RESUMO
GPR133 (ADGRD1) is an adhesion G-protein-coupled receptor that signals through Gαs/cyclic AMP (cAMP) and is required for the growth of glioblastoma (GBM), an aggressive brain malignancy. The regulation of GPR133 signaling is incompletely understood. Here, we use proximity biotinylation proteomics to identify ESYT1, a Ca2+-dependent mediator of endoplasmic reticulum-plasma membrane bridge formation, as an intracellular interactor of GPR133. ESYT1 knockdown or knockout increases GPR133 signaling, while its overexpression has the opposite effect, without altering GPR133 levels in the plasma membrane. The GPR133-ESYT1 interaction requires the Ca2+-sensing C2C domain of ESYT1. Thapsigargin-mediated increases in cytosolic Ca2+ relieve signaling-suppressive effects of ESYT1 by promoting ESYT1-GPR133 dissociation. ESYT1 knockdown or knockout in GBM slows tumor growth, suggesting tumorigenic functions of ESYT1. Our findings demonstrate a mechanism for the modulation of GPR133 signaling by increased cytosolic Ca2+, which reduces the signaling-suppressive interaction between GPR133 and ESYT1 to raise cAMP levels.
Assuntos
Cálcio , Glioblastoma , Receptores Acoplados a Proteínas G , Transdução de Sinais , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Humanos , Animais , Cálcio/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/genética , Camundongos , AMP Cíclico/metabolismo , Linhagem Celular Tumoral , Células HEK293 , Ligação Proteica , Camundongos Nus , Proteínas OncogênicasRESUMO
Mosquitoes encounter diverse microbes during their lifetime, including symbiotic bacteria, shaping their midgut ecosystem. The organization of the midgut supports microbiota persistence while defending against potential pathogens. The influx of nutrients during blood feeding triggers bacterial proliferation, challenging host homeostasis. Immune responses, aimed at controlling bacterial overgrowth, impact blood-borne pathogens such as malaria parasites. However, parasites deploy evasion strategies against mosquito immunity. Leveraging these mechanisms could help engineer malaria-resistant mosquitoes, offering a transformative tool for malaria elimination.
Assuntos
Culicidae , Microbioma Gastrointestinal , Animais , Culicidae/microbiologia , Culicidae/fisiologia , Culicidae/imunologia , Simbiose , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/imunologiaRESUMO
The dietary behaviors of Asian American (AA) young adults, who face a growing non-communicable disease burden, are impacted by complex socio-ecological forces. Family plays a crucial role in the lifestyle behaviors of AA young adults; however, little is known on the methods, contributors, and impact of familial dietary influence. This study aims to deconstruct the mechanisms of AA young adult familial dietary influence through a multi-perspective qualitative assessment. A five-phase method of dyadic analysis adapted from past research was employed to extract nuanced insights from dyadic interviews with AA young adults and family members, and ground findings in behavioral theory (the Social Cognitive Theory, SCT). 37 interviews were conducted: 18 young adults, comprising 10 different AA ethnic subgroups, and 19 family members (10 parents, 9 siblings). Participants described dietary influences that were both active (facilitating, shaping, and restricting) and passive (e.g., sharing foods or environment, mirroring food behaviors). Influences connected strongly with multiple SCT constructs (e.g., behavioral capacity, reinforcements for active influences, and expectations, observational learning for passive influences). Familial influence contributed to changes in the total amount, variety, and healthfulness of foods consumed. Intra-family dynamics were crucial; family members often leveraged each other's persuasiveness or food skills to collaboratively influence diet. AA family-based interventions should consider incorporating both passive and active forms of dietary influence within a family unit, involve multiple family members, and allow for individualization to the unique dynamics and dietary behaviors within each family unit.
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Glioblastoma (GBM) is the most common and aggressive primary brain malignancy. Adhesion G protein-coupled receptors (aGPCRs) have attracted interest for their potential as treatment targets. Here, we show that CD97 (ADGRE5) is the most promising aGPCR target in GBM, by virtue of its de novo expression compared to healthy brain tissue. CD97 knockdown or knockout significantly reduces the tumor initiation capacity of patient-derived GBM cultures (PDGCs) in vitro and in vivo. We find that CD97 promotes glycolytic metabolism via the mitogen-activated protein kinase (MAPK) pathway, which depends on phosphorylation of its C terminus and recruitment of ß-arrestin. We also demonstrate that THY1/CD90 is a likely CD97 ligand in GBM. Lastly, we show that an anti-CD97 antibody-drug conjugate selectively kills tumor cells in vitro. Our studies identify CD97 as a regulator of tumor metabolism, elucidate mechanisms of receptor activation and signaling, and provide strong scientific rationale for developing biologics to target it therapeutically in GBM.
Assuntos
Glioblastoma , Humanos , Glioblastoma/patologia , Fosforilação , Receptores Acoplados a Proteínas G/metabolismo , Transdução de SinaisRESUMO
GPR133 (ADGRD1) is an adhesion G protein-coupled receptor that signals through Gαs and is required for growth of glioblastoma (GBM), an aggressive brain malignancy. The regulation of GPR133 signaling is incompletely understood. Here, we use proximity biotinylation proteomics to identify ESYT1, a Ca2+-dependent mediator of endoplasmic reticulum-plasma membrane bridge formation, as an intracellular interactor of GPR133. ESYT1 knockdown or knockout increases GPR133 signaling, while its overexpression has the opposite effect, without altering GPR133 levels in the plasma membrane. The GPR133-ESYT1 interaction requires the Ca2+-sensing C2C domain of ESYT1. Thapsigargin-mediated increases in cytosolic Ca2+ relieve signaling-suppressive effects of ESYT1 by promoting ESYT1-GPR133 dissociation. ESYT1 knockdown or knockout in GBM impairs tumor growth in vitro, suggesting functions of ESYT1 beyond the interaction with GPR133. Our findings suggest a novel mechanism for modulation of GPR133 signaling by increased cytosolic Ca2+, which reduces the signaling-suppressive interaction between GPR133 and ESYT1 to raise cAMP levels.
RESUMO
Auditory stream segregation and informational masking were investigated in brain-lesioned individuals, age-matched controls with no neurological disease, and young college-age students. A psychophysical paradigm known as rhythmic masking release (RMR) was used to examine the ability of participants to identify a change in the rhythmic sequence of 20-ms Gaussian noise bursts presented through headphones and filtered through generalized head-related transfer functions to produce the percept of an externalized auditory image (i.e., a 3D virtual reality sound). The target rhythm was temporally interleaved with a masker sequence comprising similar noise bursts in a manner that resulted in a uniform sequence with no information remaining about the target rhythm when the target and masker were presented from the same location (an impossible task). Spatially separating the target and masker sequences allowed participants to determine if there was a change in the target rhythm midway during its presentation. RMR thresholds were defined as the minimum spatial separation between target and masker sequences that resulted in 70.7% correct-performance level in a single-interval 2-alternative forced-choice adaptive tracking procedure. The main findings were (1) significantly higher RMR thresholds for individuals with brain lesions (especially those with damage to parietal areas) and (2) a left-right spatial asymmetry in performance for lesion (but not control) participants. These findings contribute to a better understanding of spatiotemporal relations in informational masking and the neural bases of auditory scene analysis.
Assuntos
Ruído , Mascaramento Perceptivo , Humanos , Envelhecimento , Encéfalo , Limiar AuditivoRESUMO
Agriculture provides an unique opportunity for the development of robotic systems; robots must be developed which can operate in harsh conditions and in highly uncertain and unknown environments. One particular challenge is performing manipulation for autonomous robotic harvesting. This paper describes recent and current work to automate the harvesting of iceberg lettuce. Unlike many other produce, iceberg is challenging to harvest as the crop is easily damaged by handling and is very hard to detect visually. A platform called Vegebot has been developed to enable the iterative development and field testing of the solution, which comprises of a vision system, custom end effector and software. To address the harvesting challenges posed by iceberg lettuce a bespoke vision and learning system has been developed which uses two integrated convolutional neural networks to achieve classification and localization. A custom end effector has been developed to allow damage free harvesting. To allow this end effector to achieve repeatable and consistent harvesting, a control method using force feedback allows detection of the ground. The system has been tested in the field, with experimental evidence gained which demonstrates the success of the vision system to localize and classify the lettuce, and the full integrated system to harvest lettuce. This study demonstrates how existing state-of-the art vision approaches can be applied to agricultural robotics, and mechanical systems can be developed which leverage the environmental constraints imposed in such environments.
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Peptidoglycan recognition proteins (PGRPs) constitute the primary means of bacterial recognition in insects. Recent work in the model organism Drosophila has revealed the mechanisms by which the complement of PGRPs refine the sensitivity of different tissues to bacterial elicitors, permitting the persistence of commensal bacteria in the gut whilst maintaining vigilance against bacterial infection. Here, we use in vivo knockdowns and in vitro pull-down assays to investigate the role of the three major isoforms of the transmembrane receptor of the Imd pathway, PGRPLC, in basal immunity in the Anopheles coluzzii mosquito midgut. Our results indicate that the mosquito midgut is regionalized in its expression of immune effectors and of PGRPLC1. We show that PGRPLC1 and PGRPLC3 are pulled down with polymeric DAP-type peptidoglycan, while PGRPLC2 and PGRPLC3 co-precipitate in the presence of TCT, a peptidoglycan monomer. These data suggest that, as found in Drosophila, discrimination of polymeric and monomeric PGN by Anopheles PGRPLC participates in the regulation of the Imd pathway.
Assuntos
Anopheles/genética , Proteínas de Transporte/genética , Proteínas de Insetos/genética , Animais , Anopheles/metabolismo , Proteínas de Transporte/metabolismo , Feminino , Trato Gastrointestinal/metabolismo , Proteínas de Insetos/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMO
The visual color-word Stroop task is widely used in clinical and research settings as a measure of cognitive control. Numerous neuroimaging studies have used color-word Stroop tasks to investigate the neural resources supporting cognitive control, but to our knowledge all have used unimodal (typically visual) Stroop paradigms. Thus, it is possible that this classic measure of cognitive control is not capturing the resources involved in multisensory cognitive control. The audiovisual integration and crossmodal correspondence literatures identify regions sensitive to congruency of auditory and visual stimuli, but it is unclear how these regions relate to the unimodal cognitive control literature. In this study we aimed to identify brain regions engaged by crossmodal cognitive control during an audiovisual color-word Stroop task, and how they relate to previous unimodal Stroop and audiovisual integration findings. First, we replicated previous behavioral audiovisual Stroop findings in an fMRI-adapted audiovisual Stroop paradigm: incongruent visual information increased reaction time towards an auditory stimulus and congruent visual information decreased reaction time. Second, we investigated the brain regions supporting cognitive control during an audiovisual color-word Stroop task using fMRI. Similar to unimodal cognitive control tasks, a left superior parietal region exhibited an interference effect of visual information on the auditory stimulus. This superior parietal region was also identified using a standard audiovisual integration localizing procedure, indicating that audiovisual integration resources are sensitive to cognitive control demands. Facilitation of the auditory stimulus by congruent visual information was found in posterior superior temporal cortex, including in the posterior STS which has been found to support audiovisual integration. The dorsal anterior cingulate cortex, often implicated in unimodal Stroop tasks, was not modulated by the audiovisual Stroop task. Overall the findings indicate that an audiovisual color-word Stroop task engages overlapping resources with audiovisual integration and overlapping but distinct resources compared to unimodal Stroop tasks.
Assuntos
Percepção Auditiva/fisiologia , Imageamento por Ressonância Magnética/métodos , Percepção Visual/fisiologia , Adolescente , Adulto , Feminino , Giro do Cíngulo/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Lobo Parietal/fisiologia , Tempo de Reação/fisiologia , Teste de Stroop , Adulto JovemRESUMO
Auditory and visual speech information are often strongly integrated resulting in perceptual enhancements for audiovisual (AV) speech over audio alone and sometimes yielding compelling illusory fusion percepts when AV cues are mismatched, the McGurk-MacDonald effect. Previous research has identified three candidate regions thought to be critical for AV speech integration: the posterior superior temporal sulcus (STS), early auditory cortex, and the posterior inferior frontal gyrus. We assess the causal involvement of these regions (and others) in the first large-scale (N = 100) lesion-based study of AV speech integration. Two primary findings emerged. First, behavioral performance and lesion maps for AV enhancement and illusory fusion measures indicate that classic metrics of AV speech integration are not necessarily measuring the same process. Second, lesions involving superior temporal auditory, lateral occipital visual, and multisensory zones in the STS are the most disruptive to AV speech integration. Further, when AV speech integration fails, the nature of the failure-auditory vs visual capture-can be predicted from the location of the lesions. These findings show that AV speech processing is supported by unimodal auditory and visual cortices as well as multimodal regions such as the STS at their boundary. Motor related frontal regions do not appear to play a role in AV speech integration.
Assuntos
Percepção Auditiva/fisiologia , Encéfalo/fisiopatologia , Rede Nervosa/fisiopatologia , Percepção da Fala/fisiologia , Fala/fisiologia , Percepção Visual/fisiologia , Encéfalo/diagnóstico por imagem , Sinais (Psicologia) , Feminino , Lateralidade Funcional/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Rede Nervosa/diagnóstico por imagem , Neuroimagem , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologiaRESUMO
Synthetic and natural steroid hormones have attracted some attention in recent years as endocrine active substances (EAS) that interact or interfere with the endocrine system. Endogenous hormones occur naturally in food of animal origin, among which bovine milk represents an important source. This study was conducted to determine the occurrence of steroid hormones (oestrogens, androgens, progestogens and glucocorticoids) in cow's milk samples from three farms in Switzerland. An isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of 12 hormones in milk. Some hormonal levels from individual cows showed large variations. The average levels of the hormones analysed (17α-estradiol = 31 ng kg(-)(1), 17ß-estradiol = 6 ng kg(-)(1), estrone = 159 ng kg(-)(1), 4-androstenedione = 684 ng kg(-)(1), progesterone = 15486 ng kg(-)(1), 17-hydroxyprogesterone = 214 ng kg(-)(1), cortisone = 112 ng kg(-)(1), and cortisol = 235 ng kg(-)(1)) were comparable with literature data. Estriol, testosterone and androstenediols were not detected at their respective limit of quantification. No significant differences of hormonal content among milk from cows at different lactation/calving numbers were evidenced, except for progesterone and 4-androstenedione. Due to confounding parameters linked to the physiological stage of the animal, like pregnancy and gestational stage (pregnancy trimester), the causal correlation between the variation of the levels for these two hormones and the lactation/calving number could not be unambiguously demonstrated.