated that the upper portion of the sediments were affected by anthropogenic influences. The comparison of trace element concentration with SQGs denoted that Cr, Ni, and As could pose potential adverse effect to the organisms that live in and near the sedimentary environment. Factor analysis revealed the origin and behaviour of the studied elements during transportation and deposition processes in both the ecosystems (i.e. estuary and lagoon). The results of this study provided an in-depth understanding of variations in elemental concentration and pollution status of sediment profile in coastal transitional environments that would aid in sustainable management.


Assuntos
Metais Pesados , Poluentes Químicos da Água , Ecossistema , Monitoramento Ambiental/métodos , Sedimentos Geológicos/química , Metais Pesados/análise , México , Poluentes Químicos da Água/análise
10.
Nat Commun ; 13(1): 817, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35145124

RESUMO

Social behaviours characterize cooperative, mutualistic, aggressive or parental interactions that occur among conspecifics. Although the Ventral Tegmental Area (VTA) has been identified as a key substrate for social behaviours, the input and output pathways dedicated to specific aspects of conspecific interaction remain understudied. Here, in male mice, we investigated the activity and function of two distinct VTA inputs from superior colliculus (SC-VTA) and medial prefrontal cortex (mPFC-VTA). We observed that SC-VTA neurons display social interaction anticipatory calcium activity, which correlates with orienting responses towards an unfamiliar conspecific. In contrast, mPFC-VTA neuron population activity increases after initiation of the social contact. While protracted phasic stimulation of SC-VTA pathway promotes head/body movements and decreases social interaction, inhibition of this pathway increases social interaction. Here, we found that SC afferents mainly target a subpopulation of dorsolateral striatum (DLS)-projecting VTA dopamine (DA) neurons (VTADA-DLS). While, VTADA-DLS pathway stimulation decreases social interaction, VTADA-Nucleus Accumbens stimulation promotes it. Altogether, these data support a model by which at least two largely anatomically distinct VTA sub-circuits oppositely control distinct aspects of social behaviour.


Assuntos
Vias Neurais/fisiologia , Orientação Espacial/fisiologia , Interação Social , Colículos Superiores/patologia , Área Tegmentar Ventral/fisiologia , Animais , Neurônios Dopaminérgicos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Núcleo Accumbens/fisiologia , Córtex Pré-Frontal/fisiologia , Comportamento Social
11.
BMJ Open Respir Res ; 8(1)2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34544735

RESUMO

INTRODUCTION: The diaphragm is the main muscle of inspiration, and its dysfunction contributes to adverse clinical outcomes in critically ill patients. We recently reported the infiltration of SARS-CoV-2, and the development of fibrosis, in the diaphragm of critically ill patients with COVID-19. In the current study, we aimed to characterise myofiber structure in the diaphragm of critically ill patients with COVID-19. METHODS: Diaphragm muscle specimens were collected during autopsy from patients who died of COVID-19 in three academic medical centres in the Netherlands in April and May 2020 (n=27). We studied diaphragm myofiber gene expression and structure and compared the findings obtained to those of deceased critically ill patients without COVID-19 (n=10). RESULTS: Myofibers of critically ill patients with COVID-19 showed on average larger cross-sectional area (slow-twitch myofibers: 2441±229 vs 1571±309 µm2; fast-twitch myofibers: 1966±209 vs 1225±222 µm2). Four critically ill patients with COVID-19 showed extremely large myofibers, which were splitting and contained many centralised nuclei. RNA-sequencing data revealed differentially expressed genes involved in muscle regeneration. CONCLUSION: Diaphragm of critically ill patients with COVID-19 has distinct myopathic features compared with critically ill patients without COVID-19, which may contribute to the ongoing dyspnoea and fatigue in the patients surviving COVID-19 infection.


Assuntos
COVID-19 , Estado Terminal , Diafragma/patologia , Idoso , Autopsia , COVID-19/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Musculares Esqueléticas/patologia , Países Baixos
12.
Mol Psychiatry ; 26(11): 6531-6549, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34035473

RESUMO

Mutations in the RAB39B gene cause X-linked intellectual disability (XLID), comorbid with autism spectrum disorders or early Parkinson's disease. One of the functions of the neuronal small GTPase RAB39B is to drive GluA2/GluA3 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) maturation and trafficking, determining AMPAR subunit composition at glutamatergic postsynaptic neuronal terminals. Taking advantage of the Rab39b knockout murine model, we show that a lack of RAB39B affects neuronal dendritic spine refinement, prompting a more Ca2+-permeable and excitable synaptic network, which correlates with an immature spine arrangement and behavioural and cognitive alterations in adult mice. The persistence of immature circuits is triggered by increased hypermobility of the spine, which is restored by the Ca2+-permeable AMPAR antagonist NASPM. Together, these data confirm that RAB39B controls AMPAR trafficking, which in turn plays a pivotal role in neuronal dendritic spine remodelling and that targeting Ca2+-permeable AMPARs may highlight future pharmaceutical interventions for RAB39B-associated disease conditions.


Assuntos
Espinhas Dendríticas , Deficiência Intelectual , Proteínas rab de Ligação ao GTP , Animais , Cálcio , Espinhas Dendríticas/fisiologia , Camundongos , Plasticidade Neuronal , Neurônios/fisiologia , Receptores de Glutamato/fisiologia , Proteínas rab de Ligação ao GTP/fisiologia
13.
Glob Chang Biol ; 27(15): 3474-3486, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33964101

RESUMO

Climate change and warming ocean temperatures are a threat to coral reef ecosystems. Since the 1980s, there has been an increase in mass coral bleaching and associated coral mortality due to more frequent and severe thermal stress. Although most research has focused on the role of temperature, coral bleaching is a product of the interacting effects of temperature and other environmental variables such as solar radiation. High light exacerbates the effects of thermal stress on corals, whereas reductions in light can reduce sensitivity to thermal stress. Here, we use an updated global dataset of coral bleaching observations (n = 35,769) from 1985 to 2017 and satellite-derived datasets of SST and clouds to examine for the first time at a global scale the influence of cloudiness on the likelihood of bleaching from thermal stress. We find that among coral reefs exposed to severe bleaching-level heat stress (Degree Heating Weeks >8°Cˑweek), bleaching severity is inversely correlated with the interaction of heat stress and cloud fraction anomalies (p < 0.05), such that higher cloudiness implies reduced bleaching response. A Random Forest model analysis employing different set of environmental variables shows that a model employing Degree Heating Weeks and the 30-day cloud fraction anomaly most accurately predicts bleaching severity (Accuracy = 0.834; Cohen's Kappa = 0.769). Based on these results and global warm-season cloudiness patterns, we develop a 'cloudy refugia' index which identifies the central equatorial Pacific and French Polynesia as regions where cloudiness is most likely to protect corals from bleaching. Our findings suggest that incorporating cloudiness into prediction models can help delineate bleaching responses and identify reefs which may be more resilient to climate change.


Assuntos
Antozoários , Recifes de Corais , Animais , Ecossistema , Resposta ao Choque Térmico , Polinésia , Temperatura
14.
J Gen Physiol ; 153(4)2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33651884

RESUMO

Adrenal chromaffin cells (CCs) in rodents express rapidly inactivating, tetrodotoxin (TTX)-sensitive sodium channels. The resulting current has generally been attributed to Nav1.7, although a possible role for Nav1.3 has also been suggested. Nav channels in rat CCs rapidly inactivate via two independent pathways which differ in their time course of recovery. One subpopulation recovers with time constants similar to traditional fast inactivation and the other ∼10-fold slower, but both pathways can act within a single homogenous population of channels. Here, we use Nav1.3 KO mice to probe the properties and molecular components of Nav current in CCs. We find that the absence of Nav1.3 abolishes all Nav current in about half of CCs examined, while a small, fast inactivating Nav current is still observed in the rest. To probe possible molecular components underlying slow recovery from inactivation, we used mice null for fibroblast growth factor homology factor 14 (FGF14). In these cells, the slow component of recovery from fast inactivation is completely absent in most CCs, with no change in the time constant of fast recovery. The use dependence of Nav current reduction during trains of stimuli in WT cells is completely abolished in FGF14 KO mice, directly demonstrating a role for slow recovery from inactivation in determining Nav current availability. Our results indicate that FGF14-mediated inactivation is the major determinant defining use-dependent changes in Nav availability in CCs. These results establish that Nav1.3, like other Nav isoforms, can also partner with FGF subunits, strongly regulating Nav channel function.


Assuntos
Células Cromafins , Sódio , Animais , Fatores de Crescimento de Fibroblastos/genética , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.3 , Ratos , Bloqueadores dos Canais de Sódio , Tetrodotoxina/farmacologia
15.
Nature ; 591(7850): 396-401, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33731948

RESUMO

The future of the global ocean economy is currently envisioned as advancing towards a 'blue economy'-socially equitable, environmentally sustainable and economically viable ocean industries1,2. However, tensions exist within sustainable development approaches, arising from differing perspectives framed around natural capital or social equity. Here we show that there are stark differences in outlook on the capacity for establishing a blue economy, and on its potential outcomes, when social conditions and governance capacity-not just resource availability-are considered, and we highlight limits to establishing multiple overlapping industries. This is reflected by an analysis using a fuzzy logic model to integrate indicators from multiple disciplines and to evaluate their current capacity to contribute to establishing equitable, sustainable and viable ocean sectors consistent with a blue economy approach. We find that the key differences in the capacity of regions to achieve a blue economy are not due to available natural resources, but include factors such as national stability, corruption and infrastructure, which can be improved through targeted investments and cross-scale cooperation. Knowledge gaps can be addressed by integrating historical natural and social science information on the drivers and outcomes of resource use and management, thus identifying equitable pathways to establishing or transforming ocean sectors1,3,4. Our results suggest that policymakers must engage researchers and stakeholders to promote evidence-based, collaborative planning that ensures that sectors are chosen carefully, that local benefits are prioritized, and that the blue economy delivers on its social, environmental and economic goals.


Assuntos
Política Ambiental , Modelos Econômicos , Oceanos e Mares , Desenvolvimento Sustentável/economia , Lógica Fuzzy , Objetivos
16.
J Gen Physiol ; 153(4)2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33647101

RESUMO

Voltage-dependent sodium (Nav) current in adrenal chromaffin cells (CCs) is rapidly inactivating and tetrodotoxin (TTX)-sensitive. The fractional availability of CC Nav current has been implicated in regulation of action potential (AP) frequency and the occurrence of slow-wave burst firing. Here, through recordings of Nav current in rat CCs, primarily in adrenal medullary slices, we describe unique inactivation properties of CC Nav inactivation that help define AP firing rates in CCs. The key feature of CC Nav current is that recovery from inactivation, even following brief (5 ms) inactivation steps, exhibits two exponential components of similar amplitude. Various paired pulse protocols show that entry into the fast and slower recovery processes result from largely independent competing inactivation pathways, each of which occurs with similar onset times at depolarizing potentials. Over voltages from -120 to -80 mV, faster recovery varies from ∼3 to 30 ms, while slower recovery varies from ∼50 to 400 ms. With strong depolarization (above -10 mV), the relative entry into slow or fast recovery pathways is similar and independent of voltage. Trains of short depolarizations favor recovery from fast recovery pathways and result in cumulative increases in the slow recovery fraction. Dual-pathway fast inactivation, by promoting use-dependent accumulation in slow recovery pathways, dynamically regulates Nav availability. Consistent with this finding, repetitive AP clamp waveforms at 1-10 Hz frequencies reduce Nav availability 80-90%, depending on holding potential. These results indicate that there are two distinct pathways of fast inactivation, one leading to conventional fast recovery and the other to slower recovery, which together are well-suited to mediate use-dependent changes in Nav availability.


Assuntos
Células Cromafins , Potenciais de Ação , Animais , Ratos , Sódio , Tetrodotoxina/farmacologia
17.
Proc Natl Acad Sci U S A ; 118(3)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33431687

RESUMO

Goblet cells (GCs) are specialized cells of the intestinal epithelium contributing critically to mucosal homeostasis. One of the functions of GCs is to produce and secrete MUC2, the mucin that forms the scaffold of the intestinal mucus layer coating the epithelium and separates the luminal pathogens and commensal microbiota from the host tissues. Although a variety of ion channels and transporters are thought to impact on MUC2 secretion, the specific cellular mechanisms that regulate GC function remain incompletely understood. Previously, we demonstrated that leucine-rich repeat-containing protein 26 (LRRC26), a known regulatory subunit of the Ca2+-and voltage-activated K+ channel (BK channel), localizes specifically to secretory cells within the intestinal tract. Here, utilizing a mouse model in which MUC2 is fluorescently tagged, thereby allowing visualization of single GCs in intact colonic crypts, we show that murine colonic GCs have functional LRRC26-associated BK channels. In the absence of LRRC26, BK channels are present in GCs, but are not activated at physiological conditions. In contrast, all tested MUC2- cells completely lacked BK channels. Moreover, LRRC26-associated BK channels underlie the BK channel contribution to the resting transepithelial current across mouse distal colonic mucosa. Genetic ablation of either LRRC26 or BK pore-forming α-subunit in mice results in a dramatically enhanced susceptibility to colitis induced by dextran sodium sulfate. These results demonstrate that normal potassium flux through LRRC26-associated BK channels in GCs has protective effects against colitis in mice.


Assuntos
Colite/genética , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Mucina-2/genética , Animais , Colite/patologia , Colite/prevenção & controle , Colite/terapia , Colo/metabolismo , Colo/patologia , Modelos Animais de Doenças , Células Caliciformes/metabolismo , Células Caliciformes/patologia , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Potenciais da Membrana/genética , Camundongos , Técnicas de Patch-Clamp
18.
J Chem Inf Model ; 60(9): 4124-4130, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32692571

RESUMO

The DIA-DB is a web server for the prediction of diabetes drugs that uses two different and complementary approaches: (a) comparison by shape similarity against a curated database of approved antidiabetic drugs and experimental small molecules and (b) inverse virtual screening of the input molecules chosen by the users against a set of therapeutic protein targets identified as key elements in diabetes. As a proof of concept DIA-DB was successfully applied in an integral workflow for the identification of the antidiabetic chemical profile in a complex crude plant extract. To this end, we conducted the extraction and LC-MS based chemical profile analysis of Sclerocarya birrea and subsequently utilized this data as input for our server. The server is open to all users, registration is not necessary, and a detailed report with the results of the prediction is sent to the user by email once calculations are completed. This is a novel public domain database and web server specific for diabetes drugs and can be accessed online through http://bio-hpc.eu/software/dia-db/.


Assuntos
Diabetes Mellitus , Preparações Farmacêuticas , Computadores , Bases de Dados Factuais , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes , Internet , Software
19.
eNeuro ; 7(2)2020.
Artigo em Inglês | MEDLINE | ID: mdl-32144144

RESUMO

Huntington's disease (HD) is a neurodegenerative disease notably characterized by progressive motor symptoms. Although the loss of medium spiny neurons (MSNs) in the striatum has been associated with motor deficits, premanifest patients already present cognitive deficiencies and show early signs of motor disabilities. Here, in a YAC128 HD mouse model, we identified impairment in motor skill consolidation at the age of 11-14 weeks. Using optogenetic stimulation, we found that excitatory synaptic transmission from motor cortex to MSNs located in the dorsolateral part of the striatum (DLS) is altered. Using single pellet reaching task, we observed that while motor skill consolidation is accompanied by a dynamic change in AMPA/NMDA ratio in wild-type (WT) mice, this form of synaptic plasticity does not occur in YAC128 mice. This study not only proposes new meaningful insight in the synaptopathic mechanisms of HD, but also highlights that deficit in motor skill consolidation-dependent synaptic plasticity at motor cortex to DLS synapses represents an early biomarker for HD.


Assuntos
Doença de Huntington , Córtex Motor , Doenças Neurodegenerativas , Animais , Corpo Estriado , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Destreza Motora , Plasticidade Neuronal , Sinapses
20.
ACM arq. catarin. med ; 49(1): 78-90, jan.-mar. 2020.
Artigo em Português | LILACS-Express | LILACS | ID: biblio-1096082

RESUMO

Objetivo: Descrever os atendimentos oftalmológicos realizados em uma unidade geral de pronto atendimento. Métodos: Estudo prospectivo, observacional e descritivo cuja coleta de dados foi realizada em prontuários de pacientes atendidos na unidade por queixas oftalmológicas no período entre julho e novembro de 2018. Resultados: Foram revisados 445 prontuários de pacientes oftalmológicos, representando 2,18% do número total de pacientes atendidos no período. Foram encontrados 182 (40,89%) pacientes com diagnóstico de conjuntivite, 139 (31,23%) de trauma ocular e 78 (17,52%) com outros diagnósticos. Dentre os pacientes com trauma ocular, 115 (82,73%) eram do sexo masculino e 42 resultaram de acidente de trabalho. Conclusões: Conclui-se que a maioria dos pacientes oftalmológicos foi atendida com diagnóstico de conjuntivite ou trauma ocular e parte desses não faziam uso de EPI no momento da ocorrência. Os resultados permitem inferir que os médicos plantonistas precisam ter noções sobre as doenças oftalmológicas prevalentes na unidade de pronto atendimento e que desponta a necessidade de se promover campanhas para a prevenção de acidentes de trabalho junto às empresas da região, acompanhadas de fiscalização, para reduzir o acometimento de pacientes com trauma ocular resultante da não observância das normas de proteção.


Objective: To describe the ophthalmologic services performed in a general emergency care unit. Methods: Prospective, observational and descriptive study whose data collection was performed on medical records of patients seen at the unit for eye complaints in the period between July and November 2018. Results: 445 medical records of ophthalmological patients were reviewed, representing 2,18% of the number total number of patients seen in the period. 182 (40.89%) patients were diagnosed with conjunctivitis, 139 (31.23%) with ocular trauma and 78 (17.52%) with other diagnoses. Among the patients with ocular trauma, 115 (82.73%) were male and 42 resulted from an occupational accident. Conclusions: Most ophthalmologic patients were treated with a diagnosis of conjunctivitis or ocular trauma and part of them did not use PPE at the moment of the accident. The results allow us to infer that physicians on duty need to have knowledge about the ophthalmological diseases prevalent in the emergency care unit and that there is a need to promote campaigns for the prevention of work accidents with companies in the region, accompanied by inspection, reducing the involvement of patients with eye trauma who were not obeying the rules of protection.

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