RCAAP Repository

Diffuse alveolar haemorrhage related to an anti-neutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis is an extremely rare form of presentation of breast cancer. Here we report the case of a 77-year-old woman with a histological diagnosis of a papillary ductal carcinoma of the breast presenting with a diffuse alveolar haemorrhage secondary to a perinuclear ANCA-associated vasculitis. To our knowledge, this is the first case ever reported of a diffuse alveolar haemorrhage related to an ANCA-associated small vessel vasculitis as a form of presentation of breast cancer. The therapeutic approach of this paraneoplastic vasculitis included the use of corticosteroids and plasmapheresis, a very useful technique to remove endothelial aggressors (circulating antibodies) as a strategy to earn time for a proper therapeutic decision specifically directed for disease modification, but that can also be associated with several severe adverse effects, which are illustrated in our case.

Non-infectious uveitis (NIU) is a group of sight-threatening diseases that generates significant burden for the healthcare systems due to its adverse outcomes, irreversible structural complications in the eye with loss of visual function, limited clinical expertise and low-grade evidence for best practice. The usefulness of multidisciplinary care, specifically close collaboration between Rheumatologists and Ophthalmologists in NIU, has been emphasized in the literature. In this paper, the assessment tools and protocols used in our clinic are depicted and an overview of our activity with a brief description of the patients included in our registry, between 2018 and 2020 is provided. The cohort of 290 patients assessed in our NIU clinic, their demographics, sources of referral, details about immunosuppression treatment, and internal and external collaborations is described. This experience-based manuscript aims to describe the general functioning of our multidisciplinary NIU clinic, highlighting the benefits and drawbacks of multidisciplinary team management in patients with NIU, ultimately initiating a dialogue on what an NIU clinic should be and providing information for newly NIU clinics start-up. In conclusion, establishing a standardized and multidisciplinary clinic in NIU allows to systematically observe and follow-up this infrequent disease at a tertiary hospital level, thus improving quality of care delivery and research avenues.

Mutations in the MPV17 gene are associated with hepatocerebral form of mitochondrial depletion syndrome. The mechanisms through which MPV17 mutations cause respiratory chain dysfunction and mtDNA depletion is still unclear. The MPV17 gene encodes an inner membrane mitochondrial protein that was recently described to function as a non-selective channel. Although its exact function is unknown, it is thought to be important in the maintenance of mitochondrial membrane potential (ΔΨm). To obtain more information about the role of MPV17 in human disease, we investigated the effect of MPV17 knockdown and of selected known MPV17 mutations associated with MPV17 disease in vitro. We used different approaches in order to evaluate the cellular consequences of MPV17 deficiency. We found that lower levels of MPV17 were associated with impaired mitochondrial respiration and with a quiescent energetic metabolic profile. All the mutations studied destabilized the protein, resulting in reduced protein levels. We also demonstrated that different mutations caused different cellular abnormalities, including increased ROS production, decreased oxygen consumption, loss of ΔΨm, and mislocalization of MPV17 protein. Our study provides novel insight into the molecular effects of MPV17 mutations and opens novel possibilities for testing therapeutic strategies for a devastating group of disorders.

Introduction: Structural brain imaging is paramount for the diagnosis of behavioural variant of frontotemporal dementia (bvFTD), but it has low sensitivity leading to erroneous or late diagnosis. Methods: A total of 515 subjects from two different bvFTD cohorts (training and independent validation cohorts) were used to perform voxel-wise morphometric analysis to identify regions with significant differences between bvFTD and controls. A random forest classifier was used to individually predict bvFTD from deformation-based morphometry differences in isolation and together with semantic fluency. Tenfold cross validation was used to assess the performance of the classifier within the training cohort. A second held-out cohort of genetically confirmed bvFTD cases was used for additional validation. Results: Average 10-fold cross-validation accuracy was 89% (82% sensitivity, 93% specificity) using only MRI and 94% (89% sensitivity, 98% specificity) with the addition of semantic fluency. In the separate validation cohort of definite bvFTD, accuracy was 88% (81% sensitivity, 92% specificity) with MRI and 91% (79% sensitivity, 96% specificity) with added semantic fluency scores. Conclusion: Our results show that structural MRI and semantic fluency can accurately predict bvFTD at the individual subject level within a completely independent validation cohort coming from a different and independent database.

A região mediterrânica é reconhecida pela sua riqueza e diversidade biológica, sendo um hotspot de biodiversidade (Myers e tal., 2000; Blondel e tal., 2010). As paisagens na bacia do Mediterrâneo estão actualmente sujeitas a um conjunto de dinâmicas de alterações causadas pelas actividades humana, em que se destacam a intensificação agrícola e florestal e o abandono agrícola (Proença e Pereira, 2010). Estas alterações de paisagem causam alterações aos habitats e afectam as espécies que os habitam (Blondel, 2006; Sirami e tal., 2010; Gonzáles-Megías e tal., 2011). Assim, é fundamental perceber quais as respostas das diferentes espécies a estas alterações de habitat e qual a sua capacidade de adaptação, e como essas respostas se traduzem a diferentes escalas espaciais. A relação entre o número de espécies que habita uma área e a dimensão dessa área é dos padrões mais estudados em ecologia, sendo designada como a relação espécies-área (Arrhenius, 1921). A relação espécies-área tem sido largamente verificada para vários sistemas naturais, no entanto, num contexto de alteração da paisagem e dos habitats nativos, a relação espécies-área apresenta limitações ao assumir que todo o habitat é uniforme e contínuo. Uma vez que as espécies reagem diferentemente às alterações de habitat (Tews e tal., 2004), é necessário integrar o efeito da área com o efeito de habitat. Aliás, vários estudos têm-se debruçado sobre o efeito que a diversidade de habitats tem sobre a diversidade de espécies (Williamson, 1988; Tjorve, 2002; Desrochers et al. 2011) O modelo da relação espécies-área “countryside, proposto por Pereira e Daily (2006), considera não só a existência de diferentes habitats na paisagem mas também o uso diferencial dos mesmos pelos diferentes grupos de espécies. Neste contexto, o presente trabalho, tentou responder às seguintes questões: (I) Será a heterogeneidade de habitats um proxy para a diversidade de espécies? (II) É o efeito da área e o efeito da diversidade de habitats na riqueza de espécies, dependente da escala ou dependente nas características de cada grupo de espécies? Para responder a estas questões, utilizou-se a Península Ibérica como caso de estudo e analisaram-se os padrões de diversidade de passeriformes, répteis e anfíbios à escala da grelha de 10x10 Km2, testando a influência de três classes de variáveis ambientais: uso do solo, variáveis climáticas e topográficas. No caso dos passeriformes, analisou-se diversidade de cada grupo de espécies com afinidades similares para os diferentes habitats, tendo-se para isso procedido à classificação das espécies em cada um destes grupos previamente. Para responder à questão (I) realizámos uma série de análises. A relação entre os diferentes grupos de espécies e os vários preditores ambientais foi avaliada utilizando análises de correlação (Spearman´s rho). A importância relativa dos diferentes grupos de preditores (climáticos, topográficos e de habitat) na distribuição da riqueza específica foi avaliada com uma abordagem multi-modelo, onde em cada modelo de regressão linear foram considerados várias combinações de preditores (Tabela 2). A relação entre riqueza específica e a estrutura da paisagem (heterogeneidade) para Espanha, foi avaliada através de correlação de Spearman´s e análise visual de boxplots. Para responder à segunda questão (II) comparámos o desempenho do modelo espécies-área clássico (eqn 1) com o modelo countryside-SAR (eqn 2 e 3) à escala regional. O desempenho dos modelos foi comparado usando o Akaike Information Criterion (AIC) e o Root Mean Squared Error (RMSE). Todas as análises foram efectuadas no programa R (http://www.r-project.org/). Os mapas da riqueza específica construídos para a Península Ibérica mostram que a distribuição das espécies não é homogénea, e que depende do taxon (Figura 3). Cada taxon respondeu diferentemente às variáveis ambientais testadas (Tabela 3). Todos os grupos de espécies, excepto o grupo de passeriformes com afinidade para habitats agrícolas, reagiram negativamente à presença de áreas agrícolas. Todos os grupos de espécies de passeriformes mostraram uma relação negativa com a presença de floresta exótica. Estes resultados estão em acordo com outros trabalhos que mostraram que muitas espécies tendem a evitar áreas de cultivo intensivo e plantações (Diáz e tal., 1998; Donald e tal., 2001; Benton e tal, 2003). O clima revelou-se o factor principal na determinação da diversidade das espécies. No entanto, quando as variáveis de habitat são adicionadas aos modelos de regressão com variáveis climáticas, o poder explicativo dos padrões de diversidade melhora significativamente (Tabela 4). Encontrámos também uma relação entre a heterogeneidade da paisagem e a diversidade para vários grupos taxonómicos. A dominância das variáveis climáticas não surpreende dado que a esta escala regional (10x10km2) os modelos de distribuição de espécies têm usado com sucesso apenas variáveis climáticas (Wisz e Guisan 2009), mas diverge de padrões encontrados à escala local, em que a estrutura dos habitats parece ser o factor mais relevante (Atauri e Lucio, 2001; Nogués e Martínez 2004; Moreno e Pizarro, 2007). A variedade de respostas à heterogeneidade da paisagem, pelos diferentes grupos (Tabela 5, Figura 4), indica que as espécies (i.e., os grupos de espécies), usam a paisagem de diferente modo. A diversidade de espécies num habitat está ligada com a sua capacidade de fornecer as estruturas necessárias para a sua sobrevivência, zonas de predação, refugio, reprodução, etc. (Keitt e tal, 1997; Mazerolle e Villard, 1999; Atuari e Lucio, 2001; Gil-Tena e tal., 2007; Desroches e tal 2011). A comparação do modelo clássico espécies-área com o modelo countryside demonstra que, numa paisagem multi-habitat à escala regional, o modelo countryside é o que melhor explica a riqueza específica de cada um dos grupos de espécies e do total número de espécies (Tabela 6). Para investigar o efeito da escala, os resultados foram comparados com os obtidos a escala local em estudos com plantas e aves, por Proença (2009) e Guilherme (2009), respectivamente. Em ambos os trabalhos constatou-se que o modelo countryside explicava melhor os padrões espécies-área à escala da paisagem. À semelhança do encontrado à escala regional, o parâmetro de afinidade para o habitat preferencial apresentou o valor máximo em cada grupo de espécies. No entanto, enquanto na escala local os grupos de espécies apresentaram valores de afinidade significativos para os habitats alternativos, à escala regional apenas as espécies florestais mostraram afinidades baixas para os habitats alternativos.

This study aims to investigate if education (as a cognitive reserve proxy) modifies the profile of cognitive performance. We hypothesize that participants with higher education can remain functional (due to a better executive performance), despite a more severe memory impairment, compared with lower education individuals. One hundred and sixty-six mild cognitive impairment (MCI) individuals with at least one comprehensive neuropsychological evaluation were included in a retrospective, cross-sectional study and divided into two groups (Low Education-LE [1-4 years] and Medium-to-High Education-MHE [> 4 years]). A total of 22 neuropsychological measures were analyzed. Age-adjusted results were subject to simple regression analyses to determine the variance explained by education. Average scores and proportions of low performances were subject to group comparison. The results showed similar cognitive decline patterns between individuals with LE and MHE, with no significant difference in each cognitive domain. However, MHE revealed a steeper decline in certain cognitive domains, such as sustained attention and episodic memory, compared with the LE. Moreover, MHE showed a trend to higher proportion of tests affected when compared to LE. These suggest that individuals with higher education may remain in a MCI stage despite a more widespread cognitive impairment, reflecting a higher cognitive reserve.

Purpose: Rapid and effective diagnosis of Legionnaires' disease (LD) cases is extremely important so that timely and appropriate therapy can be provided, thereby lowering the morbidity and mortality rates and reducing the health and economic costs associated with this disease. Methodology: Diagnosis is established solely by microbiological tests. There are several methods available, each with different performance, sensitivity and specificity characteristics, and further understanding is required. Our objective was to assess the accuracy of urinary antigen detection, direct fluorescent antibody (DFA) staining, serological testing and the polymerase chain reaction (PCR) method versus culture analysis (the reference standard) in patients suspected of being infected with Legionella or patients with laboratory-confirmed LD. We performed a MEDLINE search in November 2014. Two authors independently assessed the trials and extracted data. Pooled analysis was performed through Meta-DiSc version 1.4. Result: The inclusion criteria were met by 11 studies. All the studies evaluated PCR and DFA tests to detect Legionella in clinical specimens, comparing them to culture techniques, and were included in the meta-analysis. The pooled sensitivity and specificity for PCR were 83 % [95 % confidence interval (CI): 79-87 %] and 90 % (95 % CI: 88-92 %), respectively. DFA was evaluated in one study and the sensitivity and specificity of this test were 67 % (95 % CI: 30-93 %) and 100 % (95 % CI: 91-100 %), respectively. PCR had high sensitivity and specificity for early diagnosis of LD. Conclusion: Culture analysis is deemed necessary for epidemiological studies, molecular strain typing and antibiotic sensibility evaluations; however, the performance of PCR in recent studies calls for additional, well-designed studies in order to achieve the best standard test, which will enable optimization of the Legionella infection diagnostic.

Aims of the study: To compare the assessment of respiratory decline with conventional tests, measurement of diaphragm compound muscle action potential (CMAP) to phrenic nerve stimulation and diaphragm thickness to ultrasound (US) investigation in amyotrophic lateral sclerosis (ALS) patients followed for a short period of time. Patients and methods: We evaluated in 40 consecutive ALS patients, the clinical functional scale (ALSFRS-R), forced vital capacity (FVC), maximal voluntary ventilation (MVV), maximal inspiratory (MIP) and expiratory (MEP) pressures, sniff nasal inspiratory pressure (SNIP), Diaphragm-CMAP (latency and amplitude) and diaphragm US (maximal and minimal diaphragm thickness during full inspiration and expiration, respectively). Patients were evaluated at study entry and 4 months later. Results: Clinical functional assessment (ALSFRS-R), MEP, SNIP, and Diaphragm-CMAP amplitude declined significantly. Conversely, FVC, MVV, MIP, and diaphragm thickness showed a non-significant decline. We found significant correlations between all variables measured at both evaluation times. Conclusion: In this study, we included patients who might be potentially eligible for a clinical trial and re-evaluated them within 4 months. In this short time, diaphragm thickness as assessed by US is not sensitive to detect changes. However, Diaphragm-CMAP amplitude was confirmed to be a sensitive non-volitional method to measure respiratory function in ALS.

Estudo preliminar sobre o impacto da Ciência Aber-ta em todo o ciclo científico, desde o início da inves-tigação até à sua publicação, procurando conhecer, descrever e explicar as perceções de um conjunto de investigadores face ao ecossistema da Ciência Aberta. Foi usada uma metodologia qualitativa, através da realização de uma entrevista semiestru-turada. Os resultados identificam as dúvidas dos investigadores relativamente ao cumprimento das premissas da Ciência Aberta. A sistematização das suas ideias permite questionar se estes estarão preparados para estas novas experiências no cam-po da ciência e se possuirão as competências para garantir a sua autonomia na identificação de onde publicar, como publicar, como gerir os dados de investigação, como divulgar os resultados da inves-tigação, como e porque escolher canais formais e informais da ciência, como usar as tecnologias em benefício da sua visibilidade e, finalmente, como assegurar a perenidade da sua produção científica. Também a nova linguagem usada na Ciência Aber-ta suscita muitas dificuldades junto dos investigado-res. Criar programas de capacitação destinados aos investigadores é uma meta estratégica nos proces-sos de implementação deste paradigma de ciência.

No summary/description provided

As bibliotecas do ensino superior têm sido objeto de investigação nos mais diversos domínios, quer pelo seu papel determinante na construção do espaço das aprendizagens ao nível terciário, quer no estudo e desenvolvimento de políticas ou práticas que são transversais ao roteiro universitário ou politécnico. A análise da sua intervenção é pois de incontornável importância, especialmente para profissionais – que iniciam a sua carreira, ou peritos de reconhecida experiência - quer para outros interessados no tema das bibliotecas universitárias, sendo útil igualmente a decisores, professores e estudantes que se interessam pela área da informação e biblioteconomia em geral. Reconhecendo esse papel fundamental das bibliotecas universitárias, a presente obra procura colmatar uma lacuna nesta área, abrangendo múltiplas perspetivas, que procuram estabelecer pontes entre Portugal e o Brasil, através dos contributos dos diferentes autores. Partindo de uma perspetiva histórica, é feita uma reflexão sobre o papel e o valor das bibliotecas universitárias também na atualidade, nas suas diversas vertentes. Focando-se no contexto da gestão do conhecimento e relacionando as tecnologias, a Ciência Aberta e a investigação, bem como as questões da qualidade e impacto, são aprofundados os principais temas que estruturam as atividades desenvolvidas nestas organizações, incluindo perspetivas de futuro. O livro procura assim dar um contributo para o conhecimento destas matérias tão importantes para a vida académica e para a sociedade em geral, com influências determinantes no bem-estar, desenvolvimento da cidadania e aprendizagem ao longo da vida.

A ideia de mudança perpassa as bibliotecas universitárias o que impele os bibliotecários das instituições do ensino superior a repensar o seu papel e atuação em permanência. Por um lado, a construção de Recomendações para as bibliotecas do ensino superior, procura trazer estabilidade e segurança, criando orientações a serem aplicadas na prática. Por outro, as mudanças no ensino superior, nas tecnologias e recursos eletrónicos, e nas práticas de gestão, podem ser percebidas como elementos desestabilizadores, potenciando inseguranças nas ações desenvolvidas. É apresentado o documento orientador Recomendações para as Bibliotecas do Ensino Superior de Portugal 2020-2022, descrevendo-se o trabalho que esteve na sua origem, bem como a receção por parte dos bibliotecários de ensino superior em Portugal e as suas perspetivas de futuro face à aplicação destas mesmas recomendações. O presente estudo procura refletir sobre a dupla condição das bibliotecas do Ensino Superior na sua procura de equilíbrio entre a estabilidade e a inovação, numa constante adaptação. Conclui-se que a preparação e o planeamento assentes em linhas orientadoras funcionam como estabilizadores, que ancoram as ações desenvolvidas, enquanto que os ventos de mudança permitem a exploração de novos caminhos e práticas, potenciando-se assim um contexto virtuoso de atuação.

Multiple system atrophy (MSA) is characterized clinically by parkinsonism, cerebellar, autonomic, and corticospinal features of variable severity. When the presentation is only parkinsonism, the disease might be difficult to differentiate from Parkinson's disease (PD). We present a case of an 80-year-old man with previous diagnosis of PD. One year after the diagnosis, he had a whiplash cervical trauma due to a tricycle accident caused by a hole in the road. This low-energy trauma caused an unstable C4-C5 cervical fracture with spinal cord injury, which required surgical decompression and stabilization. Neurological examination showed marked postural instability, no rest and postural tremor, finger tapping slowed on the right, spastic tetraparesis (ASIA D) - predominantly on the left side, brisk deep tendon reflexes in the upper and lower extremities, and bilateral extensor plantar response. He also presented with vertical gaze restriction, mild hypometria in horizontal saccades, moderate dysphagia, and dysphonia. As atypical parkinsonism was suspected, he underwent an MRI that revealed conjunction of findings suggestive of parkinsonian-type MSA. In our case, we hypothesize that the loss of postural reflexes, as an early manifestation of MSA, did not allow the patient to have an effective reaction response to a low-energy trauma, resulting in a more severe injury. With this case report, we speculate that the severe spinal lesions caused by minor accidents can be an early sign of postural instability, which may lead to clinical suspicion of neurodegenerative disorder manifested by postural reflexes impairment.

The neurotrophin brain-derived neurotrophic factor (BDNF) mediates activity-dependent long-term changes of synaptic strength in the CNS. The effects of BDNF are partly mediated by stimulation of local translation, with consequent alterations in the synaptic proteome. The ubiquitin-proteasome system (UPS) also plays an important role in protein homeostasis at the synapse by regulating synaptic activity. However, whether BDNF acts on the UPS to mediate the effects on long-term synaptic potentiation (LTP) has not been investigated. In the present study, we show similar and nonadditive effects of BDNF and proteasome inhibition on the early phase of synaptic potentiation (E-LTP) induced by theta-burst stimulation of rat hippocampal CA1 synapses. The effects of BDNF were blocked by the proteasome activator IU1, suggesting that the neurotrophin acts by decreasing proteasome activity. Accordingly, BDNF downregulated the proteasome activity in cultured hippocampal neurons and in hippocampal synaptoneurosomes. Furthermore, BDNF increased the activity of the deubiquitinating enzyme UchL1 in synaptoneurosomes and upregulated free ubiquitin. In contrast to the effects on posttetanic potentiation, proteasome activity was required for BDNF-mediated LTP. These results show a novel role for BDNF in UPS regulation at the synapse, which is likely to act together with the increased translation activity in the regulation of the synaptic proteome during E-LTP.

Parkinson's Disease (PD) is a complex and multifactorial disorder of both idiopathic and genetic origin. Thus far, more than 20 genes have been linked to familial forms of PD. Two of these genes encode for ATP13A2 and alpha-synuclein (asyn), proteins that seem to be members of a common network in both physiological and disease conditions. Thus, two different hypotheses have emerged supporting a role of ATP13A2 and asyn in metal homeostasis or in autophagy. Interestingly, an appealing theory might combine these two cellular pathways. Here we review the novel findings in the interaction between these two proteins and debate the exciting roads still ahead.

Located at the confluence of the Sorraia and Tagus rivers, the Ponta da Erva area receives annually a large number of Barn Owl juveniles during the post-fledging dispersal period. The landscape is composed by pastures and agricultural fields separated by a large system of drainage ditches and fences, providing a suitable foraging habitat for this species. The recent conversion of a large number of fields into rice paddies - a rising tendency - may represent a significant degradation of this habitat. Based on a previous work (Tomé 1994), this study aimed to evaluate the effect of the land use changes through analysis of temporal and spatial variation of the species abundance over the period of post-fledging dispersal. Nocturnal car transects were carried out on a weekly basis, between July, 17, 2009 and February, 11 2010, during the first three and half hours after sunset, along a 22.5 kilometers route covering most of the area. Barn Owl abundance varied during the study period, with a maximum of 2.3 birds/km in August, coinciding with the arrival of juveniles to Ponta da Erva, and a minimum value of 0.178 birds/km in February, in the beginning of the breeding period. Habitat use was studied by performing three binary logistic regression models for summer, autumn and winter, comparing the presences with random locations where owls were absent. Results were similar to those obtained by Tomé (1994), concerning the use of the several biotopes over time, the importance of cereal stubbles, and the negative influence of grazing. In regard to rice paddies, the importance of this biotope increased considerably after harvest, during the autumn. In addition, Barn Owl diet was studied through pellet analysis. The results did not differ markedly from those observed previously by Tomé (1994), highlighting a very significant increase in the consumption of Pelophylax perezi and significant reduction of Crocidura russula.

Distance learning gained publicity and exposure with the pandemic context, attracting more students and the interest of research, consolidating its position of relevance, namely in higher education. This study seeks to reflect on the use of the conceptual map as an active learning strategy, with a view to greater student involvement in a distance university. From the context of a curricular unit with different strategies, which includes, in addition to the traditional reading of documents, the inclusion of videos and or activities in which each student participates in a committed way, it was proposed to use concept maps as powerful tools to engage students. This strategy was aligned with peer feedback. The testimonies left by the students who participated in this case study prove what the literature has said: that the active learning approach based on concept maps positively achieves the objectives and results that aim at successful learning and that the feedback from peers reinforces student self-regulation, enabling insights that improve their learning as a whole.

Brain-derived neurotrophic factor (BDNF) and its high-affinity full-length (FL) receptor, TrkB-FL, play a central role in the nervous system by providing trophic support to neurons and regulating synaptic plasticity and memory. TrkB and BDNF signaling are impaired in Alzheimer's disease (AD), a neurodegenerative disease involving accumulation of amyloid-β (Aβ) peptide. We recently showed that Aβ leads to a decrease of TrkB-FL receptor and to an increase of truncated TrkB receptors by an unknown mechanism. In the present study, we found that (1) Aβ selectively increases mRNA levels for the truncated TrkB isoforms without affecting TrkB-FL mRNA levels, (2) Aβ induces a calpain-mediated cleavage on TrkB-FL receptors, downstream of Shc-binding site, originating a new truncated TrkB receptor (TrkB-T') and an intracellular fragment (TrkB-ICD), which is also detected in postmortem human brain samples, (3) Aβ impairs BDNF function in a calpain-dependent way, as assessed by the inability of BDNF to modulate neurotransmitter (GABA and glutamate) release from hippocampal nerve terminals, and long-term potentiation in hippocampal slices. It is concluded that Aβ-induced calpain activation leads to TrkB cleavage and impairment of BDNF neuromodulatory actions.

Malaria imposes a horrific public health burden - hundreds of millions of infections and millions of deaths - on large parts of the world. While this unacceptable health burden and its economic and social impact have made it a focal point of the international development agenda, it became consensual that malaria control or elimination will be difficult to attain prior to gain a better understanding of the complex interactions occurring between its main players: Plasmodium, the causative agent of disease, and its hosts. Practical and ethical limitations exist regarding the ability to carry out research with human subjects or with human samples. In this review, we highlight how rodent models of infection have contributed significantly during the past decades to a better understanding of the basic biology of the parasite, host response and pathogenesis.

Bone Marrow Tyrosine kinase in the chromosome X (BMX) is a TEC family kinase associated with numerous pathological pathways in cancer cells. Covalent inhibition of BMX activity holds promise as a therapeutic approach against cancer. To screen for potent and selective covalent BMX inhibitors, large quantities of highly pure BMX are normally required which is challenging with the currently available production and purification processes. Here, we developed a scalable production process for the human recombinant BMX (hrBMX) using the insect cell-baculovirus expression vector system. Comparable expression levels were obtained in small-scale shake flasks (13 mL) and in stirred-tank bioreactors (STB, 5 L). A two-step chromatographic-based process was implemented, reducing purification times by 75% when compared to traditional processes, while maintaining hrBMX stability. The final production yield was 24 mg of purified hrBMX per litter of cell culture, with a purity of > 99%. Product quality was assessed and confirmed through a series of biochemical and biophysical assays, including circular dichroism and dynamic light scattering. Overall, the platform herein developed was capable of generating 100 mg purified hrBMX from 5 L STB in just 34 days, thus having the potential to assist in-vitro covalent ligand high-throughput screening for BMX activity inhibition.