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Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes. Scala et al. identify six de novo variants in RAC3, which encodes a small GTPase, in 10 unrelated subjects with neurodevelopmental phenotypes. In vivo and in vitro analyses in mice reveal that RAC3 variants cause morpho-functional defects in cortical neurons through variant-specific mechanisms, disrupting corticogenesis.

A network of scientists involved in shipment of live insects has met and generated a series of articles on issues related to live insect transport. The network is diverse, covering large-scale commercial interests, government operated areawide control programmes, biomedical research and many smaller applications, in research, education and private uses. Many insect species have a record of safe transport, pose minimal risks and are shipped frequently between countries. The routine shipments of the most frequently used insect model organism for biomedical research, Drosophila melanogaster, is an example. Successful large-scale shipments from commercial biocontrol and pollinator suppliers also demonstrate precedents for low-risk shipment categories, delivered in large volumes to high quality standards. Decision makers need access to more information (publications or official papers) that details actual risks from the insects themselves or their possible contaminants, and should propose proportionate levels of management. There may be harm to source environments when insects are collected directly from the wild, and there may be harm https://doi.org/10.20506/rst.41.1.3319 Scientific and Technical Review 41 (1) 2022 220 to receiving environments. Several risk frameworks include insects and various international coordinating bodies, with experience of guidance on relevant risks, exist. All stakeholders would benefit from an integrated overview of guidance for insect shipping, with reference to types of risk and categories of magnitude, without trying for a single approach requiring universal agreement. Proposals for managing uncertainty and lack of data for smaller or infrequent shipments, for example, must not disrupt trade in large volumes of live insects, which are already supporting strategic objectives in several sectors.

Introducción: La estenosis carotídea es responsable de un 20% de todos los ictus isquémicos. Teniendo en cuenta que la aterosclerosis es una enfermedad inflamatoria crónica, es posible que determinados marcadores de inflamación permitan predecir el riesgo de recurrencia de ictus, y otras complicaciones vasculares en pacientes con estenosis carotídea grave (>70%) sometidos a endarterectomía carotídea. El objetivo principal del presente estudio fue determinar si los niveles circulantes de metaloproteasas (MMPs) de matriz extracelular (MMP-1, MMP-2, MMP-7, MMP-9 y MMP-10), el inhibidor tisular de MMPs (TIMP-1) y la cuantificación de la inflamación in vivo de la placa carotídea estudiada de forma no invasiva mediante 18F-FDG-PET / CT son útiles para diferenciar entre pacientes con estenosis carótidea sintomáticas y asintomáticas, o en la predicción de eventos vasculares recurrentes en pacientes con estenosis carotídea sometidos a endarterectomía. Pacientes y métodos: Estudio de cohorte prospectivo, longitudinal multicéntrico. Se reclutaron pacientes atendidos en la Unidad de Ictus del Hospital de Navarra y la Clínica Universidad de Navarra con edades comprendidas entre 50-80 años con diagnóstico de infarto cerebral (con déficit menor) o AIT de origen aterotrombótico por estenosis carotídea grave, y pacientes con estenosis carotídea grave asintomática, que fueron sometidos a endarterectomía carotídea. Se obtuvieron muestras de plasma y suero 2 días antes de la cirugía y se analizaron los niveles de MMP-1, MMP-2, MMP-7, MMP9, MMP-10, TIMP-1, HDL, LDL, proteína C reactiva y velocidad de sedimentación globular. Se realizó un estudio 18F-FDG-PET / CT para cuantificar el metabolismo de la pared vascular de ambas carótidas y otros territorios vasculares, como reflejo de la presencia de inflamación intraplaca. Se realizaron estudios histológicos e inmunohistoquímicos con anticuerpos dirigidos frente a MMP-10, MMP-9, TIMP-1 y CD68 en la placa carotídea extraída quirúrgicamente mediante endarterectomía. Asimismo, se incluyeron en el estudio 26 controles sanos, trabajadores de la Universidad de Navarra, comparables en edad y sexo a la población de pacientes. Resultados: Se incluyeron 31 pacientes consecutivos con estenosis carotídea sintomática (n=23) o asintomática (n=8) grave a los que se les realizó endarterectomía carotídea entre julio de 2013 y marzo de 2016. Los pacientes con estenosis carotídea presentaron niveles circulantes de MMP-1, MMP-7 y MMP-10 significativamente más elevados que los controles sanos. No se encontró ninguna correlación entre las MMPs circulantes y el grado de inflamación en la placa carotídea in vivo evaluado mediante 18F-FDG-PET / CT. El TIMP-1 intraplaca se correlacionó moderadamente con su nivel plasmático (r = 0,42 p = 0,02) y con la captación de 18F-FDG-PET / CT (r = 0,38 p = 0,05). Después de una mediana de seguimiento de 1077 días, se registraron 4 eventos cerebrovasculares, 7 eventos cardiovasculares y 11 eventos vasculares periféricos que requirieron hospitalización. El nivel de MMP-7 circulante fue capaz de predecir eventos más allá de los factores de riesgo tradicionales (HR = 1,15 p = 0,006). Cuando el modelo de regresión se asoció con las variables de interés, la capacidad de la 18F-FDG-PET / CT para predecir eventos vasculares no fue significativa. Conclusiones: Los hallazgos del presente estudio no apoyan el uso de 18FFDG-PET / CT o los niveles de metaloproteasas o sus inhibidores para diferenciar estenosis carotídeas sintomáticas o asintomáticas y tampoco para establecer el riesgo de recurrencia de ictus. Nuestros hallazgos proporcionan evidencia de que la MMP-7 circulante podría representar un biomarcador de eventos cardiovasculares recurrentes en pacientes con estenosis carotídea grave.

Few-shot sound event detection is the task of detecting sound events, despite having only a few labelled examples of the class of interest. This framework is particularly useful in bioacoustics, where often there is a need to annotate very long recordings but the expert annotator time is limited. This paper presents an overview of the second edition of the few-shot bioacoustic sound event detection task included in the DCASE 2022 challenge. A detailed description of the task objectives, dataset, and baselines is presented, together with the main results obtained and characteristics of the submitted systems. This task received submissions from 15 different teams from which 13 scored higher than the baselines. The highest F-score was of 60% on the evaluation set, which leads to a huge improvement over last year's edition. Highly-performing methods made use of prototypical networks, transductive learning, and addressed the variable length of events from all target classes. Furthermore, by analysing results on each of the subsets we can identify the main difficulties that the systems face, and conclude that few-show bioacoustic sound event detection remains an open challenge., Comment: submitted to DCASE2022 workshop

The excavations undertaken at the Campo de Hockey site in 2008 led to the identification of a major Neolithic necropolis in the former Island of San Fernando (Bay of Cádiz). This work presents the results of the latest studies, which indicate that the site stands as one of the oldest megalithic necropolises in the Iberian Peninsula. The main aim of this work is to present with precision the chronology of this necropolis through a Bayesian statistical model that confirms that the necropolis was in use from c. 4300 to 3800 cal BC. The presence of prestige grave goods in the earliest and most monumental graves suggest that the Megalithism phenomenon emerged in relation to maritime routes linked to the distribution of exotic products. We also aim to examine funerary practices in these early megalithic communities, and especially their way of life and the social reproduction system. As such, in addition to the chronological information and the Bayesian statistics, we provide the results of a comprehensive interdisciplinary study, including anthropological, archaeometric and genetic data., State Research Agency (SRA), European Commission HAR2017-87324-P 2014-2020 ERDF Operational Programme, Department of Economy, Knowledge, Business and University of the Regional Government of Andalusia FEDER-UCA18-106917 CEIMAR CEIJ-015, European Social Fund (ESF) D1113102E3, Junta de Andalucia

Background and PurposeA NO-mediated desensitization of vasoconstrictor responses evoked by stimulation of (1)-adrenoceptors has been reported in different vessels. We investigated the involvement of each (1)-adrenoceptor subtype and constitutive NOS isoforms and the influence of ageing and hypertension on this process. Experimental ApproachWistar and spontaneously hypertensive rats (SHR), 16, 32, 52 and 72weeks-old, were used to evaluate the desensitization process. Expression of (1)-adrenoceptor subtypes, endothelial NOS (eNOS) and neuronal NOS (nNOS) were determined in rat aorta and left ventricle (LV). Expression levels were also evaluated in LV of a group of heart failure patients with a wide age range. Key ResultsRepeated application of phenylephrine decreased subsequent (1)-adrenoceptor-mediated vasoconstriction by increasing nNOS protein expression in aorta, but not in tail or mesenteric resistance arteries, where mRNA levels of nNOS were undetectable. This desensitization process disappeared in the absence of endothelium or in the presence of L-NAME (100M), nNOS inhibitors, SMTC (1M) and TRIM (100M), and 5-methylurapidil (100nM, (1A)-antagonist), but not BMY7378 (10nM, (1D)-antagonist). The (1A)/nNOS-mediated desensitization was absent in aged SHR and Wistar animals, where the expression of (1A)-adrenoceptors was reduced in aorta and LV. In human LV, a negative correlation was found between age and (1A)-adrenoceptor expression. Conclusions and ImplicationsThe (1A)-adrenoceptor subtype, through endothelial nNOS-derived NO, may act as a physiological brake' against the detrimental effects of excessive (1)-adrenoceptor-mediated vasoconstriction. Reduced (1A)-adrenoceptor- and nNOS-mediated desensitization in aged patients could be involved in the age-dependent elevation of adrenergic activity.

Background:Difficult intubation (DI) in obstetrics is more common than in other settings. Therefore it is important to dispose of methods that facilitate ventilation and tracheal intubation (TI) to avoid life-threatening complications in both mother and child.Case report:The patient was a 30-year-old, 62 kg, woman at 40-weeks gestation presented for emergency CS due to severe fetal bradycardia. Preoperative airway assessment included a Mallampati grade 2 and a thyromental distance > 6.5cm. After rapid-sequence induction (RSI), direct laryngoscopy revealed an unexpected Cormack Lehane grade 4 view. The TT was inserted immediately maintaining the cricoid pressure. After obtained a 100% POGO score view TT cuff was inflated and the patient's lungs were easily ventilated with 13 cm H2O positive pressure. Intubation through the channel guide was easily accomplished. The procedure was carried out uneventfully and a healthy male infant was delivered.Discussion:DI is a leading cause of anesthetic-related maternal death. The ''gold standard'' airway management in obstetrics is an RSI with standard direct laryngoscopy to insert a styletted ETT accompanied by cricoid pressure, but this approach is not without its pitfalls. When traditional laryngoscopy is unsuccessful, the next attempt could be the use of a video laryngoscope. However, it may fail, prolonging the period of apnea. After a failed second attempt at TI, the use of a supraglottic device must be considered. However, they offer the lungs no protection from regurgitated gastric contents. The TT is a supraglottic airway and an anatomically-shaped bladed video laryngoscope (VL). TT combines the advantages of VL with several additional benefits:1. The gastric tube provides functional separation of the respiratory and gastrointestinal tracts and allows aspirate stomach content. The seal created protects the airway from aspiration until TI is accomplished;2. Optimal ventilation can be maintained throughout the process of TI, promoting the shortest apneic time;3. The conduit guides the transglottic passage of the ETT, under vision leading to a high first-attempt intubation rate;4. The blade prevents the epiglottis from down-folding.