A stochastic model of hippocampal synaptic plasticity with geometrical readout of enzyme dynamics.

Discovering the rules of synaptic plasticity is an important step for understanding brain learning. Existing plasticity models are either (1) top-down and interpretable, but not flexible enough to account for experimental data, or (2) bottom-up and biologically realistic, but too intricate to interpret and hard to fit to data. To avoid the shortcomings of these approaches, we present a new plasticity rule based on a geometrical readout mechanism that flexibly maps synaptic enzyme dynamics to predict plasticity outcomes. We apply this readout to a multi-timescale model of hippocampal synaptic plasticity induction that includes electrical dynamics, calcium, CaMKII and calcineurin, and accurate representation of intrinsic noise sources. Using a single set of model parameters, we demonstrate the robustness of this plasticity rule by reproducing nine published ex vivo experiments covering various spike-timing and frequency-dependent plasticity induction protocols, animal ages, and experimental conditions. Our model also predicts that in vivo-like spike timing irregularity strongly shapes plasticity outcome. This geometrical readout modelling approach can be readily applied to other excitatory or inhibitory synapses to discover their synaptic plasticity rules.

Novel CaLB-like Lipase Found Using ProspectBIO, a Software for Genome-Based Bioprospection.

Enzymes have been highly demanded in diverse applications such as in the food, pharmaceutical, and industrial fuel sectors. Thus, in silico bioprospecting emerges as an efficient strategy for discovering new enzyme candidates. A new program called ProspectBIO was developed for this purpose as it can find non-annotated sequences by searching for homologs of a model enzyme directly in genomes. Here we describe the ProspectBIO software methodology and the experimental validation by prospecting for novel lipases by sequence homology to Candida antarctica lipase B (CaLB) and conserved motifs. As expected, we observed that the new bioprospecting software could find more sequences (1672) than a conventional similarity-based search in a protein database (733). Additionally, the absence of patent protection was introduced as a criterion resulting in the final selection of a putative lipase-encoding gene from Ustilago hordei (UhL). Expression of UhL in Pichia pastoris resulted in the production of an enzyme with activity towards a tributyrin substrate. The recombinant enzyme activity levels were 4-fold improved when lowering the temperature and increasing methanol concentrations during the induction phase in shake-flask cultures. Protein sequence alignment and structural modeling showed that the recombinant enzyme has high similarity and capability of adjustment to the structure of CaLB. However, amino acid substitutions identified in the active pocket entrance may be responsible for the differences in the substrate specificities of the two enzymes. Thus, the ProspectBIO software allowed the finding of a new promising lipase for biotechnological application without the need for laborious and expensive conventional bioprospecting experimental steps.

Análise do tempo de retirada do respirador artificial no paciente submetido a traqueostomia precoce e após sete dias de ventilação mecânica invasiva / Análisis del tiempo de retiro del ventilador mecánico en pacientes sometidos a traqueotomía temprana y después de siete días de ventilación mecánica invasiva / Analysis of removal time of artificial ventilator in patients submitted to early tracheostomy, after seven days of invasive mechanical ventilation

RESUMO A realização da traqueostomia precoce pode reduzir o tempo de ventilação do paciente, facilitando o desmame da prótese ventilatória. Além disso, reduz os custos de internação. Este estudo tem como objetivo analisar o tempo de retirada do respirador no paciente traquestomizado precocemente após sete dias de ventilação. Trata-se de pesquisa documental, retrospectiva, de carácter descritivo, sendo a coleta de dados realizada nos documentos de indicadores hospitalares de unidade de terapia intensiva de um hospital da Zona da Mata mineira. Foram coletados dados de 50 pacientes que obtiveram sucesso e preencheram os critérios de desmame da ventilação mecânica, entre homens e mulheres, com média de idade de 56,6 anos. Para análise estatística, os pacientes foram divididos em dois grupos: grupo precoce, de pacientes que realizaram traqueostomia com menos de sete dias de intubação orotraqueal; e grupo tardio, de pacientes que permaneceram por mais de sete dias com tubo orotraqueal até a realização da traqueostomia. Obtivemos um resultado significativo (p=0,04) quanto aos dias em ventilação mecânica após a realização de traqueostomia, demonstrando que nos pacientes com traqueostomia precoce houve menos dias em ventilação mecânica invasiva do que nos pacientes com traqueostomia tardia. Foi constatado um resultado significativamente menor do tempo de ventilação dos pacientes traquestomizados precocemente quando comparados com a traqueostomia tardia. Ensaios clínicos randomizados de alta qualidade são necessários para avaliar melhor as possíveis diferenças da retirada da ventilação mecânica entre pacientes traqueostomizados.

RESUMEN La realización de traqueotomía temprana puede reducir el tiempo de ventilación del paciente, facilitando la desconexión del soporte ventilatorio. Además, reduce los costes de hospitalización. Este estudio tiene como objetivo analizar el tiempo de retiro del ventilador en los pacientes traqueostomizados tempranamente después de siete días de soporte ventilatorio. Se trata de una investigación documental, retrospectiva, descriptiva, que recopiló los datos de documentos hospitalarios de la unidad de cuidados intensivos de un hospital en Zona da Mata en Minas Gerais (Brasil). Se recogieron datos de 50 pacientes, entre hombres y mujeres con promedio de edad de 56,6 años, que tuvieron éxito y cumplieron los criterios para la desconexión del ventilador mecánico. Para el análisis estadístico, se dividieron a los pacientes en dos grupos: Grupo temprano, pacientes que se sometieron a traqueotomía con menos de siete días de intubación orotraqueal; y Grupo tardío, pacientes que permanecieron más de siete días con un tubo orotraqueal hasta la realización de la traqueotomía. Hubo un resultado significativo (p=0,04) con respecto a los días de ventilación mecánica tras la realización de traqueotomía, lo que demuestra que los pacientes con traqueotomía temprana pasaron menos días con ventilador mecánico invasivo que los pacientes con traqueotomía tardía. Se encontró un resultado significativamente menor del tiempo de ventilación de los pacientes con traqueostomía temprana en comparación a los pacientes con traqueotomía tardía. Se necesitan ensayos clínicos aleatorios de alta calidad para evaluar mejor las posibles diferencias en el retiro del ventilador mecánico entre los pacientes traqueostomizados.

ABSTRACT Early tracheostomy can reduce patient ventilation time, facilitating the weaning process and reducing hospitalization costs. This study analyzes the removal time of ventilators in patients submitted to early tracheostomy, after seven days of ventilation. This is a documentary, retrospective, and descriptive research. Data were collected from documents with hospital indicators of an intensive care unit in the Zona da Mata region in Minas Gerais. Data consisted of 50 patients who were successful in the weaning of mechanical ventilation and met the study criteria. They were both men and women, with a mean age of 56.6 years. For statistical analysis, the patients were divided into two groups: an early group - patients who underwent tracheostomy with less than seven days of orotracheal intubation; and a late group - patients who remained for more than seven days with orotracheal tube before tracheostomy. We obtained a significant result (p=0.04) regarding the days on mechanical ventilation after tracheostomy, demonstrating that patients with early tracheostomy remained fewer days on invasive mechanical ventilation than patients with late tracheostomy. A significantly lower result of ventilation time was observed in patients submitted to early compared with late tracheostomy. High-quality randomized clinical trials are needed to better evaluate the possible differences in mechanical ventilation withdrawal among tracheostomized patients.

Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A.

Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked periventricular nodular heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, with some reports suggesting that this might represents a separate syndrome allelic to XL-PH, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH). Here, we report a cohort of 11 males and females with both hypomorphic and null mutations in FLNA that manifest a wide spectrum of connective tissue and vascular anomalies. The spectrum of cutaneous defects was broader than previously described and is inconsistent with a specific type of EDS. We also extend the range of vascular anomalies associated with XL-PH to included peripheral arterial dilatation and atresia. Based on these observations, we suggest that there is little molecular or clinical justification for considering EDS-PH as a separate entity from XL-PH, but instead propose that there is a spectrum of vascular and connective tissues anomalies associated with this condition for which all individuals with loss-of-function mutations in FLNA should be evaluated. In addition, since some patients with XL-PH can present primarily with a joint hypermobility syndrome, we propose that screening for cardiovascular manifestations should be offered to those patients when there are associated seizures or an X-linked pattern of inheritance.

Risco ocupacional para trabalhadores expostos ao temefós no programa de controle do vetor da dengue no Distrito Federal / Occupational risk for wor kers exposed to temephos on Distrito Federal Dengue`s Vector Control Program

Objetivo. Conhecer os aspectos epidemiológicos, clínicos e laboratoriais da exposição ocupacional ao agrotóxico organofosforado temefós. Método. Trata-se de estudo descritivo, retrospectivo, transverso, cujos dados foram colhidos dos registros de trabalhadores do Programa de Controle do Vetor da Dengue no Distrito Federal com suspeita de intoxicação pelo organofosforado temefós. O diagnóstico de intoxicação foi feito pela dosagem sérica de acetilcolinesterase e por meio das manifestações clínicas. Usou-se o teste de Fisher para análise estatística. O valor p < 0,05 foi considerado significante. Resultados. A média de idade dos 108 trabalhadores avaliados com intoxicação pelo temefós foi 42 anos, e 61,1% foram masculinos. Cinquenta e dois (48,1%) encontraram-se afastados do serviço por um a dois anos. A maioria das exposições (86,1%) foi pelas vias cutânea e respiratória. Sintomas e sinais de intoxicação estiveram presentes em29,6% dos trabalhadores, e 45% deles tiveram alterações no sistema nervoso central, como cefaleia, tontura, amnésia. A adesão ao uso completo ou incompleto de equipamentos de proteção individual foi significativamente maior entre homens (56,1%) do que entre mulheres (14,3%). Conclusão. O uso de temefós para controle do vetor da dengue associa-se a intoxicação dos trabalhadores envolvidos no serviço. É possível que a baixa utilização de equipamentos de proteção possa contribuir para isso.

Objective. To know the epidemiologic, clinic and laboratorial aspects of occupational exposure to the organophosphorus insecticide temephos. Method. This is a descriptive, retrospective and cross-sectional study. Data were obtained from outpatient service records of the Distrito Federal dengue's vector control program with suspect of organophosphate temephos poison. Poison diagnosis by temephos was made using acetilcolinesterase activity in the hematias and clinical manifestations. The Fisher test was used for statistical analysis. P less than 0.05 was considered significant. Results. The age average of workers was 42 years-old, being 61.1% men, 48.1% were licensed, with prevailing of 1 or 2 years of occupational license. The majority of expositions were through skin and aerial way. Only 29.6% of workers presented some kind of symptoms and signs. Central nervous system changes were prevalent on 45%, as cephalalgia, dizzyness, amnesia. The individual protection equipment used in adhesion was bigger between men (56.1%) than between women (14.3%). Conclusion. The use of temephos to control the dengue vector is associated with the poisoning of workers involved in the service. It is possible that the low use of protective equipment can contribute to it.