Piperine, quercetin, and curcumin identified as promising natural products for topical treatment of cutaneous leishmaniasis.

Leishmania braziliensis (L. braziliensis) causes cutaneous leishmaniasis (CL) in the New World. The costs and the side effects of current treatments render imperative the development of new therapies that are affordable and easy to administer. Topical treatment would be the ideal option for the treatment of CL. This underscores the urgent need for affordable and effective treatments, with natural compounds being explored as potential solutions. The alkaloid piperine (PIP), the polyphenol curcumin (CUR), and the flavonoid quercetin (QUE), known for their diverse biological properties, are promising candidates to address these parasitic diseases. Initially, the in vitro cytotoxicity activity of the compounds was evaluated using U-937 cells, followed by the assessment of the leishmanicidal activity of these compounds against amastigotes of L. braziliensis. Subsequently, a golden hamster model with stationary-phase L. braziliensis promastigote infections was employed. Once the ulcer appeared, hamsters were treated with QUE, PIP, or CUR formulations and compared to the control group treated with meglumine antimoniate administered intralesionally. We observed that the three organic compounds showed high in vitro leishmanicidal activity with effective concentrations of less than 50 mM, with PIP having the highest activity at a concentration of 8 mM. None of the compounds showed cytotoxic activity for U937 macrophages with values between 500 and 700 mM. In vivo, topical treatment with QUE daily for 15 days produced cured in 100% of hamsters while the effectiveness of CUR and PIP was 83% and 67%, respectively. No failures were observed with QUE. Collectively, our data suggest that topical formulations mainly for QUE but also for CUR and PIP could be a promising topical treatment for CL. Not only the ease of obtaining or synthesizing the organic compounds evaluated in this work but also their commercial availability eliminates one of the most important barriers or bottlenecks in drug development, thus facilitating the roadmap for the development of a topical drug for the management of CL caused by L. braziliensis.

Numerical coupling of 0D and 1D models in networks of vessels including transonic flow conditions. Application to short-term transient and stationary hemodynamic simulation of postural changes.

When modeling complex fluid networks using one-dimensional (1D) approaches, boundary conditions can be imposed using zero-dimensional (0D) models. An application case is the modeling of the entire human circulation using closed-loop models. These models can be considered as a tool to investigate short-term transient and stationary hemodynamic responses to postural changes. The first shortcoming of existing 1D modeling methods in simulating these sudden maneuvers is their inability to deal with rapid variations in flow conditions, as they are limited to the subsonic case. On the other hand, numerical modeling of 0D models representing microvascular beds, venous valves or heart chambers is also currently modeled assuming subsonic flow conditions in 1D connecting vessels, failing when transonic and supersonic flow conditions appear. Therefore, if numerical simulation of sudden maneuvers is a goal in closed-loop models, it is necessary to reformulate the current methodologies used when coupling 0D and 1D models, allowing the correct handling of flow evolution for both subsonic and transonic conditions. This work focuses on the extension of the general methodology for the Junction Riemann Problem (JRP) when coupling 0D and 1D models. As an example of application, the short-term transient response to head-up tilt (HUT) from supine to upright position of a closed-loop model is shown, demonstrating the potential, capability and necessity of the presented numerical models when dealing with sudden maneuvers.

Unique synapomorphies and high diversity in South American Raji-related Epstein-Barr virus genomes.

BACKGROUND: Epstein-Barr virus (EBV) is a human gammaherpesvirus etiologically linked to several benign and malignant diseases. EBV-associated malignancies exhibit an unusual global distribution that might be partly attributed to virus and host genetic backgrounds. OBJECTIVES: To assemble a new genome of EBV (CEMO3) from a paediatric Burkitt's lymphoma from Rio de Janeiro State (Southeast Brazil). In addition, to perform global phylogenetic analysis using complete EBV genomes, including CEMO3, and investigate the genetic relationship of some South American (SA) genomes through EBV subgenomic targets. METHODS: CEMO3 was sequenced through next generation sequencing and its coverage and gaps were corrected through the Sanger method. CEMO3 and 67 EBV genomes representing diverse geographic regions were evaluated through maximum likelihood phylogenetic analysis. Further, the polymorphism of subgenomic regions of some SA EBV genomes were assessed. FINDINGS: The whole bulk tumour sequencing yielded 23,217 reads related to EBV, which 172,713 base pairs of the newly EBV genome CEMO3 was assembled. The CEMO3 and most SA EBV genomes clustered within the SA subclade closely related to the African Raji strain, forming the South American/Raji clade. Notably, these Raji-related genomes exhibit significant genetic diversity, characterised by distinctive synapomorphies at some gene levels absent in the original Raji strain. CONCLUSION: The CEMO3 represents a new South American EBV genome assembled. Albeit the majority of EBV genomes from SA are Raji-related, it harbours a high diversity different from the original Raji strain.

Screening of the antileishmanial and antiplasmodial potential of synthetic 2-arylquinoline analogs.

In this study, six analogs of 2-arylquinoline were synthesized and evaluated for their in vitro and in vivo antiplasmodial and leishmanicidal activity. At a later stage, hemolytic activity and druggability were tested in vitro and in silico, respectively, observing as a result: firstly, compounds showed half-maximal effective concentration (EC50) values between 3.6 and 19.3 µM. Likewise, a treatment using the compounds 4a-f caused improvement in most of the treated hamsters and cured some of them. Regarding the antiplasmodial activity, the compounds showed moderate to high activity, although they did not show hemolytic activity. Furthermore, 4e and 4f compounds were not able to control P. berghei infection when administered to animal models. Molecular dynamic simulations, molecular docking and ligand binding affinity indicate good characteristics of the studied compounds, which are expected to be active. And lastly, the compounds are absorbable at the hematoencephalic barrier but not in the gastrointestinal tract. In summary, ADMET properties suggest that these molecules may be used as a safe treatment against Leishmania.

Does Lidocaine Shorten Seizure Duration in Electroconvulsive Therapy?

BACKGROUND: Electroconvulsive therapy (ECT) is an effective short-term treatment for schizophrenia and depression, amongst other disorders. Lidocaine is typically added to reduce pain from intravenous propofol injection. However, depending on the dose used in the ECT setting, it can shorten seizure duration. The aim of this study was to investigate the effect of lidocaine dose on seizure duration. METHODS: This retrospective, naturalistic cohort study included 169 patients treated with ECT. We examined 4714 ECT sessions with propofol or propofol plus lidocaine. Ictal quality was manually rated by visual inspection. The main outcome of this study was the relation of lidocaine with seizure duration after controlling for socio-demographic, ECT, and other anesthetic variables. RESULTS: There was a significant negative association between lidocaine usage and seizure duration. Multivariate analyses showed that seizure duration was shortened by an average of 3.21 s in sessions with lidocaine. Moreover, in this subgroup, there was a significant negative dose-dependent association between lidocaine dose and seizure length. Complementarily, a significant positive association between preictal BIS and seizure length was found in the subgroup of sessions where preictal was used. CONCLUSIONS: We provide additional evidence highlighting the importance of caution regarding lidocaine dosing due to the effect on seizure length in the ECT setting. It is advisable for clinicians to exercise caution when administering lidocaine regarding its dosing and seizure length in ECT settings. Future investigation is needed to assess causal relationships by studying certain vulnerable groups or employing other charge calculation techniques, such as the titration method.

Temporal Evaluation of the Surface Area of Treated Skin Ulcers Caused by Cutaneous Leishmaniasis and Relation with Optical Parameters in an Animal Model: A Proof of Concept.

Cutaneous leishmaniasis (CL) is a neglected disease caused by an intracellular parasite of the Leishmania genus. CL lacks tools that allow its understanding and treatment follow-up. This article presents the use of metrical and optical tools for the analysis of the temporal evolution of treated skin ulcers caused by CL in an animal model. Leishmania braziliensis and L. panamensis were experimentally inoculated in golden hamsters, which were treated with experimental and commercial drugs. The temporal evolution was monitored by means of ulcers' surface areas, as well as absorption and scattering optical parameters. Ulcers' surface areas were obtained via photogrammetry, which is a procedure that allowed for 3D modeling of the ulcer using specialized software. Optical parameters were obtained from a spectroscopy study, representing the cutaneous tissue's biological components. A one-way ANOVA analysis was conducted to identify relationships between both the ulcers' areas and optical parameters. As a result, ulcers' surface areas were found to be related to the following optical parameters: epidermis thickness, collagen, keratinocytes, volume-fraction of blood, and oxygen saturation. This study is a proof of concept that shows that optical parameters could be associated with metrical ones, giving a more reliable concept during the assessment of a skin ulcer's healing.

Unique synapomorphies and high diversity in South American Raji-related Epstein-Barr virus genomes

BACKGROUND Epstein-Barr virus (EBV) is a human gammaherpesvirus etiologically linked to several benign and malignant diseases. EBV-associated malignancies exhibit an unusual global distribution that might be partly attributed to virus and host genetic backgrounds. OBJECTIVES To assemble a new genome of EBV (CEMO3) from a paediatric Burkitt's lymphoma from Rio de Janeiro State (Southeast Brazil). In addition, to perform global phylogenetic analysis using complete EBV genomes, including CEMO3, and investigate the genetic relationship of some South American (SA) genomes through EBV subgenomic targets. METHODS CEMO3 was sequenced through next generation sequencing and its coverage and gaps were corrected through the Sanger method. CEMO3 and 67 EBV genomes representing diverse geographic regions were evaluated through maximum likelihood phylogenetic analysis. Further, the polymorphism of subgenomic regions of some SA EBV genomes were assessed. FINDINGS The whole bulk tumour sequencing yielded 23,217 reads related to EBV, which 172,713 base pairs of the newly EBV genome CEMO3 was assembled. The CEMO3 and most SA EBV genomes clustered within the SA subclade closely related to the African Raji strain, forming the South American/Raji clade. Notably, these Raji-related genomes exhibit significant genetic diversity, characterised by distinctive synapomorphies at some gene levels absent in the original Raji strain. CONCLUSION The CEMO3 represents a new South American EBV genome assembled. Albeit the majority of EBV genomes from SA are Raji-related, it harbours a high diversity different from the original Raji strain.

Nutritional Assessment of the Infant Population of the Chirikyacu Indigenous Community of Peru.

Malnutrition is one of the main public health problems affecting early childhood development, compromising the health and quality of life of thousands of Peruvian children. The main contribution of this work is the analysis of the nutritional status of the infant population of the Chirikyacu Indigenous Community of Peru in order to evaluate current and future food policies. It is a cross-sectional study with a sample of 19 children between 6 months and 6 years of age. Sociodemographic, anthropometric, clinical variables and dietary habits were analyzed from 7 January to 4 February 2018. The mean age of the children was 29.74 months (SD = 23.91). We found statistically significant differences between the BMI values of boys and girls (p < 0.05; Mann−Whitney test). According to the z-scores, 35.29% suffer from malnutrition, although in no case is it severe. Hair, nails and skin were in good condition in general, except for some cases showing signs of nutritional deficiency. Dietary patterns are based on legumes, vegetables, dairy products, ice cream, cookies and sweets, and are considered insufficient to cover basic needs; water intake was also insufficient. Breastfeeding lasted an average of 14 months (SD = 2.9). We found a prevalence of malnutrition higher than that established by the WHO in Latin America among the children of Chirikyacu. The dietary pattern is insufficient to cover basic needs, so it is necessary to continue with nutritional educational interventions to improve it.

The Validity and Reliability of the FANTASTIC Questionnaire for Nutritional and Lifestyle Studies in University Students.

The FANTASTIC questionnaire is a scientific instrument that can be used by health professionals for quickly and effectively measuring the quality of life and lifestyle of people. It is a simple questionnaire that measures different dimensions including nutritional status, but the possibility of using it as a resource for studies in the nutritional field (regardless of its correlation with this) has never been considered, nor has it been used for studies in university populations. The aim was to validate the FANTASTIC questionnaire to report on the participant's lifestyle in a Spanish university population by using a cross-sectional study. A sample of 501 participants was obtained. The study was approved by the Ethics Research Committee of Catholic University of Valencia, and written informed consent was obtained from all participants. Sociodemographic, lifestyle variables, habitual diet, and nutrition-related lifestyle were collected individually. Participants also completed the self-administered FANTASTIC questionnaire. The reliability analysis of the FANTASTIC questionnaire revealed a Cronbach's Alpha statistic result of 0.797. The Kaiser-Meyer-Olkin (KMO) value was 0.786, with a significant Bartlett's Test of Sphericity (p = 0.000). This shows that the FANTASTIC questionnaire has good internal consistency and good construct validity. A retest was performed in four weeks' time, showing excellent intraclass correlation values. We consider the applicability of the FANTASTIC questionnaire for nutritional studies in Spanish university students to be appropriate, and most students have high scores in the nutritional aspects of the questionnaire, showing correct diet implementation and good cooking skills.

Therapeutic Efficacy of Arnica in Hamsters with Cutaneous Leishmaniasis Caused by Leishmania braziliensis and L. tropica.

Leishmaniasis may occur in three different clinical forms, namely, visceral, mucocutaneous and cutaneous, which are caused by different species of trypanosomatid protozoans of the genus Leishmania. Pentavalent antimonials are the leading treatment for cutaneous leishmaniasis despite the hepatic, renal, and cardiac toxicity. In addition, the response of some Leishmania species to pentavalent antimonials is increasingly poorer, and therefore new and more potent therapeutic alternatives are needed. Arnica montana L., Asteraceae, is a traditional medicinal plant of Europe and preparations of its flowers are commonly used externally to treat disorders of the musculoskeletal system as well as superficial inflammatory conditions. Previous studies have shown that Arnica tincture (AT), an ethanolic extract prepared from the flowerheads of Arnica montana as well as isolated Arnica sesquiterpene lactones (STLs) have antileishmanial activity in vitro against L. donovani and L. infantum, as well as in vivo against L. braziliensis. In this work, we studied the in vitro cytotoxicity and antileishmanial activity of AT and STLs against both L. braziliensis and L. tropica. The in vivo therapeutic effect of AT was studied in hamsters with cutaneous Leishmaniasis (CL) caused by experimental infection with L. braziliensis and L. tropica. Furthermore, various semisolid Arnica preparations were also evaluated against L. braziliensis. The STLs and the AT possess a very high in vitro activity against both Leishmania species with median effective concentrations (EC50) ranging from 1.9 to 5.9 µg/mL. The AT was not cytotoxic for human tissue macrophages, skin fibroblasts, and hepatic cells. The therapeutic response of hamsters infected with L. braziliensis to the topical treatment with AT was 87.5% at a dose of 19.2 µg STL/2× day/60 d, 72.7% at doses of 19.2 µg STL/1× d/60 d and 67% at a dose of 38.4 µg STL/2× d/60 d. In turn, the therapeutic response in hamsters infected with L. tropica was 100% when treated at a dose of 19.2 µg STL/2× day/60 d and 71% at a dose of 38.4 µg STL/2× d/60 d. On the other hand, the effectiveness of treatment with glucantime administered intralesionally at a dose of 200 mg/every three days for 30 days was 62.5% for L. braziliensis and 37.5% for L. tropica infection. These results are promising and encourage the implementation of clinical trials with AT in CL patients as a first step to using AT as a drug against CL.

The Role of Natural Products on Diabetes Mellitus Treatment: A Systematic Review of Randomized Controlled Trials.

The present study was carried out to relate the role of natural products in the metabolism of an increasingly prevalent disease, type 2 diabetes mellitus. At present, in addition to the pharmacological resources, an attempt is being made to treat diabetes mellitus with natural products. We carried out a systematic review of studies focusing on the role of natural products on diabetes mellitus treatment. The bibliographic search was done through Medline (Pubmed) and Web of Science. From 193 records, the title and summary of each were examined according to the criteria and whether they met the selection criteria. A total of 15 articles were included; after reviewing the literature, it is apparent that the concept of natural products is ambiguous as no clear boundary has been established between what is natural and what is synthetic, therefore we feel that a more explicit definition of the concept of "natural product" is needed. Gut microbiota is a promising therapeutic target in the treatment of diabetes. Therefore, it would be necessary to work on the relationship between the microbiome and the benefits in the treatment of diabetes mellitus. Treatment based solely on these natural products is not currently recommended as more studies are needed.

Variation of intraocular pressure comparing rebound (TONOVET Plus®) and applanation (TONO-PEN VET®) tonometry in New Zealand rabbits treated with Amlodipine® / Variación de la presión intraocular comparando la tonometría de rebote (TONOVET Plus®) y aplanación (TONO-PEN VET®) en conejos de Nueva Zelanda tratados con Amlodipino® / Variação da pressão intraocular comparando a tonometria de rebote (TONOVET Plus®) e de aplanação (TONO-PEN VET®) em coelhos da Nova Zelândia tratados com Amlodipina®

Abstract Rabbits have played an important role in ophthalmological research processes, however in the environment there has been a deficiency of sensitive equipment in measurement of intraocular pressure for this species. To compare intraocular pressure (IOP) measured with rebound (TONOVET Plus®) and applanation (TONO-PEN VET®) tonometry in healthy New Zealand rabbits treated with Amlodipine. Twelve healthy male New Zealand white rabbits, 5 months old; two groups with 6 individuals were used in this study. The experimental group was given Amlodipine® at a dose of 5 mg/kg, once a day for a month. Blood pressure and intraocular pressure were measurement before treatment and 6 h after treatment in a period of one month. A trend is noted where the group of animals treated with amlodipine® presents lower values than the control group, both in systolic and diastolic pressure. The systolic pressure of the control group showed an average of 116.5 ± 7.9 mmHg and 117.4 ± 8.9 mmHg and the treatment group showed an average of 113.6 ± 7.9 mmHg and 111.8 ± 10.0 mmHg (pretreatment and posttreatment respectively). Tonometry: the values obtained using the TONOVET Plus® (19 ± 3 mmHg) are on average higher than the values obtained using the TONO-PEN VET® (17 ± 3 mmHg). It was possible to demonstrate the relationship between systemic blood pressure and intraocular pressure in New Zealand white rabbits. Rebound tonometry showed less variability in results than applanation tonometry. This study confirmed that both tonometers are reliable for measuring IOP in rabbits.

Resumen Los conejos han jugado un papel importante en los procesos de investigación oftalmológica, sin embargo, en el medio ha existido una deficiencia de equipos sensibles en la medición de la presión intraocular para esta especie. Para comparar la presión intraocular (PIO) medida con la tonometría de rebote (TONOVET Plus®) y aplanación (TONO-PEN VET®) en conejos Nueva Zelanda sanos y tratados con Amlodipino, fueron usados doce conejos Nueva Zelanda, machos, sanos, de 5 meses de edad y distribuidos en dos grupos con 6 individuos cada uno. El grupo experimental recibió Amlodipino® en una dosis de 5 mg/kg, una vez al día durante un mes. La presión arterial y la presión intraocular se midieron antes del tratamiento y 6 h después del tratamiento en un período de un mes. Se observa una tendencia donde el grupo de animales tratados con amlodipino® presenta valores más bajos que el grupo control, tanto en presión sistólica como diastólica. La presión sistólica del grupo control mostró un promedio de 116,5 ± 7,9 mmHg y 117,4 ± 8,9 mmHg y el grupo de tratamiento mostró un promedio de 113,6 ± 7,9 mmHg y 111,8 ± 10,0 mmHg (pretratamiento y postratamiento respectivamente). Tonometría: los valores obtenidos con el TONOVET Plus® (19 ± 3 mmHg) son en promedio superiores a los valores obtenidos con el TONO-PEN VET® (17 ± 3 mmHg). Fue posible demostrar la relación entre la presión arterial sistémica y la presión intraocular en conejos blancos Nueva Zelanda. La tonometría de rebote mostró menos variabilidad en los resultados que la tonometría de aplanamiento. Este estudio confirmó que ambos tonómetros son confiables para medir la PIO en conejos.

Resumo Os coelhos têm desempenhado um papel importante nos processos de pesquisa oftalmológica, porém no meio tem havido uma deficiência de equipamentos sensíveis na medida da pressão intraocular para esta espécie. Comparar a pressão intraocular (PIO) medida com tonometria de rebote (TONOVET Plus®) e de aplanação (TONO-PEN VET®) em coelhos saudáveis da Nova Zelândia tratados com Amlodipina®. Foram utilizados neste estudo doze coelhos brancos da Nova Zelândia, machos saudáveis, 5 meses de idade; distribuído em dois grupos com 6 indivíduos cada um. O grupo experimental recebeu Amlodipina® na dose de 5 mg / kg, uma vez ao dia durante um mês. A pressão arterial e a pressão intraocular foram medidas antes do tratamento e 6 horas após o tratamento em um período de um mês. Nota-se uma tendência onde o grupo de animais tratados com amlodipina® apresenta valores inferiores ao grupo controle, tanto na pressão sistólica quanto na diastólica. A pressão sistólica do grupo controle apresentou média de 116,5 ± 7,9 mmHg e 117,4 ± 8,9 mmHg e o grupo tratamento apresentou média de 113,6 ± 7,9 mmHg e 111,8 ± 10,0 mmHg (pré-tratamento e pós-tratamento, respectivamente). Tonometria: os valores obtidos com o TONOVET Plus® (19 ± 3 mmHg) são em média superiores aos valores obtidos com o TONO-PEN VET® (17 ± 3 mmHg). Foi possível demonstrar a relação entre a pressão arterial sistêmica e a pressão intraocular em coelhos brancos da Nova Zelândia. A tonometria de rebote mostrou menos variabilidade nos resultados do que a tonometria de aplanação. Este estudo confirmou que ambos os tonômetros são confiáveis para medir a PIO em coelhos.

Are the Growth Standards of the World Health Organization Valid for Spanish Children? The SONEV Study.

Background: The use of different growth tables to assess the population's nutritional status has given rise to a series of limitations arising from the lack of consensus and uniform methodological criteria. This leads to a disparity of results that prevent an accurate and reliable diagnosis of whether a child is overweight or obese. Objective: The purpose of this study was to develop growth references for weight, height, and body mass index for Eastern-Spanish children from 6 to 16 years of age. Methods: The final sample used to fit the growth curves was made up of 1,102 observations. The 2007 WHO curves are currently used for Child Health Service Cards. Therefore, to make the comparison of the internal values obtained as realistic as possible, the same construction method has been used for the internal curves, modeling age as a continuous variable and simultaneously adjusting the curves, smoothing them using cubic splines and further smoothing the edge effects by means of data extending above or below the upper and lower age limits. Results: Growth curves for percentiles were constructed for both sexes and higher values were noticeably found to set as growth-standard compared to WHO-standards. Conclusion: Our analysis shows that the WHO 2007 standard references are not suitable for Eastern-Spanish children. The standards shown in this study are much more realistic and current, and we believe that their use will help healthcare professionals more effectively combat the current epidemic of overweight and obesity.

Diffuse Reflectance Parameters of Treated Leishmaniasis Cutaneous Ulcers and Association with Histopathologies in an Animal Model: A Proof of Concept.

Cutaneous leishmaniasis (CL) is a parasitic disease that produces chronic skin ulcers. Although it has a worldwide presence, it is a neglected disease that still requires novel tools for its management. In order to study the use of optical tools in CL, this article presents a preliminary study of the correlation between CL histopathological and optical parameters. Optical parameters correspond to absorption and scattering coefficients obtained from diffuse reflectance spectra of treated CL in golden hamsters. Independently, histopathological data were collected from the same hamsters. As a result, after Spearman correlation and the Kruskal-Wallis test, inverse correlation was found between absorption/scattering optical parameters and inflammatory histopathological values, such as the scattering parameter related to the diameter of fibroblasts with the histopathological parameters of fibrosis, polymorphonuclear neutrophils, lymphocytes, plasmocytes, hyperplasia, and Leishmania, and the absorption parameter oxygen saturation showed a relation with the granulation tissue histopathological parameter. These correlations agree with the expected behavior of tissue composition during the healing process in CL. The results correspond to a proof of concept that shows that optical diffuse reflectance-based tools and methods could be considered as an alternative to assist in CL diagnosis and treatment follow-up.

FGGA-lnc: automatic gene ontology annotation of lncRNA sequences based on secondary structures.

The study of long non-coding RNAs (lncRNAs), greater than 200 nucleotides, is central to understanding the development and progression of many complex diseases. Unlike proteins, the functionality of lncRNAs is only subtly encoded in their primary sequence. Current in-silico lncRNA annotation methods mostly rely on annotations inferred from interaction networks. But extensive experimental studies are required to build these networks. In this work, we present a graph-based machine learning method called FGGA-lnc for the automatic gene ontology (GO) annotation of lncRNAs across the three GO subdomains. We build upon FGGA (factor graph GO annotation), a computational method originally developed to annotate protein sequences from non-model organisms. In the FGGA-lnc version, a coding-based approach is introduced to fuse primary sequence and secondary structure information of lncRNA molecules. As a result, lncRNA sequences become sequences of a higher-order alphabet allowing supervised learning methods to assess individual GO-term annotations. Raw GO annotations obtained in this way are unaware of the GO structure and therefore likely to be inconsistent with it. The message-passing algorithm embodied by factor graph models overcomes this problem. Evaluations of the FGGA-lnc method on lncRNA data, from model and non-model organisms, showed promising results suggesting it as a candidate to satisfy the huge demand for functional annotations arising from high-throughput sequencing technologies.

Antileishmanial activity of synthetic analogs of the naturally occurring quinolone alkaloid N-methyl-8-methoxyflindersin.

Leishmaniasis is a neglected, parasitic tropical disease caused by an intracellular protozoan from the genus Leishmania. Quinoline alkaloids, secondary metabolites found in plants from the Rutaceae family, have antiparasitic activity against Leishmania sp. N-methyl-8-methoxyflindersin (1), isolated from the leaves of Raputia heptaphylla and also known as 7-methoxy-2,2-dimethyl-2H,5H,6H-pyran[3,2-c]quinolin-5-one, shows antiparasitic activity against Leishmania promastigotes and amastigotes. This study used in silico tools to identify synthetic quinoline alkaloids having structure similar to that of compound 1 and then tested these quinoline alkaloids for their in vitro antiparasitic activity against Leishmania (Viannia) panamensis, in vivo therapeutic response in hamsters suffering from experimental cutaneous leishmaniasis (CL), and ex vivo immunomodulatory potential in healthy donors' human peripheral blood (monocyte)-derived macrophages (hMDMs). Compounds 1 (natural), 2 (synthetic), and 8 (synthetic) were effective against intracellular promastigotes (9.9, 3.4, and 1.6 µg/mL medial effective concentration [EC50], respectively) and amastigotes (5.07, 7.94, and 1.91 µg/mL EC50, respectively). Compound 1 increased nitric oxide production in infected hMDMs and triggered necrosis-related ultrastructural alterations in intracellular amastigotes, while compound 2 stimulated oxidative breakdown in hMDMs and caused ultrastructural alterations in the parasite 4 h posttreatment, and compound 8 failed to induce macrophage modulation but selectively induced apoptosis of infected hMDMs and alterations in the intracellular parasite ultrastructure. In addition, synthetic compounds 2 and 8 improved the health of hamsters suffering from experimental CL, without evidence of treatment-associated adverse toxic effects. Therefore, synthetic compounds 2 and 8 are potential therapeutic candidates for topical treatment of CL.

Consistency of the Tools That Predict the Impact of Single Nucleotide Variants (SNVs) on Gene Functionality: The BRCA1 Gene.

Single nucleotide variants (SNVs) occurring in a protein coding gene may disrupt its function in multiple ways. Predicting this disruption has been recognized as an important problem in bioinformatics research. Many tools, hereafter p-tools, have been designed to perform these predictions and many of them are now of common use in scientific research, even in clinical applications. This highlights the importance of understanding the semantics of their outputs. To shed light on this issue, two questions are formulated, (i) do p-tools provide similar predictions? (inner consistency), and (ii) are these predictions consistent with the literature? (outer consistency). To answer these, six p-tools are evaluated with exhaustive SNV datasets from the BRCA1 gene. Two indices, called K a l l and K s t r o n g , are proposed to quantify the inner consistency of pairs of p-tools while the outer consistency is quantified by standard information retrieval metrics. While the inner consistency analysis reveals that most of the p-tools are not consistent with each other, the outer consistency analysis reveals they are characterized by a low prediction performance. Although this result highlights the need of improving the prediction performance of individual p-tools, the inner consistency results pave the way to the systematic design of truly diverse ensembles of p-tools that can overcome the limitations of individual members.

Detection and Mitigation of DoS and DDoS Attacks in IoT-Based Stateful SDN : An Experimental Approach.

The expected advent of the Internet of Things (IoT) has triggered a large demand of embedded devices, which envisions the autonomous interaction of sensors and actuators while offering all sort of smart services. However, these IoT devices are limited in computation, storage, and network capacity, which makes them easy to hack and compromise. To achieve secure development of IoT, it is necessary to engineer scalable security solutions optimized for the IoT ecosystem. To this end, Software Defined Networking (SDN) is a promising paradigm that serves as a pillar in the fifth generation of mobile systems (5G) that could help to detect and mitigate Denial of Service (DoS) and Distributed DoS (DDoS) threats. In this work, we propose to experimentally evaluate an entropy-based solution to detect and mitigate DoS and DDoS attacks in IoT scenarios using a stateful SDN data plane. The obtained results demonstrate for the first time the effectiveness of this technique targeting real IoT data traffic.

Computational hemodynamics in arteries with the one-dimensional augmented fluid-structure interaction system: viscoelastic parameters estimation and comparison with in-vivo data.

Mathematical models are widely recognized as a valuable tool for cardiovascular diagnosis and the study of circulatory diseases, especially to obtain data that require otherwise invasive measurements. To correctly simulate body hemodynamics, the viscoelastic properties of vessels walls are a key aspect to be taken into account as they play an essential role in cardiovascular behavior. The present work aims to apply the augmented fluid-structure interaction system of blood flow to real case studies to assess the validity of the model as a valuable resource to improve cardiovascular diagnostics and the treatment of pathologies. Main contributions of the paper include the evaluation of viscoelastic tube laws, estimation of viscoelastic parameters and comparison of models with literature results and in-vivo experiments. The ability of the model to correctly simulate pulse waveforms in single arterial segments is verified using literature benchmark test cases, designed taking into account a simple elastic behavior of the wall in the upper thoracic aorta and in the common carotid artery. Furthermore, in-vivo pressure waveforms, extracted from tonometric measurements performed on four human common carotid arteries and two common femoral arteries, are compared to numerical solutions. It is highlighted that the viscoelastic damping effect of arterial walls is required to avoid an overestimation of pressure peaks. Finally, an effective procedure to estimate the viscoelastic parameters of the model is herein proposed, which returns hysteresis curves of the common carotid arteries dissipating energy fractions in line with values calculated from literature hysteresis loops in the same vessel.