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1.
Cell ; 166(6): 1512-1525.e12, 2016 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-27610573

RESUMO

Acute infections are associated with a set of stereotypic behavioral responses, including anorexia, lethargy, and social withdrawal. Although these so-called sickness behaviors are the most common and familiar symptoms of infections, their roles in host defense are largely unknown. Here, we investigated the role of anorexia in models of bacterial and viral infections. We found that anorexia was protective while nutritional supplementation was detrimental in bacterial sepsis. Furthermore, glucose was necessary and sufficient for these effects. In contrast, nutritional supplementation protected against mortality from influenza infection and viral sepsis, whereas blocking glucose utilization was lethal. In both bacterial and viral models, these effects were largely independent of pathogen load and magnitude of inflammation. Instead, we identify opposing metabolic requirements tied to cellular stress adaptations critical for tolerance of differential inflammatory states. VIDEO ABSTRACT.


Assuntos
Gerenciamento Clínico , Jejum , Glucose/metabolismo , Comportamento de Doença/fisiologia , Influenza Humana/metabolismo , Listeriose/metabolismo , Apoio Nutricional/efeitos adversos , Animais , Antimetabólitos/uso terapêutico , Células Cultivadas , Desoxiglucose/uso terapêutico , Glucose/administração & dosagem , Humanos , Inflamação , Influenza Humana/fisiopatologia , Influenza Humana/terapia , Lipopolissacarídeos , Listeriose/mortalidade , Listeriose/fisiopatologia , Listeriose/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Poli I-C , Sepse/induzido quimicamente , Sepse/prevenção & controle , Fator de Transcrição CHOP/metabolismo
2.
Nucleic Acids Res ; 51(20): 11056-11079, 2023 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-37823600

RESUMO

Zinc finger (ZNF) motifs are some of the most frequently occurring domains in the human genome. It was only recently that ZNF proteins emerged as key regulators of genome integrity in mammalian cells. In this study, we report a new role for the Krüppel-type ZNF-containing protein ZNF432 as a novel poly(ADP-ribose) (PAR) reader that regulates the DNA damage response. We show that ZNF432 is recruited to DNA lesions via DNA- and PAR-dependent mechanisms. Remarkably, ZNF432 stimulates PARP-1 activity in vitro and in cellulo. Knockdown of ZNF432 inhibits phospho-DNA-PKcs and increases RAD51 foci formation following irradiation. Moreover, purified ZNF432 preferentially binds single-stranded DNA and impairs EXO1-mediated DNA resection. Consequently, the loss of ZNF432 in a cellular system leads to resistance to PARP inhibitors while its overexpression results in sensitivity. Taken together, our results support the emerging concept that ZNF-containing proteins can modulate PARylation, which can be embodied by the pivotal role of ZNF432 to finely balance the outcome of PARPi response by regulating homologous recombination.


Assuntos
Poli ADP Ribosilação , Poli Adenosina Difosfato Ribose , Humanos , DNA/genética , DNA/metabolismo , Dano ao DNA , Reparo do DNA , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli Adenosina Difosfato Ribose/metabolismo
3.
Artigo em Inglês | MEDLINE | ID: mdl-39155309

RESUMO

PURPOSE: [18F]SynVesT-1, a positron emission tomography (PET) radiotracer for the synaptic vesicle glycoprotein 2A (SV2A), demonstrates kinetics similar to [11C]UCB-J, with high brain uptake, fast kinetics fitting well with the one-tissue compartment (1TC) model, and excellent test-retest reproducibility. Challenges arise due to the similarity between k2 and [Formula: see text] (efflux rate of the reference region), when applying the simplified reference tissue model (SRTM) and related methods in [11C]UCB-J studies to accurately estimate [Formula: see text]. This study evaluated the suitability of these methods to estimate [18F]SynVesT-1 binding using centrum semiovale (CS) or cerebellum (CER) as reference regions. METHOD: Seven healthy participants underwent 120-min PET scans on the HRRT scanner with [18F]SynVesT-1. Six participants underwent test and retest scans. Arterial blood sampling and metabolite analysis provided input functions for the 1TC model, serving as the gold standard for kinetic parameters values. SRTM, coupled SRTM (SRTMC) and SRTM2 estimated were applied to estimate [Formula: see text](ref: CS) and DVRCER(ref: CER) values. For SRTM2, the population average of [Formula: see text] was determined from the 1TC model applied to the reference region. Test-retest variability and minimum scan time were also calculated. RESULTS: The 1TC k2 (1/min) values for CS and CER were 0.031 ± 0.004 and 0.021 ± 0.002, respectively. Although SRTMC [Formula: see text] was much higher than 1TC [Formula: see text], SRTMC underestimated BPND(ref: CS) and DVRCER by an average of 3% and 1% across regions, respectively, due to similar bias in k2 and [Formula: see text] estimation. SRTM underestimated BPND(ref: CS) by an average of 3%, but with the CER as reference region, SRTM estimation was unstable and DVRCER underestimation varied by region (mean 10%). Using population average [Formula: see text] values, SRTM2 BPND and DVRCER showed the best agreement with 1TC estimates. CONCLUSION: Our findings support the use of population [Formula: see text] value in SRTM2 with [18F]SynVesT-1 for the estimation of [Formula: see text] or DVRCER, regardless of the choice of reference region.

4.
Eur J Nucl Med Mol Imaging ; 51(4): 1012-1022, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37955791

RESUMO

PURPOSE: Aging is a major societal concern due to age-related functional losses. Synapses are crucial components of neural circuits, and synaptic density could be a sensitive biomarker to evaluate brain function. [11C]UCB-J is a positron emission tomography (PET) ligand targeting synaptic vesicle glycoprotein 2A (SV2A), which can be used to evaluate brain synaptic density in vivo. METHODS: We evaluated age-related changes in gray matter synaptic density, volume, and blood flow using [11C]UCB-J PET and magnetic resonance imaging (MRI) in a wide age range of 80 cognitive normal subjects (21-83 years old). Partial volume correction was applied to the PET data. RESULTS: Significant age-related decreases were found in 13, two, and nine brain regions for volume, synaptic density, and blood flow, respectively. The prefrontal cortex showed the largest volume decline (4.9% reduction per decade: RPD), while the synaptic density loss was largest in the caudate (3.6% RPD) and medial occipital cortex (3.4% RPD). The reductions in caudate are consistent with previous SV2A PET studies and likely reflect that caudate is the site of nerve terminals for multiple major tracts that undergo substantial age-related neurodegeneration. There was a non-significant negative relationship between volume and synaptic density reductions in 16 gray matter regions. CONCLUSION: MRI and [11]C-UCB-J PET showed age-related decreases of gray matter volume, synaptic density, and blood flow; however, the regional patterns of the reductions in volume and SV2A binding were different. Those patterns suggest that MR-based measures of GM volume may not be directly representative of synaptic density.


Assuntos
Substância Cinzenta , Glicoproteínas de Membrana , Humanos , Idoso de 80 Anos ou mais , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/metabolismo , Glicoproteínas de Membrana/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Sinapses/metabolismo
5.
J Acoust Soc Am ; 155(4): 2339-2346, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38557734

RESUMO

In the stress-energy tensor formalism, the symmetry between absorption and scattering coefficients, as proven by measurements combined with simulations, is counterintuitive. By introducing the wall admittance, we show that the scattering coefficient is partly created by the real part of the wall admittance combined with the active intensity, that is, is partly due to absorption. However, for curved surfaces or finite source distances, it also depends on the imaginary part of the wall admittance in combination with the reactive intensity, which confers its genuine scattering properties inversely proportional to the distances to the sources. Thus, for plane waves impinging on plane boundaries, or purely real admittances, scattering reduces to absorption.

6.
PLoS Genet ; 16(11): e1009183, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33137104

RESUMO

Loss of von Hippel-Lindau protein pVHL function promotes VHL diseases, including sporadic and inherited clear cell Renal Cell Carcinoma (ccRCC). Mechanisms controlling pVHL function and regulation, including folding and stability, remain elusive. Here, we have identified the conserved cochaperone prefoldin complex in a screen for pVHL interactors. The prefoldin complex delivers non-native proteins to the chaperonin T-complex-protein-1-ring (TRiC) or Cytosolic Chaperonin containing TCP-1 (CCT) to assist folding of newly synthesized polypeptides. The pVHL-prefoldin interaction was confirmed in human cells and prefoldin knock-down reduced pVHL expression levels. Furthermore, when pVHL was expressed in Schizosaccharomyces pombe, all prefoldin mutants promoted its aggregation. We mapped the interaction of prefoldin with pVHL at the exon2-exon3 junction encoded region. Low levels of the PFDN3 prefoldin subunit were associated with poor survival in ccRCC patients harboring VHL mutations. Our results link the prefoldin complex with pVHL folding and this may impact VHL diseases progression.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Neoplasias Renais/genética , Chaperonas Moleculares/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Chaperonina com TCP-1 , Técnicas de Silenciamento de Genes , Células HEK293 , Células HeLa , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Chaperonas Moleculares/genética , Mutação , Ligação Proteica/genética , Dobramento de Proteína , Proteólise , Schizosaccharomyces , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/genética
7.
J Fish Biol ; 103(2): 202-219, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37190911

RESUMO

This review examines the published literature on the distribution and species richness of the family Mugilidae around six continents as well as their phylogenetic relationships in a time-calibrated tree. Three mugilid species-rich regions were identified globally, namely the Coral Triangle, southern Asia and southern Africa, all of which have between 16 and 18 morphologically recognized species. Two of the species hotspots are tropical, and only southern Africa incorporates temperate waters. The centre of mugilid evolution and then global dispersion appears to be located in the tropical waters of the Indo-Pacific. Speciation within the family was promoted mainly by plate tectonics, eustatic sea-level changes, tropical climate and high habitat diversity within this region. The number of these tropical species that radiated out to the coastal waters of Africa and America was clearly less than the number that remained in the central Indo-Pacific region. Nonetheless, access by tropical mugilid species was greater to Africa than the Americas because of the direct tropical and subtropical coastal connectivity to the former continent. This enabled more tropical mugilids to reach Africa than America, with the latter probably relying on Palaeocene "island hopping" or "rafting" to move eastwards across the Pacific Ocean. In addition, tropical mugilids were able to access warm western and central African coastal waters from the Pacific prior to the closure of the Tethys Sea gap in the eastern Mediterranean and prior to the development of the cool Benguela Current upwelling off the southwest African coast, and from America through at least two transatlantic rafting events.


Assuntos
Antozoários , Smegmamorpha , Animais , Filogenia , Ecossistema , África Austral
8.
Neuroimage ; 264: 119678, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36261057

RESUMO

Head motion presents a continuing problem in brain PET studies. A wealth of motion correction (MC) algorithms had been proposed in the past, including both hardware-based methods and data-driven methods. However, in most real brain PET studies, in the absence of ground truth or gold standard of motion information, it is challenging to objectively evaluate MC quality. For MC evaluation, image-domain metrics, e.g., standardized uptake value (SUV) change before and after MC are commonly used, but this measure lacks objectivity because 1) other factors, e.g., attenuation correction, scatter correction and parameters used in the reconstruction, will confound MC effectiveness; 2) SUV only reflects final image quality, and it cannot precisely inform when an MC method performed well or poorly during the scan time period; 3) SUV is tracer-dependent and head motion may cause increases or decreases in SUV for different tracers, so evaluating MC effectiveness is complicated. Here, we present a new algorithm, i.e., motion corrected centroid-of-distribution (MCCOD) to perform objective quality control for measured or estimated rigid motion information. MCCOD is a three-dimensional surrogate trace of the center of tracer distribution after performing rigid MC using the existing motion information. MCCOD is used to inform whether the motion information is accurate, using the PET raw data only, i.e., without PET image reconstruction, where inaccurate motion information typically leads to abrupt changes in the MCCOD trace. MCCOD was validated using simulation studies and was tested on real studies acquired from both time-of-flight (TOF) and non-TOF scanners. A deep learning-based brain mask segmentation was implemented, which is shown to be necessary for non-TOF MCCOD generation. MCCOD is shown to be effective in detecting abrupt translation motion errors in slowly varying tracer distribution caused by the motion tracking hardware and can be used to compare different motion estimation methods as well as to improve existing motion information.


Assuntos
Processamento de Imagem Assistida por Computador , Tomografia por Emissão de Pósitrons , Humanos , Processamento de Imagem Assistida por Computador/métodos , Tomografia por Emissão de Pósitrons/métodos , Movimento (Física) , Algoritmos , Encéfalo/diagnóstico por imagem
9.
Neuroimage ; 252: 119031, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35257856

RESUMO

Head motion during PET scans causes image quality degradation, decreased concentration in regions with high uptake and incorrect outcome measures from kinetic analysis of dynamic datasets. Previously, we proposed a data-driven method, center of tracer distribution (COD), to detect head motion without an external motion tracking device. There, motion was detected using one dimension of the COD trace with a semiautomatic detection algorithm, requiring multiple user defined parameters and manual intervention. In this study, we developed a new data-driven motion detection algorithm, which is automatic, self-adaptive to noise level, does not require user-defined parameters and uses all three dimensions of the COD trace (3DCOD). 3DCOD was first validated and tested using 30 simulation studies (18F-FDG, N = 15; 11C-raclopride (RAC), N = 15) with large motion. The proposed motion correction method was tested on 22 real human datasets, with 20 acquired from a high resolution research tomograph (HRRT) scanner (18F-FDG, N = 10; 11C-RAC, N = 10) and 2 acquired from the Siemens Biograph mCT scanner. Real-time hardware-based motion tracking information (Vicra) was available for all real studies and was used as the gold standard. 3DCOD was compared to Vicra, no motion correction (NMC), one-direction COD (our previous method called 1DCOD) and two conventional frame-based image registration (FIR) algorithms, i.e., FIR1 (based on predefined frames reconstructed with attenuation correction) and FIR2 (without attenuation correction) for both simulation and real studies. For the simulation studies, 3DCOD yielded -2.3 ± 1.4% (mean ± standard deviation across all subjects and 11 brain regions) error in region of interest (ROI) uptake for 18F-FDG (-3.4 ± 1.7% for 11C-RAC across all subjects and 2 regions) as compared to Vicra (perfect correction) while NMC, FIR1, FIR2 and 1DCOD yielded -25.4 ± 11.1% (-34.5 ± 16.1% for 11C- RAC), -13.4 ± 3.5% (-16.1 ± 4.6%), -5.7 ± 3.6% (-8.0 ± 4.5%) and -2.6 ± 1.5% (-5.1 ± 2.7%), respectively. For real HRRT studies, 3DCOD yielded -0.3 ± 2.8% difference for 18F-FDG (-0.4 ± 3.2% for 11C-RAC) as compared to Vicra while NMC, FIR1, FIR2 and 1DCOD yielded -14.9 ± 9.0% (-24.5 ± 14.6%), -3.6 ± 4.9% (-13.4 ± 14.3%), -0.6 ± 3.4% (-6.7 ± 5.3%) and -1.5 ± 4.2% (-2.2 ± 4.1%), respectively. In summary, the proposed motion correction method yielded comparable performance to the hardware-based motion tracking method for multiple tracers, including very challenging cases with large frequent head motion, in studies performed on a non-TOF scanner.


Assuntos
Processamento de Imagem Assistida por Computador , Tomografia por Emissão de Pósitrons , Algoritmos , Encéfalo/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador/métodos , Cinética , Movimento (Física) , Movimento , Tomografia por Emissão de Pósitrons/métodos
10.
Neuroimage ; 264: 119674, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36243269

RESUMO

Brain cannabinoid 1 receptors (CB1Rs) contribute importantly to the regulation of autonomic tone, appetite, mood and cognition. Inconsistent results have been reported from positron emission tomography (PET) studies using different radioligands to examine relationships between age, gender and body mass index (BMI) and CB1R availability in healthy individuals. In this study, we examined these variables in 58 healthy individuals (age range: 18-55 years; 44 male; BMI=27.01±5.56), the largest cohort of subjects studied to date using the CB1R PET ligand [11C]OMAR. There was a significant decline in CB1R availability (VT) with age in the pallidum, cerebellum and posterior cingulate. Adjusting for BMI, age-related decline in VT remained significant in the posterior cingulate among males, and in the cerebellum among women. CB1R availability was higher in women compared to men in the thalamus, pallidum and posterior cingulate. Adjusting for age, CB1R availability negatively correlated with BMI in women but not men. These findings differ from those reported using [11C]OMAR and other radioligands such as [18F]FMPEP-d2 and [18F]MK-9470. Although reasons for these seemingly divergent findings are unclear, the choice of PET radioligand and range of BMI in the current dataset may contribute to the observed differences. This study highlights the need for cross-validation studies using both [11C]OMAR and [18F]FMPEP-d2 within the same cohort of subjects.


Assuntos
Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Masculino , Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Índice de Massa Corporal , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/diagnóstico por imagem , Receptor CB1 de Canabinoide
11.
J Nucl Cardiol ; 29(1): 216-225, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32415628

RESUMO

OBJECTIVES: We aimed to develop a dynamic imaging technique for a novel PET superoxide tracer, [18F]DHMT, to allow for absolute quantification of myocardial reactive oxygen species (ROS) production in a large animal model. METHODS: Six beagle dogs underwent a single baseline dynamic [18F]DHMT PET study, whereas one animal underwent three serial dynamic studies over the course of chronic doxorubicin administration (1 mg·kg-1·week-1 for 15 weeks). During the scans, sequential arterial blood samples were obtained for plasma metabolite correction. The optimal compartment model and graphical analysis method were identified for kinetic modeling. Values for the left ventricular (LV) net influx rate, Ki, were reported for all the studies and compared with the LV standard uptake values (SUVs) and the LV-to-blood pool SUV ratios from the 60 to 90 minute static images. Parametric images were also generated. RESULTS: [18F]DHMT followed irreversible kinetics once oxidized within the myocardium in the presence of superoxide, as evidenced by the fitting generated by the irreversible two-tissue (2Ti) compartment model and the linearity of Patlak analysis. Myocardial Ki values showed a weak correlation with LV SUV (R2 = 0.27), but a strong correlation with LV-to-blood pool SUV ratio (R2 = 0.92). Generation of high-quality parametric images showed superior myocardial to blood contrast compared to static images. CONCLUSIONS: A dynamic PET imaging technique for [18F]DHMT was developed with full and simplified kinetic modeling for absolute quantification of myocardial superoxide production in a large animal model.


Assuntos
Tomografia por Emissão de Pósitrons , Superóxidos , Animais , Cães , Estudos de Viabilidade , Humanos , Miocárdio , Tomografia por Emissão de Pósitrons/métodos , Espécies Reativas de Oxigênio
12.
Proc Natl Acad Sci U S A ; 116(19): 9658-9664, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31004061

RESUMO

Biodiversity loss is a major challenge. Over the past century, the average rate of vertebrate extinction has been about 100-fold higher than the estimated background rate and population declines continue to increase globally. Birth and death rates determine the pace of population increase or decline, thus driving the expansion or extinction of a species. Design of species conservation policies hence depends on demographic data (e.g., for extinction risk assessments or estimation of harvesting quotas). However, an overview of the accessible data, even for better known taxa, is lacking. Here, we present the Demographic Species Knowledge Index, which classifies the available information for 32,144 (97%) of extant described mammals, birds, reptiles, and amphibians. We show that only 1.3% of the tetrapod species have comprehensive information on birth and death rates. We found no demographic measures, not even crude ones such as maximum life span or typical litter/clutch size, for 65% of threatened tetrapods. More field studies are needed; however, some progress can be made by digitalizing existing knowledge, by imputing data from related species with similar life histories, and by using information from captive populations. We show that data from zoos and aquariums in the Species360 network can significantly improve knowledge for an almost eightfold gain. Assessing the landscape of limited demographic knowledge is essential to prioritize ways to fill data gaps. Such information is urgently needed to implement management strategies to conserve at-risk taxa and to discover new unifying concepts and evolutionary relationships across thousands of tetrapod species.


Assuntos
Biodiversidade , Evolução Biológica , Conservação dos Recursos Naturais , Extinção Biológica , Vertebrados/fisiologia , Animais
13.
Rev Infirm ; 71(285): 35-37, 2022 Nov.
Artigo em Francês | MEDLINE | ID: mdl-36599530

RESUMO

The objective of this qualitative study was to highlight the facilitating measures and difficulties encountered in continuing breastfeeding when returning to work at the Brest Regional University Hospital. The eleven mothers interviewed were able to take advantage of the solidarity in the care services to carry out their project, but simple institutional measures are still possible to facilitate this conciliation.


Assuntos
Aleitamento Materno , Retorno ao Trabalho , Feminino , Humanos , Mães , Hospitais Universitários , Pesquisa Qualitativa
14.
Neuroimage ; 238: 118248, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34119639

RESUMO

PURPOSE: 11C-UCB-J PET imaging, targeting synaptic vesicle glycoprotein 2A (SV2A), has been shown to be a useful indicator of synaptic density in Alzheimer's disease (AD). For SV2A imaging, a decrease in apparent tracer uptake is often due to the combination of gray-matter (GM) atrophy and SV2A decrease in the remaining tissue. Our aim is to reveal the true SV2A change by performing partial volume correction (PVC). METHODS: We performed two PVC algorithms, Müller-Gärtner (MG) and 'iterative Yang' (IY), on 17 AD participants and 11 cognitive normal (CN) participants using the brain-dedicated HRRT scanner. Distribution volume VT, the rate constant K1, binding potential BPND (centrum semiovale as reference region), and tissue volume were compared. RESULTS: In most regions, both PVC algorithms reduced the between-group differences. Alternatively, in hippocampus, IY increased the significance of between-group differences while MG reduced it (VT, BPND and K1 group differences: uncorrected: 20%, 27%, 17%; MG: 18%, 22%, 14%; IY: 22%, 28%, 17%). The group difference in hippocampal volume (10%) was substantially smaller than any PET measures. MG increased GM binding values to a greater extent than IY due to differences in algorithm assumptions. CONCLUSION: 11C-UCB-J binding is significantly reduced in AD hippocampus, but PVC is important to adjust for significant volume reduction. After correction, PET measures are substantially more sensitive to group differences than volumetric MRI measures. Assumptions of each PVC algorithm are important and should be carefully examined and validated. For 11C-UCB-J, the less stringent assumptions of IY support its use as a PVC algorithm over MG.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Tomografia por Emissão de Pósitrons/métodos , Circulação Cerebrovascular/fisiologia , Humanos , Compostos Radiofarmacêuticos
15.
EMBO Rep ; 20(2)2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30610016

RESUMO

RAB GTPases are central modulators of membrane trafficking. They are under the dynamic regulation of activating guanine exchange factors (GEFs) and inactivating GTPase-activating proteins (GAPs). Once activated, RABs recruit a large spectrum of effectors to control trafficking functions of eukaryotic cells. Multiple proteomic studies, using pull-down or yeast two-hybrid approaches, have identified a number of RAB interactors. However, due to the in vitro nature of these approaches and inherent limitations of each technique, a comprehensive definition of RAB interactors is still lacking. By comparing quantitative affinity purifications of GFP:RAB21 with APEX2-mediated proximity labeling of RAB4a, RAB5a, RAB7a, and RAB21, we find that APEX2 proximity labeling allows for the comprehensive identification of RAB regulators and interactors. Importantly, through biochemical and genetic approaches, we establish a novel link between RAB21 and the WASH and retromer complexes, with functional consequences on cargo sorting. Hence, APEX2-mediated proximity labeling of RAB neighboring proteins represents a new and efficient tool to define RAB functions.


Assuntos
Clatrina/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Endonucleases/metabolismo , Enzimas Multifuncionais/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Endossomos/metabolismo , Humanos , Espectrometria de Massas , Ligação Proteica , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Transporte Proteico , RNA Guia de Cinetoplastídeos
16.
J Vasc Interv Radiol ; 32(3): 360-368.e2, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33495064

RESUMO

PURPOSE: To assess the safety and clinical benefit of the Lutonix drug-coated balloon (DCB) catheter for the treatment of dysfunctional arteriovenous fistulae (AVF) and grafts (AVG) in a heterogenous real-world population. MATERIALS AND METHODS: This multicenter, prospective study enrolled 320 subjects from 12 countries in 25 sites across Europe and Asia. A total of 392 lesions were treated with the Lutonix 035 DCB catheter. Lesions were de novo and restenotic, located in every part of the circuit from the cannulation zone to central venous outflow. In-stent restenotic lesions also were treated. The primary safety endpoint was freedom from serious adverse events involving the access circuit through 30 days. The primary effectiveness endpoint was target lesion primary patency (TLPP) through 6 months. Secondary endpoints included access circuit primary patency (ACPP) at 6 months and the investigation of factors that would independently influence the primary endpoints. RESULTS: The primary safety endpoint was 95.5%, while TLPP was 73.9% at 6 months, per Kaplan-Meier survival analysis. ACPP was 71% at 6 months. TLPP for stenosis of AVFs was 78.1%. Subgroup analysis showed significantly improved TLPP when DCB was dilated for ≥120 seconds (P = .007). TLPP was significantly better when predilation occurred compared with cases where only DCB angioplasty was performed (77% vs 48.6%, P = .0005). CONCLUSIONS: The Lutonix AV Global Registry confirms that the Lutonix DCB is a safe and effective treatment option in real-world patients with dysfunctional AVF or AVG. Procedural details had a significant role in TLPP. No significant difference in TLPP was observed among different treatment areas.


Assuntos
Angioplastia com Balão/instrumentação , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Implante de Prótese Vascular/efeitos adversos , Fármacos Cardiovasculares/administração & dosagem , Materiais Revestidos Biocompatíveis , Oclusão de Enxerto Vascular/terapia , Paclitaxel/administração & dosagem , Diálise Renal , Dispositivos de Acesso Vascular , Idoso , Idoso de 80 Anos ou mais , Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/mortalidade , Derivação Arteriovenosa Cirúrgica/mortalidade , Ásia , Implante de Prótese Vascular/mortalidade , Europa (Continente) , Feminino , Oclusão de Enxerto Vascular/diagnóstico por imagem , Oclusão de Enxerto Vascular/mortalidade , Oclusão de Enxerto Vascular/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Sistema de Registros , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução Vascular
17.
Medicina (Kaunas) ; 57(4)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923830

RESUMO

This report addresses the extent to which there may be scope for preventive programmes for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and, if so, what economic benefits may accrue from the implementation of such programmes. We consider the economic case for prevention programmes, whether there is scope for preventive programmes for ME/CFS, and what are the health and economic benefits to be derived from the implementation of such programmes. We conclude that there is little scope for primary prevention programmes, given that ME/CFS is attributable to a combination of host and environmental risk factors, with host factors appearing to be most prominent, and that there are few identified modifiable risk factors that could be the focus of such programmes. The exception is in the use of agricultural chemicals, particularly organophosphates, where there is scope for intervention, and where Europe-wide programmes of health education to encourage safe use would be beneficial. There is a need for more research on risk factors for ME/CFS to establish a basis for the development of primary prevention programmes, particularly in respect of occupational risk factors. Secondary prevention offers the greatest scope for intervention, to minimise diagnostic delays associated with prolonged illness, increased severity, and increased costs.


Assuntos
Síndrome de Fadiga Crônica , Europa (Continente) , Humanos , Fatores Socioeconômicos
18.
Medicina (Kaunas) ; 57(3)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652747

RESUMO

Background and Objectives: We have conducted a survey of academic and clinical experts who are participants in the European ME/CFS Research Network (EUROMENE) to elicit perceptions of general practitioner (GP) knowledge and understanding of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and suggestions as to how this could be improved. Materials and Methods: A questionnaire was sent to all national representatives and members of the EUROMENE Core Group and Management Committee. Survey responses were collated and then summarized based on the numbers and percentages of respondents selecting each response option, while weighted average responses were calculated for questions with numerical value response options. Free text responses were analysed using thematic analysis. Results: Overall there were 23 responses to the survey from participants across 19 different European countries, with a 95% country-level response rate. Serious concerns were expressed about GPs' knowledge and understanding of ME/CFS, and, it was felt, about 60% of patients with ME/CFS went undiagnosed as a result. The vast majority of GPs were perceived to lack confidence in either diagnosing or managing the condition. Disbelief, and misleading illness attributions, were perceived to be widespread, and the unavailability of specialist centres to which GPs could refer patients and seek advice and support was frequently commented upon. There was widespread support for more training on ME/CFS at both undergraduate and postgraduate levels. Conclusion: The results of this survey are consistent with the existing scientific literature. ME/CFS experts report that lack of knowledge and understanding of ME/CFS among GPs is a major cause of missed and delayed diagnoses, which renders problematic attempts to determine the incidence and prevalence of the disease, and to measure its economic impact. It also contributes to the burden of disease through mismanagement in its early stages.


Assuntos
Síndrome de Fadiga Crônica , Médicos de Atenção Primária , Europa (Continente) , Síndrome de Fadiga Crônica/epidemiologia , Humanos , Percepção , Inquéritos e Questionários
19.
Rev Med Suisse ; 17(722): 150-154, 2021 Jan 20.
Artigo em Francês | MEDLINE | ID: mdl-33470573

RESUMO

This article summarizes the conclusion of a two-days interprofessional online workshop held under the auspices of the Brocher Foundation. The objectives were to review the impact of COVID on adolescent health and development and to generate some key responses to the situation. The pandemic has severely affected the mental health of a large proportion of adolescents and has significantly reduced access to health care. It has as well disturbed the school education of vulnerable youngsters and decreased social contacts with adults and peers. In the future, authorities should better consider the rights of young people and request their opinion and participation in decision making. Physicians should systematically explore their young patients' opinions and queries regarding the COVID and address problematic situations such as family conflicts, misuse of internet or risky behaviour.


Cet article résume le contenu d'un colloque participatif interprofessionnel en ligne de 2 jours visant à faire un état des lieux et à élaborer des réponses à la situation des adolescent·e·s à l'ère du Covid. La pandémie affecte leur santé en réduisant l'accès aux soins (confinement) et en induisant des problèmes psychologiques chez certains d'entre eux. Elle affecte la formation et la scolarité des plus démunis, réduit les contacts sociaux avec les adultes et les pairs. À l'avenir, les autorités devraient mieux respecter les droits des jeunes en sollicitant leur avis et leur participation et en adaptant leurs messages. Les médecins doivent, lors des consultations avec eux, offrir systématiquement un dialogue et des informations, et repérer des problématiques telles que conflits familiaux, abus d'internet ou prise de risque sanitaire.


Assuntos
COVID-19 , Médicos , Adolescente , Saúde do Adolescente , Humanos , Pandemias , SARS-CoV-2
20.
Rev Infirm ; 70(275): 33-34, 2021 Nov.
Artigo em Francês | MEDLINE | ID: mdl-34752358

RESUMO

In a university hospital in Brittany, health monitoring of the staff was set up at the beginning of the Covid-19 pandemic. The first results of the studies carried out in this context showed that nurses showed a greater deterioration of their physical health than other professionals. However, thanks to psychological balancing measures, nurses did not appear to be more affected in terms of psychological health and well-being at work than the other hospital workers.


Assuntos
COVID-19 , Enfermeiras e Enfermeiros , Pessoal de Saúde , Hospitais Universitários , Humanos , Pandemias/prevenção & controle , SARS-CoV-2
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