A systematic review of the clinical presentation, treatment and relapse characteristics of human Plasmodium ovale malaria

Additional file 1. Alphabetic list of included articles with overall quality of reporting and risk of bias assessment. -, not determined; overall risk of bias was declared “high” for case reports and case series; for applicable trials, overall risk of bias results from the detailed risk of bias assessment outlined in the Additional file 2; detailed completeness of reporting assessment is displayed in the Additional file 3

Digital-Twin approach to predict the drag coefficient of random arrays of spheres suspended in Giesekus viscoelastic fluids

Apresentação efetuada na 17th International Conference of Computational Methods in Sciences and Engineering (ICCMSE 2021), Greece, 2021The authors would like to acknowledge the funding by FEDER funds through the COMPETE 2020 Programme and National Funds through FCT - Portuguese Foundation for Science and Technology under the projects UIDB/05256/2020 and UIDP/05256/2020 and MIT-EXPL/TDI/0038/2019 – APROVA - Deep learning for particle-laden viscoelastic flow modelling (POCI-01-0145-FEDER-016665)

MAURICE MARTEL et PAUL MARTEL, La compagnie au Québec. Les aspects juridiques, Montréal, Wilson & Lafleur Ltée/Martel Ltée, 1989, 1019 p., ISBN 2-920831-06-2. Deuxième édition, 1990, 1021 p., ISBN 2-920831-20-8.

The seasonal variation of the protozooplanktonic community (ciliates and testate amoebae) was studied in a tropical oligotrophic reservoir in Brazil, which was under the influence of two contrasting climatic seasons (rainy/warm and dry/cold). The aim of this study was to evaluate the effect of these climatic changes on physical, chemical and biological variables in the dynamic of this community. The highest mean density of total protozoans occurred in the rainy/warm season (5683.2 ind L-1), while the lowest was in the dry/cold (2016.0 ind L-1). Considering the seasonal variations, the protozoan groups that are truly planktonic, such as the oligotrichs (Spirotrichea), predominated in the dry season, whereas during the rainy season, due to the material input and resuspension of sediment, sessile protozoans of the Peritrichia group were the most important ones. The dominant protozoans were Urotricha globosa, Cothurnia annulata, Pseudodifflugia sp. and Halteria grandinella. The highest densities of H. grandinella were associated with more oxygenated and transparent water conditions, while the highest densities of C. annulata occurred in sites with high turbidity, pH and trophic state index (TSI). The study demonstrated that density and composition of protozooplanktonic species and groups of the reservoir suffered seasonal variation due to the environmental variables (mainly temperature, turbidity, water transparency, dissolved oxygen and TSI) and the biological variables (e.g. morphological characteristics, eating habits and escape strategies from predation of the species).Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

A flexible-docking approach for the design of novel cancer peptidomimetic drugs

Cancer is the second leading cause of death worldwide and the lack of alternative therapies has kept patients dependent on classic chemotherapy. The most occurring form of cancer amongst women is breast cancer and the triple negative cell subtype (TNBC) is responsible for a high metastatic and mortality rate, as it presents molecular and genetic shifts, lacks specific targeting and responds poorly to existing therapies. Recent studies have provided convincing evidence that the therapeutic outcome of chemotherapy may be affected by the expression and activity of receptor tyrosine kinases and their phosphatase pathways (MAPK/ERK, PI3/AKT, among others). These proteins are implicated in mechanisms of cell survival, drug resistance and Epithelial-Mesenchymal Transition (EMT), and are therefore key targets for TNBC cancer cell subtype. However, many inhibitors developed for these targets have not succeeded at a clinical level and present low solubility. As a result of the pronounced decline in productivity experienced by drug discovery efforts in the last years, novel approaches to the rational design of new drugs are now being pursued. A potential solution might be the use of natural or synthetic peptides and peptidomimetics targeting protein-protein interactions essential for signaling networks function. The combination of several bioinformatic approaches (docking, virtual screening, pharmacophore models, among others) allows the use of the vast amount of existing information on available compounds and protein-protein interactions in structural databases. In this study we designed a procedure for small peptidomimetics structure-based rational drug design capable of blocking the active sites of SNAiL1, a protein that has been suggested as a potent repressor of E-cadherin expression and consequently, as an inducer of EMT transition in TNBCs. A random library was created using a composite approach for drug-like compound identification from the PubChem and Development Therapeutics NCI/NIH compound databases, which combined structure-based virtual screening (known motifs of peptide structures within proteins and small molecules) and Z-score comparison. Docking studies were performed to map the polypeptides activity and stability: (1) point alteration studies using non-natural aminoacids for helical stability over a wider range (since linear peptides adopt many confirmations in aqueous solution) using Ramachandran plot dihedral angles estimation; (2) quantitative structure-activity relationships (QSAR) using radical modification chemical studies and (3) umbrella sampling for dissociations studies. The peptidomimetic SNAiL1 model created suggested at least two radical modifications for a strong inhibition

Identification of peptides targeting human osteoarthritic chondrocytes using phage display

Osteoarthritis (OA) is one of the most common degenerative joint disease and is characterized by a progressive degradation of articular cartilage extracellular matrix (ECM) leading to loss of joint mobility and function, accompanied by chronic pain. Currently used therapies for cartilage repair are still far from generating regenerated tissue with quality and stability comparable to native cartilage. We hypothesize that alterations of chondrocyte-ECM interactions in OA affect the expression of cell surface adhesion molecules and phage display can allow the identification of high affinity peptides by screening peptide libraries against these targets. Here, we report the use of phage display to identify novel peptides which specifically bind to human chondrocytes isolated from patients with OA. Chondrocytes were isolated from healthy and osteoarthritic cartilage obtained from patients undergoing partial knee arthroplasty and characterized, in terms of expression of cell surface proteins and expression of chondrocyte-specific genes, before the panning experiments to assess their phenotypic stage. A phage library displaying random 12-amino acid peptides was first incubated with chondrocytes from healthy donors (control cells) and then with osteoarthritic chondrocytes. A 12-amino acid peptide (GFQMISNNVYMR) was identified, showing high affinity to osteoarthritic chondrocyte cells (about 8-fold higher than the wild-type phage lacking recombinant peptides - control). Bioinformatics analysis was performed by creating a protein structure database of known and stereo-chemical validated OA-associated cell membrane proteins. Protein-peptide docking revealed, from the overall complex stability, solvent accessibility and binding site prediction that the membrane protein MMP28 is expected to be the putative receptor of the identified peptide ligand. Future work will be devoted to integrate the identified peptide sequence into nanocarrier systems to provide localization of therapeutic molecules into OA cartilage. If successful, these nanocarriers can offer important insights into the regenerative mechanisms of cartilage and could be applied for developing more efficient and less invasive therapies for treating OA

Suppression of nitric oxide production in mouse macrophages by soybean flavonoids accumulated in response to nitroprusside and fungal elicitation

BACKGROUND: The anti-inflammatory properties of some flavonoids have been attributed to their ability to inhibit the production of NO by activated macrophages. Soybean cotyledons accumulate certain flavonoids following elicitation with an extract of the fungal pathogen Diaporthe phaseolorum f. sp. meridionalis (Dpm). Sodium nitroprusside (SNP), a nitric oxide donor, can substitute for Dpm in inducing flavonoid production. In this study, we investigated the effect of flavonoid-containing diffusates obtained from Dpm- and SNP-elicited soybean cotyledons on NO production by lipopolysaccharide (LPS)- and LPS plus interferon-γ (IFNγ)-activated murine macrophages. RESULTS: Significant inhibition of NO production, measured as nitrite formation, was observed when macrophages were activated in the presence of soybean diffusates from Dpm- or SNP-elicited cotyledons. This inhibition was dependent on the duration of exposure to the elicitor. Daidzein, genistein, luteolin and apigenin, the main flavonoids present in diffusates of elicited cotyledons, suppressed the NO production by LPS + IFNγ activated macrophages in a concentration-dependent manner, with IC(50 )values of 81.4 μM, 34.5 μM, 38.6 μM and 10.4 μM respectively. For macrophages activated with LPS alone, the IC(50 )values were 40.0 μM, 16.6 μM, 10.4 μM and 2.8 μM, respectively. Western blot analysis showed that iNOS expression was not affected by daidzein, was reduced by genistein, and was abolished by apigenin, luteolin and Dpm- and SNP-soybean diffusates at concentrations that significantly inhibited NO production by activated macrophages. CONCLUSIONS: These results suggest that the suppressive effect of flavonoids on iNOS expression could account for the potent inhibitory effect of Dpm- and SNP-diffusates on NO production by activated macrophages. Since the physiological concentration of flavonoids in plants is normally low, the treatment of soybean tissues with SNP may provide a simple method for substantially increasing the concentration of metabolites that are beneficial for the treatment of chronic inflammatory diseases associated with NO production

Padrões morais e valores empregados por alunos de ensino fundamental em discussões sociocientíficas

Questões sociocientíficas são dilemas sociais de natureza polêmica que envolvem moralidade e ética. O problema da validade ética do aborto possui ligações conceituais com a Ciência e é uma questão bastante controversa, representando uma questão sociocientífica. Neste trabalho, foram transcritos e analisados trechos da interação de adolescentes discutindo a questão do aborto. A unidade de análise foi o argumento segundo o padrão de Toulmin (1958), a partir do qual foram identificados valores empregados pelos alunos, como: interesses sociais e políticos; riscos e responsabilidade; valor da vida; interesses familiares e pessoais; regras de decisão; noções de limites da vida e status de pessoa. Os alunos resolveram as questões utilizando raciocínios baseados em princípios, raciocínios consequencialistas, deliberações baseadas em emoção ou em intuiçã

Illuminating milling mechanochemistry by tandem real-time fluorescence emission and Raman spectroscopy monitoring

In pursuit of accessible and interpretable methods for direct and real-time observation of mechanochemical reactions, we demonstrate a tandem spectroscopic method for monitoring of ball-milling transformations combining fluorescence emission and Raman spectroscopy, accompanied by high-level molecular and periodic density-functional theory (DFT) calculations, including periodic time-dependent (TD-DFT) modelling of solid-state fluorescence spectra. This proof-of-principle report presents this readily accessible dual-spectroscopy technique as capable of observing changes to the supramolecular structure of the model pharmaceutical system indometacin during mechanochemical polymorph transformation and cocrystallisation. The observed time-resolved in situ spectroscopic and kinetic data are supported by ex situ X-ray diffraction and solid-state nuclear magnetic resonance spectroscopy measurements. The application of first principles (ab initio) calculations enabled the elucidation of how changes in crystalline environment, that result from mechanochemical reactions, affect vibrational and electronic excited states of molecules. The herein explored interpretation of both real-time and ex situ spectroscopic data through ab initio calculations provides an entry into developing a detailed mechanistic understanding of mechanochemical milling processes and highlights the challenges of using real-time spectroscopy

Targeted therapy using phage technology: a computational and experimental breast cancer study

During the past two decades cancer biology knowledge has widely increased and shifted the paradigm of cancer treatment from nonspecific cytotoxic agents to selective, mechanism-based therapeutics. Initially, cancer drug design was focused on compounds that rapidly killed dividing cells. Though still used as the backbone of current treatments, these highly unspecific targeting drugs lead to significant toxicity for patients, narrowing the therapeutic index, and frequently lead to drug resistance. Therefore, cancer therapies are now based on cancer immunotherapy and targeted agents, whereas novel treatments are strategically combining both to improve clinical outcomes. Despite the nanotechnology advances dictating the development of targeted therapies in diverse classes of nano-based carriers, virus-based vectors still remain highly used due to its biocompatibility and specificity for the target. Particularly, bacteriophages are an interesting alternative ‘nanomedicine’ that can combine biological and chemical components into the same drug delivery system. The great potential of this novel platform for cancer therapy is the ability to genetically manipulate the virus-vector to display specific targeting moieties. Phage display technology, a general technique used for detecting interfaces of various types of interacting proteins outside of the immunological context, allows the target agents to locate the target (with an increased selection process for the specific binding – termed biopanning) and play their essential role inhibiting molecular pathways crucial for tumour growth and maintenance. Phage display specificity core is related with the binding of small peptides displayed at their coat or capsid proteins, enriched during biopanning. Bioinformatics plays an important role in testing and improving phage display libraries by effective epitope mapping, selecting from a large set of random peptides those with a high binding affinity to a target of interest. In this work we demonstrate the screening of a manually constructed 7-mer peptide library of M13KE phage particles against MDA-MB-231 and -435 cancer cell lines. Two peptides – TLATVEV and PRLNVSP – with high affinity for the referred cells were identified, respectively. Based on computationally predicted epitopes based on the peptides extracted from this library the linear peptide sequence was docked onto known membrane proteins from the used cell lines and peptides-proteins interactions were mapped. Umbrella sampling studies were performed to predict the binding affinity and to improve future rational design of binding peptides to these cancer cells