Angiogenesis is a tightly controlled dynamic process demanding a delicate equilibrium between pro-angiogenic signals and factors that promote vascular stability. The spatiotemporal activation of the ...transcriptional co-factors YAP (herein referring to YAP1) and TAZ (also known WWTR1), collectively denoted YAP/TAZ, is crucial to allow for efficient collective endothelial migration in angiogenesis. The focal adhesion protein deleted-in-liver-cancer-1 (DLC1) was recently described as a transcriptional downstream target of YAP/TAZ in endothelial cells. In this study, we uncover a negative feedback loop between DLC1 expression and YAP activity during collective migration and sprouting angiogenesis. In particular, our study demonstrates that signaling via the RhoGAP domain of DLC1 reduces nuclear localization of YAP and its transcriptional activity. Moreover, the RhoGAP activity of DLC1 is essential for YAP-mediated cellular processes, including the regulation of focal adhesion turnover, traction forces, and sprouting angiogenesis. We show that DLC1 restricts intracellular cytoskeletal tension by inhibiting Rho signaling at the basal adhesion plane, consequently reducing nuclear YAP localization. Collectively, these findings underscore the significance of DLC1 expression levels and its function in mitigating intracellular tension as a pivotal mechanotransductive feedback mechanism that finely tunes YAP activity throughout the process of sprouting angiogenesis.
The functional organization of human auditory cortex can be probed by characterizing responses to various classes of sound at different anatomical locations. Along with histological studies this ...approach has revealed a primary field in posteromedial Heschl's gyrus (HG) with pronounced induced high-frequency (70–150 Hz) activity and short-latency responses that phase-lock to rapid transient sounds. Low-frequency neural oscillations are also relevant to stimulus processing and information flow, however, their distribution within auditory cortex has not been established. Alpha activity (7–14 Hz) in particular has been associated with processes that may differentially engage earlier versus later levels of the cortical hierarchy, including functional inhibition and the communication of sensory predictions. These theories derive largely from the study of occipitoparietal sources readily detectable in scalp electroencephalography. To characterize the anatomical basis and functional significance of less accessible temporal-lobe alpha activity we analyzed responses to sentences in seven human adults (4 female) with epilepsy who had been implanted with electrodes in superior temporal cortex. In contrast to primary cortex in posteromedial HG, a non-primary field in anterolateral HG was characterized by high spontaneous alpha activity that was strongly suppressed during auditory stimulation. Alpha-power suppression decreased with distance from anterolateral HG throughout superior temporal cortex, and was more pronounced for clear compared to degraded speech. This suppression could not be accounted for solely by a change in the slope of the power spectrum. The differential manifestation and stimulus-sensitivity of alpha oscillations across auditory fields should be accounted for in theories of their generation and function.
SIGNIFICANCE STATEMENT
To understand how auditory cortex is organized in support of perception, we recorded from patients implanted with electrodes for clinical reasons. This allowed measurement of activity in brain regions at different levels of sensory processing. Oscillations in the alpha range (7–14 Hz) have been associated with functions including sensory prediction and inhibition of regions handling irrelevant information, but their distribution within auditory cortex is not known. A key finding was that these oscillations dominated in one particular non-primary field, anterolateral Heschl's gyrus, and were suppressed when subjects listened to sentences. These results build on our knowledge of the functional organization of auditory cortex and provide anatomical constraints on theories of the generation and function of alpha oscillations.
Recent developments have shown that coupling a Micromegas gaseous detector on a glass substrate with a transparent anode and a CMOS camera enables the optical readout of Micromegas detectors with a ...good spatial resolution, demonstrating that the glass Micromegas detector is well-suited for imaging. This feasibility test has been effectuated with low-energy X-ray photons also permitting energy resolved imaging. This test opens the way to different applications. Here we will focus on two applications. Namely, neutron imaging for non-destructive examination of highly gamma-ray emitting objects, such as irradiated nuclear fuel or radioactive waste. And secondly, we are developing a beta imager for the cell tagging in the field of anticancerous drug studies.
Both applications require to design the detectors in view of the specific constraints of reactor dismantling and medical applications: spatial resolution and strong gamma suppression for neutron imaging and precise rate and energy spectrum measurements for the beta.
A dedicated system consisting of a glass Micromegas detector and an ultrasensitive camera has been designed and assembled. Here we present the first results from the characterization of the detectors, as well as the first acquired images.
Background
Growing evidence indicates that amoxicillin induces herpesvirus replication in vitro. As these play a central pathophysiological role in Drug Reaction with Eosinophilia and Systemic ...Symptoms syndrome (DRESS), amoxicillin could present with specific DRESS features.
Objective
To characterize the onset patterns of amoxicillin‐associated DRESS.
Methods
All cases of DRESS (Kardaun score ≥4) involving amoxicillin and reported in the French Pharmacovigilance Database between January 1, 2004 and November 30, 2019 were included. Onset circumstances for these cases were categorized considering the onset delay from amoxicillin initiation, and the presence of concomitant medications with a compatible time to onset.
Results
A total of 146 probable cases or definite cases of DRESS were included. Three onset circumstances were identified: (i) ‘amoxicillin clear culprit’ where amoxicillin was the sole suspect drug or when concomitant drugs of compatible time to onset were not reported to cause DRESS (n = 62); (ii) ‘amoxicillin possible culprit’ in the presence of other potentially culprit drugs in addition to amoxicillin (n = 44) and (iii) ‘flare’ where amoxicillin, used after DRESS onset, induced flare‐up reactions (n = 40). The median time to onset was 5 days (IQR 2–11) in ‘clear culprit’, and 18 days (IQR 7–26) in ‘possible culprit’ cases. In ‘flare’ cases, the median latency between amoxicillin initiation and flare‐up reactions was 3 days (IQR 2–5).
Conclusions
Amoxicillin can induce DRESS with a specific early onset and exacerbate DRESS from another drug.
While competitive balance literature is robust when addressing professional sport from an economic perspective, little empirical work has focused on understanding what shapes interscholastic ...competitive balance policies. Using the theory of distributive justice as a framework, the purpose of this multiple case study was to examine the perceptions of top administrators regarding sociocultural influences on interscholastic competitive balance. Qualitative interview data collected from six state commissioners/executive directors revealed four predominant findings: (a) policy is driven by a philosophical approach that is aligned with the theory of distributive justice; (b) an overemphasis on winning strongly influences policy; (c) political influence through legal threats and state educational policy shapes committee decisions; and (d) the prevailing challenges of policy creation include school size, geography, public/nonpublic status, tradition, sport-specific characteristics, and lack of knowledge. Implications of these findings are discussed.
For many years 3H and 14C labelling of molecules of pharmaceutical interest has been performed to study their in vivo biodistribution on animal tissue sections through β-particles detection. Film ...autoradiography has progressively been replaced by digital β-imagers capable of high sensitivity, real-time imaging and activity counting for absolute quantification of radioactive compounds in tissue sections. After the discovery of the tumor heterogeneity phenomenon, research efforts for characterizing cell heterogeneity have been at the heart of oncology research, aiming at a better understanding of the causes and progression of the disease. This new perspective has also allowed for cell-targeting drugs, and radically changed both sample sizes and radiotracer activities. In this context, Medica-Plus, a transversal project gathering biologists, microfluidics specialists and detector developers, intends to perform quantification of low dose 3H- or 14C-labelled drugs inside single cells. This article reports preliminary results obtained with a prototype detector measuring tritium-generated signal.
Several successive arbovirus outbreaks have affected French Polynesia (FP) in the recent past years due to different dengue serotypes (DENV) present for several decades, Zika (ZIKV) (2013–2014) and ...chikungunya (CHIKV) (2014–2015) viruses with a potential impact on blood safety and blood supply due to the geographical isolation of these islands. This study reports an assessment of the impact of these outbreaks on blood products supply and infectious safety in FP and discuss the effectiveness of implemented preventive measures.
To ensure the infectious safety of blood products during outbreaks, several measures have successively been introduced as the selection of donors suspected of infection, the nucleic acid testing (NAT) and the pathogen reduction of platelets and plasmas.
The donor deferral rate increased by 6% between 2012 and 2014 without changes in the number of collected donations. NAT excluded five blood donations reactive for DENV RNA, 42 for ZIKV and 34 for CHIKV. As Zika screening could not been implemented before the third month of the outbreak, 36 blood products from ZIKV-infected donors were transfused to 26 recipients. However, no transfusion-transmitted arbovirus has been reported.
The last past arboviruses outbreaks did not have a significant impact on blood supply in FP. The measures introduced to prevent arbovirus transmission by transfusion were able to maintain infectious safety for all blood products without impairing self-sufficiency.
Plusieurs épidémies successives d’arbovirus ont affecté la Polynésie Française (PF) ces dernières années : les quatre sérotypes de dengue (DENV) présents depuis plusieurs décennies, les virus Zika (ZIKV) (2013–2014) et chikungunya (CHIKV) (2014–2015) avec un impact potentiel sur la sécurité transfusionnelle et l’approvisionnement en produits sanguins lié à l’isolement géographique de ces îles. Cette étude présente une évaluation de l’impact de ces épidémies sur l’approvisionnement et la sécurité infectieuse des produits sanguins en PF, et discute l’efficacité des mesures préventives adoptées.
Pour assurer la sécurité infectieuse des produits sanguins lors d’épidémies, plusieurs mesures ont été successivement introduites : la sélection des donneurs suspects d’infection, le dépistage génomique viral (DGV) et l’inactivation des pathogènes des plaquettes et du plasma.
Le taux d’exclusion des donneurs a augmenté de 6 % entre 2012 et 2014, sans diminution du nombre de dons recueillis. Le DGV a permis d’exclure cinq dons de sang réactifs pour l’ARN du DENV, 42 pour ZIKV et 34 pour CHIKV. 36 produits sanguins issus de donneurs infectés par le ZIKV ont été transfusés à 26 receveurs du fait d’un dépistage instauré au troisième mois de l’épidémie. Cependant, aucune transmission d’arbovirus par voie transfusionnelle n’a été constatée.
Les dernières épidémies d’arbovirus n’ont pas eu d’impact significatif sur l’approvisionnement en sang de la PF. Les mesures mises en place pour prévenir la transmission des arbovirus par transfusion ont permis de maintenir la sécurité infectieuse pour tous les produits sanguins sans affecter l’autosuffisance.
Describe the process for designing and creating SimUPAC 360°, a virtual reality training in anti-cancer drug production units.
A multi-centre (a University Hospital, a General Hospital and a Cancer ...Control Centre), inter-professional (pharmacists, hospital pharmacy technicians and health executives) working group has been set up. It was based on videoconferencing and online document sharing. The work was divided into six phases: choice of target audience and training objectives, definition of the business model, development of the scenario, shooting and editing, creation of the training tool and finally tests, adjustments and validation of the tool.
After brainstorming, 77 errors were proposed. Three areas have been defined: covering area, storage and production area, and isolator. They contained 15 errors among the 77 proposed and 20 points of interest. The shooting was carried out over 2 days, in 2 hospitals. Assembly was carried out by a service provider specialist in real virtuality. Before to go online, the tool was tested and validated by experts.
The establishment of a multi-centric and interdisciplinary working group, the choice of target audience, pedagogical objectives and business model ensure the economic viability and scientific and technical robustness of the tool. The scenario development requires to define: activity areas and then, number, difficulty and typology of errors.
Creation of a virtual reality training requires a consistent and structured methodology. This methodology will make it possible to develop other training scenarios.
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