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The global market of butanol is increasing due to its growing applications as solvent, flavoring agent and chemical precursor of several other compounds. Recently, the superior properties of n-butanol as a biofuel over ethanol have stimulated even more interest. (Bio)butanol is natively produced together with ethanol and acetone by Clostridium species through Acetone-Butanol-Ethanol fermentation, at non-competitive, low titers compared to petrochemical production. Different butanol production pathways have been expressed in Escherichia coli, a more accessible host compared to Clostridium species, to improve butanol titers and rates.. The bioproduction of butanol is here reviewed from a historical and theoretical perspective. All tested rational metabolic engineering strategies in E. coli to increase butanol titers are reviewed: manipulation of central carbon metabolism; elimination of competing pathways; cofactor balancing; development of new pathways; expression of homologous enzymes; consumption of different substrates and molecular biology strategies. The progress in the field of metabolic modeling and pathway generation algorithms and their potential application to butanol production are also summarized here. The main goals are to gather all the strategies, evaluate the respective progress obtained, identify and exploit the outstanding challenges. This article is protected by copyright. All rights reserved., Ministério da Ciência, Tecnologia e Ensino Superior, Grant/Award Number: ERA‐IB‐2/0002/2014; Fundação para a Ciência e a Tecnologia, Grant/Award Numbers: ERA‐IB‐2/0002/2014, LISBOA¬01¬0145¬FEDER¬007660, PD/BD/52366/2013; European Commission, Grant/Award Number: H2020‐LEIT‐BIO‐2015‐1 686070–1, info:eu-repo/semantics/publishedVersion

The cerebrovascular effects of a failing heart-pump are largely unknown. Chronic heart failure (HF) might cause pre-conditioning effect on cerebral hemodynamics but not study so far in acute stroke. We aimed to investigate if HF induces effects in dynamic cerebral autoregulation (CA), within 6 h of symptom-onset through chronic stage of ischemic stroke. We enrolled 50 patients with acute ischemic stroke. Groups with (N = 8) and without HF and 20 heathy controls were compared. Arterial blood pressure (Finometer) and cerebral blood flow velocity (transcranial Doppler) were monitored within 6 and at 24 h from symptom-onset and at 3 months. We assessed dynamic CA by transfer function analysis and cardiac disease markers. HF associated with higher phase (better dynamic CA) at ischemic hemisphere within 6 (p = 0.042) and at 24 h (p = 0.006) but this effect was not evident at 3 months (p > 0.05). Gain and coherence trends were similar between groups. We found a positive correlation between phase and admission troponin I levels (Spearman’s r = 0.348, p = 0.044). Our findings advances on the knowledge of how brain and heart interact in acute ischemic stroke by showing a sustained dynamic cerebral autoregulation response in HF patients mainly with severe aortic valve disease. Understanding the physiological mechanisms that govern this complex interplay can be useful to find novel therapeutic targets which can improve outcome in ischemic stroke.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion regulation strategy which modifies how one thinks about a situation. Participants from 87 countries/regions (N = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vs. both control conditions) had consistent effects in reducing negative emotions and increasing positive emotions across different measures. Reconstrual and repurposing had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world to build resilience during the pandemic and beyond.

© 2020 Springer Nature Switzerland AG. Part of Springer Nature., Long-term lead (Pb) exposure alters the normal development of the nervous system and physiology. It affects multiple organ systems, causing hypertension, cardiorespiratory dysfunction, being a well-known neurotoxin, inducing changes in neurogenesis, neurodegeneration, and glial cells. However, studies of the developmental effects of lead and its outcomes throughout life are lacking. Determine morphofunctional, behavioral, and cognitive developmental effects of long-term lead exposure at three different ages. Wistar rats were exposed to a Pb-acetate solution from fetal period until adulthood and compared to a non-exposed control group. General behavior and cognitive skills were evaluated by behavioral tests and physiological data and cardiorespiratory reflexes measured. Neurodegeneration, neuroinflammation, and synaptic activity were assessed by immunohistochemistry. Lead exposure caused long-lasting anxiety-like behavior and strong long-term memory impairment without changes in locomotor and exploratory activity. Hypertension was observed at all time points, concomitant with baroreflex impairment and increased chemoreflex sensitivity. Persistent neuroinflammation, transient synaptic overexcitation without neurodegeneration was observed. Long-term Pb exposure, since fetal period, causes long-lasting anxiety-like behavior, concomitant with hypertension, without general motor skills impairment. Synaptic overexcitation, reactive astrogliosis, and microgliosis could underlie behavioral and long-term memory changes, which might have been caused during developmental phases and consolidated during adulthood. Also, alterations observed in the cardiorespiratory reflexes can explain persistent hypertension. This longitudinal study identifies and characterizes lead toxicity nature and magnitude, important to devise and test potential interventions to attenuate the long-term harmful effects of lead on the nervous and cardiovascular systems., Vera Geraldes received the post-doctoral fellowship given by the Fundação para a Ciência e Tecnologia (FCT) (Ref: SFRH/BPD/119315/2016).

O processo de fabricacao de alimentos produz grande quantidade de residuos orgânicos. Uma industria de extracao de aromas, por exemplo, pode gerar, anualmente, 104 e 92 toneladas de residuo de erva-mate e guarana, respectivamente. Uma alternativa para o reaproveitamento desse material lignocelulosico seria utilizalos na producao de biocompositos com micelio fungico atuando como ligante das particulas do substrato. Sendo assim, objetivou-se nesse trabalho a producao de biocompositos a partir de Pleurotus sajor-caju utilizando os residuos de erva-mate e guarana na proporcao (1:1) (m/m), verificando a influencia da fracao de inoculo 10, 20 e 30% e da temperatura de secagem de 40 e 60°C. Para cada condicao testada foi avaliado o tempo de crescimento micelial, o teor de umidade inicial, a velocidade inicial de secagem, a resistencia a compressao, absorcao de umidade do ar e absorcao de agua. A condicao determinada foi a de 10% de inoculo e secagem a 60°C, pois apresentou maior resistencia a compressao (0,094 MPa), menor absorcao de agua (91%), maior velocidade de secagem (27,7 g/dia). Os biocompositos utilizam o crescimento biologico e nao processos de fabricacao com intenso desperdicio de energia, ainda exigem apenas residuos orgânicos de baixo custo como materia-prima, podendo preencher geometrias complexas apresentando potencial para a confeccao de embalagens, pois sao materiais seguros que apresentaram boa resistencia a compressao e baixa absorcao de umidade do ar e de agua. Palavras-chave: Pleurotus sajor-caju, residuos industriais, cultivo solido, biocompositos.

An amendment to this paper has been published and can be accessed via a link at the top of the paper., (undefined), info:eu-repo/semantics/publishedVersion

The Western hemisphere has witnessed recent immigration flows that hit European Union (EU), one leading destination for immigration. This immigration flows generated social and political debate across Europe. In one view migration flows represent an opportunity to construct a diverse social cohesion based on the respect for ethnic groups. Portuguese Government supports this view, being in line with the European Commission’s position. In another view, migration flows are perceived as a threat to existent national cultures. This view is held by political nationalisms and right-wing populism forces installed in the majority of EU countries’ parliaments, leading to the support of exclusive policies and citizens’ contestation of immigrants’ entrance. Nevertheless, this view accentuates untrusting social interactions sustained in discrimination against immigrants that already live in Europe, and thus, to unhealthy social cohesion. We theorize that European identity predicts positive attitudes towards immigrants (prosocial behavior and support for inclusive policies), whereas National identity’s predictions of attitudes towards immigrants’ inclusion depends on participants’ political tendency. Moreover, we test the mediation effect of positive (humanitarian concerns and economic benefit) and negative (jobs scarcity, cultural deterioration and invasion) arguments used in political discourses regarding immigrants’ inclusion on the relation between National and European identities and attitudes towards immigrants’ inclusion. Results (Portuguese sample, N = 176) show that national identity predicts negative attitudes towards immigrants’ inclusion, but only among right-wing individuals. This group is more susceptible to arguments focused on immigrants’ invasion and cultural deterioration, arguments that imply discrimination (devaluation) of immigrants. Contrarily, among those with left-wing political orientation, national identity predicts less contestation to immigrant’s inclusion sustained by humanitarian concerns. Interestingly, European identification weakened right-wing individuals’ adherence to discriminatory arguments and, simultaneously, increased the perceived positive economic contribution that immigrants bring to the host society, thus, increasing agreement with immigrants’ inclusion and prosocial behavior regarding them. We discuss these results by suggesting that the strength of European Identity sustained in humanitarian values among EU citizens may stimulate the construction of multicultural social cohesion, intergroup trust and social wellbeing based on democratic values, social justice and equality, and on the respect for human dignity.

Following the success of and the high demand for recombinant protein-based therapeutics during the last 25 years, the pharmaceutical industry has invested significantly in the development of novel treatments based on biologics. Mammalian cells are the major production systems for these complex biopharmaceuticals, with Chinese hamster ovary (CHO) cell lines as the most important players. Over the years, various engineering strategies and modeling approaches have been used to improve microbial production platforms, such as bacteria and yeasts, as well as to create pre-optimized chassis host strains. However, the complexity of mammalian cells curtailed the optimization of these host cells by metabolic engineering. Most of the improvements of titer and productivity were achieved by media optimization and large-scale screening of producer clones. The advances made in recent years now open the door to again consider the potential application of systems biology approaches and metabolic engineering also to CHO. The availability of a reference genome sequence, genome-scale metabolic models and the growing number of various “omics” datasets can help overcome the complexity of CHO cells and support design strategies to boost their production performance. Modular design approaches applied to engineer industrially relevant cell lines have evolved to reduce the time and effort needed for the generation of new producer cells and to allow the achievement of desired product titers and quality. Nevertheless, important steps to enable the design of a chassis platform similar to those in use in the microbial world are still missing. In this review, we highlight the importance of mammalian cellular platforms for the production of biopharmaceuticals and compare them to microbial platforms, with an emphasis on describing novel approaches and discussing still open questions that need to be resolved to reach the objective of designing enhanced modular chassis CHO cell lines., This work has been supported the Federal Ministry for Digital and Economic Affairs (bmwd), the Federal Ministry for Transport, Innovation and Technology (bmvit), the Styrian Business Promotion Agency SFG, the Standortagentur Tirol, Government of Lower Austria and ZIT - Technology Agency of the City of Vienna through the COMET-Funding Program managed by the Austrian Research Promotion Agency FFG. A.H. has been supported by the Portuguese NORTE-08-5369-FSE-000053 operation. Additional funding came from the PhD program BioToP (Biomolecular Technology of Proteins) of the Austrian Science Fund (FWF Project W1224) and MIT-Portugal PhD program (Bioengineering Systems). The funding agencies had no influence on the conduct of this research. Open Access Funding by the University of Vienna., info:eu-repo/semantics/publishedVersion

[EN] This work presents a set of laboratory experiments that can be carried out by students who are taking digital design courses in engineering programs like Electronics, Communications Systems and Mechatronics. The purpose of these labs is to help students develop their skills and confidence designing arithmetic hardware blocks through solving of specific problems. In this aspect, this paper shows a method to be followed in the laboratory to design arithmetic blocks and implement them in microcontrollers and FPGAs. More specifically, the block design of a number's multiplicative inverse (1/root x), its square root (root x) and the square root of its inverse (1/root x) are presented. To complete these exercises, knowledges on Newton-Raphson algorithm, difference equations and digital design are required. Students of our institution completed the lab practices, and after analyzing the results from student surveys and classroom observations, we found out that completing these tasks significantly contributed to the students' training in the hardware design field., Este trabajo fue financiado por el Consejo Nacional de Ciencia y Tecnología (CONACYT) de México, mediante el proyecto de Ciencia Básica número 241272

Background Actinobacillus succinogenes is a promising bacterial catalyst for the bioproduction of succinic acid from low-cost raw materials. In this work, a genome-scale metabolic model was reconstructed and used to assess the metabolic capabilities of this microorganism under producing conditions. Results The model, iBP722, was reconstructed based on the functional reannotation of the complete genome sequence of A. succinogenes 130Z and manual inspection of metabolic pathways, covering 1072 enzymatic reactions associated with 722 metabolic genes that involve 713 metabolites. The highly curated model was effective in capturing the growth of A. succinogenes on various carbon sources, as well as the SA production under various growth conditions with fair agreement between experimental and predicted data. Calculated flux distributions under different conditions show that a number of metabolic pathways are affected by the activity of some metabolic enzymes at key nodes in metabolism, including the transport mechanism of carbon sources and the ability to fix carbon dioxide. Conclusions The established genome-scale metabolic model can be used for model-driven strain design and medium alteration to improve succinic acid yields., Financially supported by BRIGIT (KBBE-2012-6-311935, FP7 project Contract nr 311935) and by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684), in addition to the BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte., info:eu-repo/semantics/publishedVersion

We would like to thank the European Union Framework Program 7 ‘BacHBerry’ (www.bachberry.eu), Project No. FP7- 613793 for financial support, the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit, COMPETE 2020 (POCI-01- 0145-FEDER-006684) and BioTecNorte operation (NORTE-01-0145- FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte.

The lipid nanoparticles, namely Nanostructured Lipid Carriers (NLC), as drug delivery systems have been investigated for several years. One of the delivery routes for which these carriers can be applied is buccal administration. However, the liquid dispersions of lipid nanoparticles can be rapidly removed from oral cavity by saliva. Thus, the development of a system that allows increased retention time on the mucosa is necessary. For this reason, the development of mucoadhesive preparations for buccal administration of lipid nanoparticles becomes important. Hydrogels prepared with mucoadhesive polymers (Carbopol® 980 and polycarbophil) constitute a promising option. The aim of this work was to develop mucoadhesive buccal hydrogels with NLC, using ibuprofen as a model drug. The obtained results showed that the developed NLC dispersions presented particles in the nanometric size range, with low polydispersity index values and efficient ability for the entrapment of the model drug. Moreover, the incorporation of NLC in hydrogels of mucoadhesive polymers resulted in preparations with desirable rheological features as well as texture (firmness and adhesiveness) and mucoadhesive properties, which could benefit the therapeutic efficacy, by increasing the residence time and easiness for topical application in the buccal mucosa. Additionally, the developed preparations exhibited sustained drug release as intended for these systems.

© 2017 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L.U. All rights reserved, Knowledge of the physiology underlying the autonomic nervous system is pivotal for understanding autonomic dysfunction in clinical practice. Autonomic dysfunction may result from primary modifications of the autonomic nervous system or be secondary to a wide range of diseases that cause severe morbidity and mortality. Together with a detailed history and physical examination, laboratory assessment of autonomic function is essential for the analysis of various clinical conditions and the establishment of effective, personalized and precise therapeutic schemes. This review summarizes the main aspects of autonomic medicine that constitute the background of cardiovascular autonomic dysfunction., O conhecimento subjacente à fisiologia do sistema nervoso autónomo é fundamental para se entender a disfunção autonómica na prática clinica. A disfunção autonómica pode resultar primariamente de modificações do sistema ou, secundariamente, a uma série de patologias conducentes a morbilidade ou mortalidade. Juntamente com a colheita detalhada da história clínica e do exame objetivo, a avaliac¸ão autonómica laboratorial torna-se essencial na análise de algumas condições clínicas e no estabelecimento de esquemas terapêuticos mais eficazes, refinados e personalizados. Assim, nesta revisão sumarizam-se os aspetos mais relevantes da fisiologia autonómica subjacente a disfunção autonómica cardiovascular.

The fragile states agenda has recently converged with the so-called culture of measuring for results, creating standards often seen by critics as donor driven. The newly established Sustainable Development Goals now invite a data revolution that can see yet more intense practices of quantification. Nevertheless, this article argues such practices can be widening windows of opportunity for change. It looks at the g7+ group of self-labeled fragile states and its tools for self-measurement. These tools closely resemble mainstream quantification, but also bring key contributions. In fact, direct opposition on the part of fragile states is perhaps as possible as it once was for the so-called Third World; on the other hand, the article suggests subtle power can perhaps be countered by subtle change.

Cigarette smoke is associated to pathological weakening of bone tissue, being considered an important playmaker in conditions such as osteoporosis and periodontal bone loss. In addition, it is also associated with an increased risk of failure in bone regeneration strategies. The present work aimed to characterize the effects of nicotine on human osteoclastogenesis over a hydroxyapatite substrate. Osteoclast precursors were maintained in the absence or presence of the osteoclastogenesis enhancers M-CSF and RANKL, and were further treated with nicotine levels representative of the concentrations observed in the plasma and saliva of smokers. It was observed that nicotine at low concentrations elicit an increase in osteoclast differentiation, but only in the presence of M-CSF and RANKL it was also able to significantly increase the resorbing ability of osteoclasts. A slight downregulation of NFkB pathway and an increase in the production of TNF-α and, particularly PGE2, were involved in the observed effects of nicotine. At high concentrations, nicotine revealed cytotoxic effects, causing a decrease in cell density. In conclusion, nicotine at levels found in the plasma of the smokers, has the ability to act directly on osteoclast precursors, inducing its osteoclastogenic differentiation. The stimulatory behavior appears to be dependent on the stage of osteoclastic differentiation of the precursor cells, which means, in the absence of M-CSF and RANKL, it only favors the initial stages of osteoclast differentiation, while in the presence of the growth factors, a significant increase in their resorbing ability is also achieved.

Background Hemorrhagic transformation and cerebral edema are feared complications of acute ischemic stroke but mechanisms are poorly understood and reliable early markers are lacking. Early assessment of cerebrovascular hemodynamics may advance our knowledge in both areas. We examined the relationship between dynamic cerebral autoregulation (CA) in the early hours post ischemia, and the risk of developing hemorrhagic transformation and cerebral edema at 24 h post stroke Methods We prospectively enrolled 46 patients from our center with acute ischemic stroke in the middle cerebral artery territory. Cerebrovascular resistance index was calculated. Dynamic CA was assessed by transfer function analysis (coherence, phase and gain) of the spontaneous blood flow velocity and blood pressure oscillations. Infarct volume, hemorrhagic transformation, cerebral edema, and white matter changes were collected from computed tomography performed at presentation and 24 h. Results At admission, phase was lower (worse CA) in patients with hemorrhagic transformation [6.6 ± 30 versus 45 ± 38°; adjusted odds ratio 0.95 (95% confidence internal 0.94–0.98), p = 0.023] and with cerebral edema [6.6 ± 30 versus 45 ± 38°, adjusted odds ratio 0.96 (0.92–0.999), p = 0.044]. Progression to edema was associated with lower cerebrovascular resistance (1.4 ± 0.2 versus 2.3 ± 1.5 mm Hg/cm/s, p = 0.033) and increased cerebral blood flow velocity (51 ± 25 versus 42 ± 17 cm/s, p = 0.033) at presentation. All hemodynamic differences resolved at 3 months Conclusions Less effective CA in the early hour post ischemic stroke is associated with increased risk of hemorrhagic transformation and cerebral edema, possibly reflecting breakthrough hyperperfusion and microvascular injury. Early assessment of dynamic CA could be useful in identifying individuals at risk for these complications.

The composition of a cell in terms of macromolecular building blocks and other organic molecules underlies the metabolic needs and capabilities of a species. Although some core biomass components such as nucleic acids and proteins are evident for most species, the essentiality of the pool of other organic molecules, especially cofactors and prosthetic groups, is yet unclear. Here we integrate biomass compositions from 71 manually curated genome-scale models, 33 large-scale gene essentiality datasets, enzyme-cofactor association data and a vast array of publications, revealing universally essential cofactors for prokaryotic metabolism and also others that are specific for phylogenetic branches or metabolic modes. Our results revise predictions of essential genes in Klebsiella pneumoniae and identify missing biosynthetic pathways in models of Mycobacterium tuberculosis. This work provides fundamental insights into the essentiality of organic cofactors and has implications for minimal cell studies as well as for modeling genotype-phenotype relations in prokaryotic metabolic networks., J.C.X. was sponsored by Fundação para a Ciência e Tecnologia, Portugal [Grant SFRH/BD/81626/2011]. This study was supported by the European Molecular Biology Laboratory, the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit, COMPETE 2020 (POCI-01–0145-FEDER-006684) and BioTecNorte operation (NORTE-01–0145-FEDER-000004) funded by European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. This project has received funding from the European Union's Horizon 2020 research and innovation programme under Grant agreement no 686070.

Genome-scale metabolic models (GEMs) can be used to evaluate genotype-phenotype relationships and their application to microbial strain engineering is increasing in popularity. Some of the algorithms used to simulate the phenotypes of mutant strains require the determination of a wild-type flux distribution. However, the accuracy of this reference, when calculated with flux balance analysis, has not been studied in detail before. Here, the wild-type simulations of selected GEMs for Saccharomyces cerevisiae have been analysed and most of the models tested predicted erroneous fluxes in central pathways, especially in the pentose phosphate pathway. Since the problematic fluxes were mostly related to areas of the metabolism consuming or producing NADPH/NADH, we have manually curated all reactions including these cofactors by forcing the use of NADPH/NADP+ in anabolic reactions and NADH/NAD+ for catabolic reactions. The curated models predicted more accurate flux distributions and performed better in the simulation of mutant phenotypes., FCT -Fuel Cell Technologies Program(SFRH/BD/51111/2010)

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmicb. 2019.01283/full#supplementary-material, A high-quality GSM model for Streptococcus pneumoniae R6 model strain (iDS372), comprising 372 genes and 529 reactions, was developed. The construction of this model involved performing a genome-wide reannotation to identify the metabolic capacity of the bacterium. A reaction representing the abstraction of the biomass composition was reconciled from several studies reported in the literature and previous models, and included in the model. The final model comprises two compartments and manifold automatically generated gene rules. The validation was performed with experimental data from recent studies, regarding the usability of carbon sources, the effect of the presence of oxygen and the requirement of amino acids for growth. This model can be used to better understand the metabolism of this major pathogen, provide clues regarding new drug targets and eventually design strategies for fighting infections by these bacteria., This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684) and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 – Programa Operacional Regional doNorte. This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreementno.686070., info:eu-repo/semantics/publishedVersion

Computational strain optimisation methods (CSOMs) have been successfully used to exploit genome-scale metabolic models, yielding strategies useful for allowing compound overproduction in metabolic cell factories. Minimal cut sets are particularly interesting since their definition allows searching for intervention strategies that impose strong growth-coupling phenotypes, and are not subject to optimality bias when compared with simulation-based CSOMs. However, since both types of methods have different underlying principles, they also imply different ways to formulate metabolic engineering problems, posing an obstacle when comparing their outputs., “DeYeastLibrary – Designer yeast strain library optimized for metabolic engineering applications”, Ref.ERA-IB-2/0003/2013, funded by national funds through FCT/MCTES, DD-DeCaf and SHIKIFACTORY100, both funded by the European Union through the Horizon 2020 research and innovation programme (grant agreements no. 686070 and 814408). This study was also supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2019 unit and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. The authors acknowledge the use of computing facilities within the scope of the Search-ON2: Revitalization of HPC infrastructure of UMinho” project (NORTE-07-0162-FEDER-000086), co-funded by the North Portugal Regional Operational Programme (ON.2 – O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF). VV also thanks funding from FCT/MCTES for the PhD studentship with reference SFRH/BD/118657/2016., info:eu-repo/semantics/publishedVersion

The uncertain relationship between genotype and phenotype can make strain engineering an arduous trial and error process. To identify promising gene targets faster, constraint-based modelling methodologies are often used, although they remain limited in their predictive power. Even though the search for gene knock-outs is fairly established in constraint-based modelling, most strain design methods still model gene up/down-regulations by forcing the corresponding flux values to fixed levels without taking in consideration the availability of resources. Here, we present a constraint-based algorithm, the Turnover Dependent Phenotypic Simulation (TDPS) that quantitatively simulates phenotypes in a resource conscious manner. Unlike other available algorithms, TDPS does not force flux values and considers resource availability, using metabolite production turnovers as an indicator of metabolite abundance. TDPS can simulate up-regulation of metabolic reactions as well as the introduction of heterologous genes, alongside gene deletion and down-regulation scenarios. TDPS simulations were validated using engineered Saccharomyces cerevisiae strains available in the literature by comparing the simulated and experimental production yields of the target metabolite. For many of the strains evaluated, the experimental production yields were within the simulated intervals and the relative strain performance could be predicted with TDPS. However, the algorithm failed to predict some of the production changes observed experimentally, suggesting that further improvements are necessary. The results also showed that TDPS may be helpful in finding metabolic bottlenecks, but further experiments would be required to confirm these findings., ortuguese Foundation forScience and Technology (FCT) under the scope of thestrategic funding of UID/BIO/04469/2019 unit and Bio-TecNorte operation (NORTE-01-0145-FEDER-000004)funded by the European Regional Development Fund under the scope of Norte2020−Programa Operacional Regional doNorte. This project has received funding from the EuropeanUnion’s Horizon 2020 research and innovation programmeunder Grant Agreement No. 686070 and from the NovoNordisk Foundation. The work of Rui Pereira was supported by a PhD grant from FCT (ref SFRH/BD/51111/2010), info:eu-repo/semantics/publishedVersion

Dissertação de Mestrado Integrado em Arquitetura, com a especialização em Arquitetura apresentada na Faculdade de Arquitetura da Universidade de Lisboa para obtenção do grau de Mestre. Símbolos da arquitectura doméstica, os Paços medievais provêm das novas formas de pensar e viver o quotidiano, aliado à demostração e hierarquização do poder senhorial de um tempo medieval. Em O Paço como ‘habitação simbólica’ hierarquizadora de um território na contemporaneidade desenvolve-se um estudo focado na evolução e principais características dos Paços medievais portugueses como elementos estruturantes do território. Património que caracteriza a identidade e a memória das cidades, mas que muitas vezes, são desvalorizados e/ou deixados ao abandono. O Paço Real de Belas surge pela importância que adquire na formação e estruturação da vila de Belas e pela própria relevância patrimonial, hoje, é um património “esquecido”, que aliado ás questões de despovoamento dos centros históricos, dita a descaracterização na malha urbana. Deste modo, a componente prática adquire suporte nas questões teóricas desenvolvidas para dar resposta à proposta urbana e arquitectónica. O plano urbano incide sobre a Praça 5 de Outubro, na procura da revitalização do centro histórico de Belas é proposto a requalificação da praça onde o Paço Real de Belas assume lugar de destaque, assim, a nível arquitectónico a valorização do património enquanto elemento de referência do lugar aparece como forma de promover a oferta cultural na sociedade e devolver a identidade local. ABSTRACT: Symbols of domestic architecture, the medieval Palaces come from new ways of thinking and living the daily life, allied to the demonstration and hierarchy of the manorial power of a medieval time. In The Palace as a ‘symbolic dwelling' hierarchical of a territory in the contemporaneity, a study is developed focusing on the evolution and main characteristics of the portuguese medieval Palaces as structuring elements of the territory, heritage that characterizes the identity and the memory of the cities, but that often are devalued and/or left to abandonment. The Royal Palace of Belas emerges, from the importance it acquires, in the formation and structuring of the village of Belas and from its own heritage relevance. Today, it is a "forgotten" heritage, which adds to the issues of depopulation of historic centers, given the decharacterization in the urban fabric. In this way, the practical component acquires support in the theoretical questions developed to respond to the urban and architectural proposal. The urban plan is focused on Praça 5 de Outubro, in search of a revitalization of the historic center of Belas. The proposal will be based on the requalification of the square, turning the Royal Palace into a prominent place. Therefore, on the architectural level, the valuation of heritage as a reference point of the place appears as a way of promoting the cultural offer in society and returning the local identity. N/A

Portugal presents the highest incidence of stage 5 chronic kidney disease in Europe. It is speculated that a high consumption of non-steroidal anti-inflammatory drugs (NSAIDS) may contribute to this high incidence. Our aim was to characterize the prescription of non-steroidal anti-inflammatory drugs to patients with diabetes mellitus in Portugal.We analyzed the national prescription database in triennium 2015 - 2017. In patients with diabetes mellitus, we evaluated the prescription of non-steroidal anti-inflammatory drugs according to age, gender and region of the patient and specialty of the prescribing physician. We evaluated the prescription of non-steroidal anti-inflammatory drugs in all patients with diabetes mellitus, in patients with presumed renal impairment, and in those with concomitant prescription of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists.We analyzed 23 320 620 prescriptions, corresponding to 610 157 adults, including 104 306 patients with diabetes mellitus. The most prescribed non-steroidal anti-inflammatory drugs were ibuprofen (20.1%), metamizole (14.7%), and diclofenac (11.4%). The prescription of non-steroidal anti-inflammatory drugs was higher in females, in patients aged 51 - 70 years and in the Alentejo region. Non-steroidal anti-inflammatory drugs were prescribed to 70.6% of patients with diabetes mellitus, from which 10.6% were prescribed ≥ 10 packages during the three years. Among patients with diabetes mellitus on angiotensin converting enzyme inhibitors/angiotensin receptor antagonists and with presumed reduction in kidney function, 69.3% were prescribed non-steroidal anti-inflammatory drugs and 11.5% were prescribed ≥ 10 packages during the three years.The level of prescribing of non-steroidal anti-inflammatory drugs to patients with diabetes mellitus is high. The concern of reducing non-steroidal anti-inflammatory drugs prescription to patients already on angiotensin converting enzyme inhibitors/angiotensin receptor antagonists and/or decreased renal function does not seem to exist.In Portugal, the level of prescribing of non-steroidal anti-inflammatory drugs to patients with diabetes mellitus should be reduced, particularly in the subgroups identified with higher prescription and with higher risk of progression to stage 5 chronic kidney disease.Introdução: Portugal apresenta a incidência mais elevada de doença renal crónica estádio 5 na Europa. Especula-se que o elevado consumo de anti-inflamatórios não esteroides possa contribuir para esta incidência. O objetivo do presente estudo foi caracterizar a prescrição de anti-inflamatórios não esteroides a doentes com diabetes mellitus em Portugal. Material e Métodos: Na Base de Dados Nacional de Prescrições do Ministério da Saúde, triénio 2015 - 2017, analisámos a prescrição de anti-inflamatórios não esteroides em doentes com diabetes mellitus, de acordo com a idade, género e região do doente e a especialidade do médico prescritor. Avaliámos a prescrição de anti-inflamatórios não esteroides no total de doentes com diabetes mellitus, em doentes com diminuição presumida da função renal e naqueles com prescrição concomitante de inibidores da enzima de conversão da angiotensina ou antagonistas dos recetores da angiotensina. Resultados: Analisámos 23 320 620 prescrições, correspondendo a 610 157 adultos, dos quais 104 306 doentes com diabetes mellitus. Os anti-inflamatórios não esteroides mais prescritos foram ibuprofeno (20,1%), metamizol (14,7%) e diclofenac (11,4%). A prescrição foi mais frequente nas mulheres, nos doentes com 51 - 70 anos e no Alentejo. Foram prescritos anti-inflamatórios não esteroides a 70,6% dos doentes com diabetes mellitus, dos quais 10,6% receberam prescrições de ≥ 10 embalagens durante os três anos. Dos doentes com diabetes mellitus medicados com inibidores da enzima de conversão da angiotensina ou antagonistas dos receptores da angiotensina e com diminuição presumida da taxa de filtração glomerular, 69,3% receberam prescrição de anti-inflamatórios não esteroides e 11,5% receberam ≥ 10 embalagens durante os três anos. Discussão: A prescrição de anti-inflamatórios não esteroides na diabetes mellitus é elevada. Não parece existir uma preocupação na menor utilização de anti-inflamatórios não esteroides em doentes simultaneamente medicados com inibidores da enzima de conversão da angiotensina ou antagonistas dos recetores da angiotensina e/ou com diminuição da função renal. Conclusão: A prescrição de anti-inflamatórios não esteroides em Portugal a doentes com diabetes mellitus deverá ser reduzida, particularmente nos subgrupos identificados com prescrição mais elevada e com maior risco de progressão para doença renal crónica estádio 5.

The emphasis on digitizing and computational modelling of physical phenomena began in the telecommunication sector with the appearance of the large-scale integration microprocessors and micro-controllers, them was possible to produce architectures with enough processing and memory capacity to supply the needs of the applications, specially the health applications. One of those is the Valsalva Maneuver (VM), used as a test that verifies the functional integrity of the autonomic nervous system and stands out in scientific research as an instrument to evaluate functions and control of the cardiovascular system. The aim of this device is to improve the execution of VM giving more control of the manoeuvre and reduce the repetitions, in tests that use tilt-table, or bed rest together with the VM, the position of the patient turns hard to visualize the pressure that are doing, this created device gives a one hand solution that integrates all that are need to perform the manoeuvre, and an IEEE 802.11 connection that allows the motorization of the process through a computer or a smartphone, and save the data of intrathoracic pressure at the end for analysis.

Practices of using active methodologies as facilitating tools in the teaching-learning process in higher education are increasing, especially in bioengineering courses. The university is a good model for facilitating the implementation of innovative processes due to its role and proximity to science, teaching and research. To embrace this challenge, the university is reaching a broader interaction with the community, from the area of scientific education that includes the awakening of children to science and research. Thus, this article reports on the pilot experience of the Laboratory of Cardiovascular Autonomic Function of the Cardiovascular Center of the University of Lisbon, in the approach of different academic and scientific knowledge together with society as a means to stimulate the pleasure of science and research in children.

Abstract. Participants ( N = 119) played the “Dictator Game” (computer mediated) with two bogus computer-simulated players, one of whom, the Dictator, distributed money across ten trials, either as extremely unfair (Inflexible Dictator) or being less unfair (Flexible Dictator). The other player either protested against (Protest condition) or did not react (Apathy condition) to the dictator’s decision, after each trial. We measured participants’ self-reported anger and disinterest, physiological skin conductance (SCL), heart rate (HR), and number and type of comments directed to the Dictator. Anger and number of comments were lower in the Apathy than in the Protest condition. Participants’ SCL, HR, and protest comments decreased in the Apathy condition, and increased in the Protest condition. Protest assumed a more punitive tone in the Inflexible than in the Flexible Dictator condition. We discuss these results’ contribution to understand individuals’ motivation to engage in protest and apathy, and the role of emotions in that process.

Plants synthesize a variety of different secondary metabolites, such as polyphenols, terpenoids, alkaloids, etc., with pharmaceutical and nutraceutical importance. Polyphenols have shown numerous health benefits with rare side effects. However, the extraction of these compounds from natural sources cannot meet the increasing consumer demand for natural products, and its purification is often difficult, making the overall process too expensive. In contrast, microbial production of polyphenols is a powerful alternative to produce natural products in large amounts, in an environmentally sustainable way. Nevertheless, plant-derived polyphenols are not naturally produced by microorganisms and therefore require the integration of the heterologous pathway from plants through genetic engineering techniques. In the present chapter, the recent advances in microbial production of plant-derived polyphenols, emphasizing on flavonoids, anthocyanins, curcuminoids, and stilbenes, have been summarized. In addition, different strategies used to increase the product yield, and the production processes are also highlighted., We would like to thank the European Union Framework Program 7 “BacHBerry” (www.bachberry.eu), Project No. FP7- 613793 for financial support, the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/ BIO/04469 unit, COMPETE 2020 (POCI-01-0145-FEDER-006684), and BiotecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020–Programa Operacional Regional do Norte., info:eu-repo/semantics/publishedVersion

In recent years microorganisms have been engineered towards synthesizing interesting plant polyphenols such as flavonoids and stilbenes from glucose. Currently, low endogenous supply of malonylCoA, indispensable for plant polyphenol synthesis, impedes high product titers. Usually, limited malonylCoA availability during plant polyphenol production is avoided by supplementing fatty acid synthesisinhibiting antibiotics such as cerulenin, which are known to increase the intracellular malonylCoA pool as a side effect. Motivated by the goal of microbial polyphenol synthesis being independent of such expensive additives, we used rational metabolic engineering approaches to modulate regulation of fatty acid synthesis and flux into the citric acid cycle in Corynebacterium glutamicum strains capable of flavonoid and stilbene synthesis. Initial experiments showed that sole overexpression of genes coding for the native malonylCoAforming acetylCoA carboxylase is not sufficient for increasing polyphenol production in C. glutamicum. Hence, the intracellular acetylCoA availability was also increased by reducing the flux into the citric acid cycle through reduction of citrate synthase activity. In defined cultivation medium, the constructed C. glutamicum strains accumulated 24 mg/L (0.088 mM) naringenin or 112 mg/L (0.49 mM) resveratrol from glucose without supplementation of phenylpropanoid precursor molecules or any inhibitors of fatty acid synthesis., We would like to thank the European Union Framework Program 7 ''BacHBerry'' (www.bachberry.eu), Project No. FP7‐ 613793 for financial support and also the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/ BIO/04469 unit, COMPETE 2020 (POCI‐01–0145‐FEDER‐006684) and BiotecNorte operation (NORTE‐01–0145‐FEDER‐000004) funded by the European Regional Development Fund under the scope of Norte2020 ‐ Programa Operacional Regional do Norte. Furthermore, we would like to thank Dr. Tino Polen for providing the plasmids to replace the gltA promoter by dapA promoter variants., info:eu-repo/semantics/publishedVersion

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Uma das técnicas cirúrgicas atuais mais populares para o tratamento da ruptura do ligamento cruzado cranial é o avanço da tuberosidade tibial (TTA). Esta pesquisa teve como objetivo comparar cinco métodos de cálculo desse avanço descritos por Dennler et al. (2006), Hoffmann et al. (2006), Vezzoni (2010), Ness (2011) e Koch (2016), verificando entre os dois joelhos do mesmo animal, se a quantidade de avanço necessária seria a mesma. Para isso os dois joelhos de 40 cães foram radiografados. No presente estudo observou-se que não há diferença significante entre os métodos de Hoffmann, de Ness e de Koch, porém há diferença entre tais métodos e os métodos de Dennler e de Vezzoni pré estabelecidas. Houve também índice de confiança moderado ao comparar o método do quadro pré definido com todos os outros métodos, assim como o da tangente comum com todos os outros métodos, exceto o do platô tibial, que demonstrou um índice de confiabilidade bom. Tal resultado positivo também foi observado ao comparar os demais métodos entre si. Quanto ao lado, não foi observada diferença significante entre membros direito e esquerdo, exceto no método descrito por Ness (2011) (p = 0,038).

If we tried to list every known chemical reaction within an organismhuman, plant or even bacteriawe would get quite a long and confusing read. But when this information is represented in so-called genome-scale metabolic networks, we have the means to access computationally each of those reactions and their interconnections. Some parts of the network have alternatives, while others are unique and therefore can be essential for growth. Here, we simulate growth and compare essential reactions and genes for the simplest type of unicellular speciesprokaryotesto understand which parts of their metabolism are universally essential and potentially ancestral. We show that similar patterns of essential reactions echo phylogenetic relationships (this makes sense, as the genome provides the building plan for the enzymes that perform those reactions). Our computational predictions correlate strongly with experimental essentiality data. Finally, we show that a crucial step of protein synthesis (tRNA charging) and the synthesis and transformation of small molecules that enzymes require (cofactors) are the most essential and conserved parts of metabolism in prokaryotes. Our results are a step further in understanding the biology and evolution of prokaryotes but can also be relevant in applied studies including metabolic engineering and antibiotic design., This work was supported by grants from: the Fundac ¸ão para a Ciência e a Tecnologia (http:// www.fct.pt) with award number UID/BIO/04469/2013, the European Regional Development Fund (http://www.norte2020.pt) with award number NORTE-01-0145-FEDER-000004 (https://www. ceb.uminho.pt/Projects/Details/6040), Horizon 2020 (https://ec.europa.eu/programmes/ horizon2020) with award number 686070 (http:// dd-decaf.eu/) and COMPETE2020 with award number POCI-01-0145-FEDER-006684 to JCX and IR and the Fundação para a Ciência e a Tecnologia (http://www.fct.pt) with award number SFRH/BD/81626/2011 to JCX. The funders had no role in study design, data collectionand analysis, decision to publish, or preparation of the manuscript., info:eu-repo/semantics/publishedVersion

Mannosylglycerate (MG) is one of the most widespread compatible solutes among marine microorganisms adapted to hot environments. This ionic solute holds excellent ability to protect proteins against thermal denaturation, hence a large number of biotechnological and clinical applications have been put forward. However, the current prohibitive production costs impose severe constraints towards large-scale applications. All known microbial producers synthesize MG from GDP-mannose and 3-phosphoglycerate via a two-step pathway in which mannosyl-3-phosphoglycerate is the intermediate metabolite. In an early work, this pathway was expressed in Saccharomyces cerevisiae with the goal to confirm gene function (Empadinhas et al. in J Bacteriol 186:4075--4084, 2004), but the level of MG accumulation was low. Therefore, in view of the potential biotechnological value of this compound, we decided to invest further effort to convert S. cerevisiae into an efficient cell factory for MG production., This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684), BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020—Programa Operacional Regional do Norte and also by project LISBOA-01-0145-FEDER-007660 (Microbiologia Molecular, Estrutural e Celular) funded by FEDER through COMPETE2020—Programa Operacional Competitividade e Internacionalização (POCI). Cristiana Faria was supported by a Ph.D. Grant from FCT (Ref. SFRH/ BD/79552/2011)., info:eu-repo/semantics/publishedVersion

Sequence data from this article can be found in the GenBank/EMBL data libraries under accession numbers: KX262844.1 (RsUGT72B14, R. sachalinensis); AY547304.1 (RsUGT73B6. R. sachalinensis); NP_418458.1 (malE, E. coli); NP_415214.1 (pgm, E. coli); NP_415752.1 (galU, E. coli); NM_001180688.3 (aro10, S. cerevisiae), and NP_417484.1 (yqhD, E. coli)., Edible berries are considered to be among nature's treasure chests as they contain a large number of (poly)phenols with potentially health-promoting properties. However, as berries contain complex (poly)phenol mixtures, it is challenging to associate any interesting pharmacological activity with a single compound. Thus, identification of pharmacologically interesting phenols requires systematic analyses of berry extracts. Here, raspberry (Rubus idaeus, var. Prestige) extracts were systematically analyzed to identify bioactive compounds against pathological processes of neurodegenerative diseases. Berry extracts were tested on different Saccharomyces cerevisiae strains expressing disease proteins associated with Alzheimer's, Parkinson's, or Huntington's disease or amyotrophic lateral sclerosis. After identifying bioactivity against Huntington's disease, the extract was fractionated and the obtained fractions were tested in the yeast model, which revealed that salidroside, a glycosylated phenol, displayed significant bioactivity. Subsequently, a metabolic route to salidroside was reconstructed in S. cerevisiae and Corynebacterium glutamicum. The best-performing S. cerevisiae strain was capable of producing 2.1 mM (640 mg L-1) salidroside from glucose in shake flasks, whereas an engineered C. glutamicum strain could efficiently convert the precursor tyrosol to salidroside, accumulating up to 32 mM (9,700 mg L-1) salidroside in bioreactor cultivations (yield: 0.81 mol mol-1). Targeted yeast assays verified that salidroside produced by both organisms has the same positive effects as salidroside of natural origin., We express our gratitude to Dr. Rute Neves (Chr. Hansen A/S, Denmark), Prof. Dr. Jochen Förster and Dr. Alexey Dudnik (The Nova Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Denmark), who coordinated the BacHBerry project. We also thank Prof. Dr. Ian Macreadie (Centre of Excellence for Alzheimer’s Disease Research & Care, School of Exercise, Biomedical & Health Sciences, Edith Cowan University, WA, Australia) for providing p416_GPD-GFP_AB42; Prof. Dr. Tiago Outeiro (University Medical Center Gottingen, Department of Neurodegeneration and Restorative Research, Germany) for providing W303-1A_Syn and W303-1A TU; Prof. Dr. Flaviano Giorgini (Department of Genetics and Genome Biology, University of Leicester, UK) for providing p425GAL1_HTT103Q; and Prof. Dr. Greg Petsko (Department of Biochemistry and Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, U.S.) for providing pYES_GAL1pr-FUS-GFP and pYES_CT., info:eu-repo/semantics/publishedVersion

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated., Background: Depressive symptoms are common in individuals suffering from severe somatic conditions. There is a lack of interventions and evidence-based interventions aiming to reduce depressive symptoms in patients with severe somatic conditions. The aim of the NEVERMIND project is to address these issues and provide evidence by testing the NEVERMIND system, designed to reduce and prevent depressive symptoms in comparison to treatment as usual. Methods: The NEVERMIND study is a parallel-groups, pragmatic randomised controlled trial to assess the effectiveness of the NEVERMIND system in reducing depressive symptoms among individuals with severe somatic conditions. The NEVERMIND system comprises a smart shirt and a user interface, in the form of a mobile application. The system is a real-time decision support system, aiming to predict the severity and onset of depressive symptoms by modelling the well-being condition of patients based on physiological data, body movement, and the recurrence of social interactions. The study includes 330 patients who have a diagnosis of myocardial infarction, breast cancer, prostate cancer, kidney failure, or lower limb amputation. Participants are randomised in blocks of ten to either the NEVERMIND intervention or treatment as usual as the control group. Clinical interviews and structured questionnaires are administered at baseline, at 12 weeks, and 24 weeks to assess whether the NEVERMIND system is superior to treatment as usual. The endpoint of primary interest is Beck Depression Inventory II (BDI-II) at 12 weeks defined as (i) the severity of depressive symptoms as measured by the BDI-II. Secondary outcomes include prevention of the onset of depressive symptoms, changes in quality of life, perceived stigma, and self-efficacy. Discussion: There is a lack of evidence-based interventions aiming to reduce and prevent depressive symptoms in patients with severe somatic conditions. If the NEVERMIND system is effective, it will provide healthcare systems with a novel and innovative method to attend to depressive symptoms in patients with severe somatic conditions., The NEVERMIND project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 689691. The funding body had no role in the design of the study and collection as well as in writing the manuscript. Open access funding provided by Karolinska Institute.

In the era of next-generation sequencing and ubiquitous assembly and binning of metagenomes, new putative genome sequences are being produced from isolate and microbiome samples at ever-increasing rates. Genome-scale metabolic models have enormous utility for supporting the analysis and predictive characterization of these genomes based on sequence data. As a result, tools for rapid automated reconstruction of metabolic models are becoming critically important for supporting the analysis of new genome sequences. Many tools and algorithms have now emerged to support rapid model reconstruction and analysis. Here, we are comparing and contrasting the capabilities and output of a variety of these tools, including ModelSEED, Raven Toolbox, PathwayTools, SuBliMinal Toolbox and merlin.FBA, Flux Balance Analysis; GEM, genome-scale metabolic model; GPR, gene\textendashprotein\textendashreaction association; GUI, graphical user interfaces; KBase, DOE Systems Biology Knowledgebase; LP, linear programing; MILP, Mixed-Integer Linear Programing; SBML, Systems Biology Markup Language, This work was supported by the U.S. Department of Energy, Office of Biological and Environmental Research; under contract DE-AC02-06CH11357 as a part of the DOE Knowledgebase project., info:eu-repo/semantics/publishedVersion